Gallic acid derived aza Michael adducts at diarylpropanone framework exhibit antiproliferative and synergistic antibacterial activities

Gallic acid derived aza Michael adducts at diarylpropanone framework exhibit antiproliferative and synergistic antibacterial activities | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Gallic acid derived aza Michael adducts at diarylpropanone framework exhibit antiproliferative and synergistic antibacterial activities Sneha Singh, Sana Khan, Alka Kurmi, Ranjana Das, Barsha Thapa, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4140948/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Development of resistance against most of the clinical antibiotics is a menace to their use in future. Present study aimed at design and synthesis of some microtubule dynamics modulators as antibacterial and anticancer agents. Eight diverse Aza Michael adducts were prepared at diarylpropenone core with desired motifs in 38–57% yields. Compound 6b showed significant antiproliferative activity against leukemic cell line K562. While compound 6h exhibited potent antibacterial activity against methicillin resistant Staphylococcus aureus and methicillin resistant S. epidermidis . In the checker board experiment 6h showed synergistic effect in combination of penicillin and also with norfloxacin, up to four-fold reduction in quantity of the antibiotic drug. Its effect was bacteriostatic as evident from time kill assay. The 3,4,5-trimethoxyphenyl motif induces antitubulin effect in Aza Michael adduct 6b for anticancer activity. Both the leads can further be optimized for better efficacy in future. Aza Michael adducts antibacterial anticancer acute oral toxicity Figures Figure 1 Figure 2 Figure 3 Figure 4 1. INTRODUCTION Antimicrobial resistance has been identified as one of the top threats to public healthcare by WHO in 2023 [ 1 ]. Most of the pathogens exhibit multidrug resistance (MDR) and extensive drug resistance (XDR). Some of the organisms like Staphylococcus aureus , Methicillin resistant S. aureus (MRSA), Streptococcus pneumonia , Pseudomonas aeruginosa and Mycobacterium tuberculosis (MTb) have developed even pan-drug resistance (PDR) also known as ‘Superbugs’ [ 2 ]. The WHO has released a list of such ‘priority pathogens’ posing acute threat to human health [ 3 ]. The rising prevalence of multidrug resistant bacteria can best be tackled with developing newer antibacterial agents. Over the years, a diverse group of target oriented antibacterials have been developed to inhibit the biosynthesis of bacterial cell wall or biosynthesis of important macromolecule like DNA/RNA or any crucial protein. There are several worthy targets lacking good leads despite possessing druggable active sites. Perhaps “polypharmacology” approach may provide some new opportunities to researchers. Tubulin-microtubule dynamics is considered one of the most successful approaches to develop cancer chemotherapeutics. In our studies we designed an antitubulin pharmacophore using ‘Fragment Based Drug Discovery (FBDD)’ approach. According to FBDD, a fragment is a small portion of a pharmacophore of molecular weight ~ 150Da and has high quality (Crucial) interactions with the receptor protein [ 4 ]. FBDD has become an established lead finding technology yielding encouraging results to pharma industry and also other researcher laboratories [ 5 ]. Inspired from some of the natural antitubulin agents, we kept a 3,4,5-trimethoxyphenyl fragment in the basic pharmacophore to induce antitubulin effect (Fig. 1 ) [ 6 ]. Further, recently protein complex NDC80 has been found a good target for the development of antibacterial agents. NDC80 is an important element of bacterial kinetochore that plays a crucial role in the attachment of microtubules to the chromosomes. NDC80 complex mediates interactions between the microtubules and chromosomes during mitosis [ 7 ]. In the present study, we incorporated two different 3,4,5-trimethoxyphenyl motifs at two different ends. One unit has restricted rotation due to ketone group while, another was kept flexible. Further, an amino alkyl unit was introduced via aza Michael reaction to have better bioavailability of this pharmacophore. Eight diverse aza Michael adducts were prepared on a reduced chalcone unit as possible tubulin-microtubule dynamics modulators and evaluated for anticancer and antibacterial activities. 2. results 2.1. Chemical synthesis The synthetic strategy has been depicted in Scheme 1 . The basic core was prepared by the condensation of 3,4,5,-trimetheoxyacetophenone ( 1 ) and 3, 4, 5- trimethoxybenzaldehyde ( 2 ) in 7% KOH in aqueous-methanolic solution (1:9) to get the desired hexamethoxychalcone ( 3 ) via Claisen-Schmidt reaction in 95% yield. Chalcone 3 was reduced with H 2 -Palladium charcoal (5%, Pd-C) to reduced chalcone 4 in 82% yield. The reduced chalcone 4 was treated with glacial acetic acid, formaldehyde and morpholine to afford compound 5 in 62% yield. Compound 5 was treated with various amines in Na 2 CO 3 - water- acetonitrile system to get desired compounds 6a - 6h in 32–57% yield via Aza Michael reaction. All the intermediates and final products were confirmed by spectroscopy. Detailed spectral analysis in included in materials and method section. 2.2. Antiproliferative activity Antiproliferative activity of compounds 6a - 6h was assessed by Sulphorhodamine assay as illustrated in Table 1 . Among these only compounds 6b and 6g exhibited significant cytotoxicity against K562 cell line with IC 50 = 7.69 µM and 13.31 µM respectively. Table 1 In- vitro cytoxicity of Micheal base derivatives against K-562 cell line and MDA-MB-231 cell line (IC 50 in µM). S. No. Compd. Cytotoxicity IC 50 (µM) S. No. Compd. Cytotoxicity IC 50 (µM) K562 MDA-MB231 K562 MDA-MB231 1. 6a ˃100 83.35 ± 2.27 6. 6f ˃100 71.11 ± 4.2 2. 6b 7.69 ± 1.99 86.52 ± 4.78 7. 6g 13.31 ± 0.35 53.23 ± 2.21 3. 6c 59.76 ± 12.33 57.09 ± 4.25 8. 6h 26.35 ± 1.37 ˃100 4. 6d ˃100 63.26 ± 3.5 9. DOX 1.77 ± 0.16 9.18 ± 2.16 5. 6e 45.65 ± 0.35 56.73 ± 3.04 10. PDT ND 86.11 ± 8.2 *DOX = doxorubicin, PDT = Podophyllotoxin; ND = not determined 2.3. Effect on tubulin polymerisation The effect of compound 6b on tubulin polymerization was assessed as tubulin kinetics graph as depicted in Fig. 2 . Compound 6b enhanced microtubule polymerization, acting as microtubule stabilizer. Podophyllotoxin inhibited tubulin polymerisation while paclitaxel showed stabilization effect. 2.4. Antibacterial activity In preliminary antibacterial evaluation against the Staphylococcus aureus, Staphylococcus epidermidis , Methicillin-resistant Staphylococcus aureus , Methicillin-resistant Staphylococcus epidermidis strains, compounds 6e , 6f , and 6h showed significant activity. Compounds 6e and 6f exhibited antibacterial effect against S. aureus strain, with zone of inhibition of 6 mm and 7 mm respectively. While 6h showed better antibacterial effect among all the four strains. It was also effective against methicillin resistance Staphylococcus epidermis. But the antibacterial effect of all these compounds was much lower than the standard drug penicillin G (13–44 mm). Results depicted in ST1 (Supplementary information). 2.5. Broth dilution method The anti-bacterial activity was further confirmed by evaluating minimum inhibitory concentration against all the four strains. Among these 6e , 6f , and 6h exhibited significant antibacterial activity i.e. MIC ≤ 500 µg/mL. However, 6h showed very good MIC i.e. (62.5–125 µg/mL) further, minimum bacterial concentration was also evaluated. Compound 6h exhibited good MBC activity (125 µg/mL). Both MIC and MBC results are shown in Table 2 . Table 2 Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) of Michael amines by Broth dilution method S. No. Compd. MIC (µg/mL) against Bacterial strains S. No. Compd. MBC (µg/mL) against Bacterial strains SA SE MRSA MRSE SA SE MRSA MRSE 1 6e 250 - - - 1 6e 500 - - - 2 6f 500 500 - 500 2 6f 1000 1000 - 1000 3 6h 125 62.5 62.5 62.5 3 6h 250 125 125 125 4 Pen.-G 50 0.097 100 50 4 Pen.-G 50 0.097 100 50 Rest were inactive up to 1000 µg/mL concentration. 2.6. Time kill assay Time-kill kinetics assay was performed to determine the bactericidal or bacteriostatic activity of compound 6h . The results are depicted in ST2 (Supplementary information). The same is expressed by plotting log 10 cfu/mL against time (h) in Fig. 3. 2.7. Combination study by Checkerboard method Checkerboard method is used to determine the impact on potency of the combination of antibiotics in comparison to their individual activities. This comparison is then represented as the fractional inhibitory concentration index (FICI) value. At FICI value ≤ 0 is synergism; FICI value > 0.5–4 is indifference; and FICI value > 4 is antagonism. 6h was evaluated against 5 strains the SA- Staphylococcus aureus (MTCC96), SE -Staphylococcus epidermidis (MTCC435), MS -Mycobacterium smegmatis (UDSC mc 2 155), MR SA- Methicillin-resistant Staphylococcus aureus (ATCC33591), MRSE - Methicillin-resistant Staphylococcus epidermidis (ATCC51625) for combination study against bacterial strains with known antibacterial drugs. Among all the combination 6h showed synergistic effect with penicillin in MRSA Strain and with norfloxacin was shown synergistic effect with norfloxacin in MRSE Strain. Results are shown in Table 3 . Table 3 MIC (µg/mL) of 6h against Bacterial strains alone and in combination. SN Type Drugs Time Remark 1 SA --- Penicillin 6h PEN FIC 6h FIC FICI MOI Combination 25 31.25 0.5 0.25 0.75 Indifference Alone 50 125 --- --- --- --- 2 SA --- Norfloxacin 6h Nor. FIC 6h FIC FICI MOI Combination 1.56 7.81 0.5 0.06 0.56 Indifference Alone 3.12 125 --- --- --- --- 3 SE --- Penicillin 6h PEN FIC 6h FIC FICI MOI Combination 0.01 31.25 0.1 0.5 0.6 Indifference Alone 0.09 62.5 --- --- --- --- 4 SE --- Norfloxacin 6h Nor FIC 6h FIC FICI MOI Combination 0.39 31.25 0.5 0.5 1 Indifference Alone 0.78 62.5 --- --- --- --- 5 MS --- Rifampicin 6h RIF FIC 6h FIC FICI MOI Combination 0.15 62.5 0.24 0.5 0.74 Indifference Alone 0.625 125 --- --- --- --- 6 MS --- Gentamicin 6h GEN FIC 6h FIC FICI MOI Combination 2.08 62.5 0.5 0.5 1 Indifference Alone 4.16 125 --- --- --- --- 7 MRSA --- Penicillin 6h PEN FIC 6h FIC FICI MOI Combination 25 15.62 0.25 0.24 0.49 Synergistic Alone 100 62.5 --- --- --- --- 8 MRSA --- Norfloxacin 6h NOR FIC 6h FIC FICI MOI Combination 1.56 31.25 0.5 0.5 1 Indifference Alone 3.12 62.5 --- --- --- --- 9 MRSE --- Penicillin 6h PEN FIC 6h FIC FICI MOI Combination 12.5 31.25 0.25 0.5 0.75 Indifference Alone 50 62.5 --- --- --- --- 10 MRSE --- Norfloxacin 6h NOR FIC 6h FIC FICI MOI Combination 0.19 15.62 0.25 0.24 0.49 Synergistic Alone 0.78 62.5 --- --- --- --- 11 SA --- Penicillin 6h PEN FIC 6h FIC FICI MOI Combination 25 31.25 0.5 0.25 0.75 Indifference Alone 50 125 --- --- --- --- 12 SA --- Norfloxacin 6h Nor. FIC 6h FIC FICI MOI Combination 1.56 7.81 0.5 0.06 0.56 Indifference Alone 3.12 125 --- --- --- --- 13 SE --- Penicillin 6h PEN FIC 6h FIC FICI MOI Combination 0.01 31.25 0.1 0.5 0.6 Indifference Alone 0.09 62.5 --- --- --- --- 14 SE --- Norfloxacin 6h Nor FIC 6h FIC FICI MOI Combination 0.39 31.25 0.5 0.5 1 Indifference Alone 0.78 62.5 --- --- --- --- 15 MS --- Rifampicin 6h RIF FIC 6h FIC FICI MOI Combination 0.15 62.5 0.24 0.5 0.74 Indifference Alone 0.625 125 --- --- --- --- 16 MS --- Gentamicin 6h GEN FIC 6h FIC FICI MOI Combination 2.08 62.5 0.5 0.5 1 Indifference Alone 4.16 125 --- --- --- --- 17 MRSA --- Penicillin 6h PEN FIC 6h FIC FICI MOI Combination 25 15.62 0.25 0.24 0.49 Synergistic Alone 100 62.5 18 MRSA --- Norfloxacin 6h NOR FIC 6h FIC FICI MOI Combination 1.56 31.25 0.5 0.5 1 Indifference Alone 3.12 62.5 --- --- --- --- 19 MRSE --- Penicillin 6h PEN FIC 6h FIC FICI MOI Combination 12.5 31.25 0.25 0.5 0.75 Indifference Alone 50 62.5 --- --- --- --- 20 MRSE --- Norfloxacin 6h NOR FIC 6h FIC FICI MOI Combination 0.19 15.62 0.25 0.24 0.49 Synergistic Alone 0.78 62.5 --- --- --- --- 21 SA --- Penicillin 6h PEN FIC 6h FIC FICI MOI Combination 25 31.25 0.5 0.25 0.75 Indifference Alone 50 125 --- --- --- --- 22 SA --- Norfloxacin 6h Nor. FIC 6h FIC FICI MOI Combination 1.56 7.81 0.5 0.06 0.56 Indifference Alone 3.12 125 --- --- --- --- 23 SE --- Penicillin 6h PEN FIC 6h FIC FICI MOI Combination 0.01 31.25 0.1 0.5 0.6 Indifference Alone 0.09 62.5 --- --- --- --- 24 SE --- Norfloxacin 6h Nor FIC 6h FIC FICI MOI Combination 0.39 31.25 0.5 0.5 1 Indifference Alone 0.78 62.5 --- --- --- --- 25 MS --- Rifampicin 6h RIF FIC 6h FIC FICI MOI Combination 0.15 62.5 0.24 0.5 0.74 Indifference Alone 0.625 125 --- --- --- --- 26 MS --- Gentamicin 6h GEN FIC 6h FIC FICI MOI Combination 2.08 62.5 0.5 0.5 1 Indifference Alone 4.16 125 --- --- --- --- 27 MRSA --- Penicillin 6h PEN FIC 6h FIC FICI MOI Combination 25 15.62 0.25 0.24 0.49 Synergistic Alone 100 62.5 --- --- --- --- 28 MRSA --- Norfloxacin 6h NOR FIC 6h FIC FICI MOI Combination 1.56 31.25 0.5 0.5 1 Indifference Alone 3.12 62.5 --- --- --- --- 29 MRSE --- Penicillin 6h PEN FIC 6h FIC FICI MOI Combination 12.5 31.25 0.25 0.5 0.75 Indifference Alone 50 62.5 --- --- --- --- 30 MRSE --- Norfloxacin 6h NOR FIC 6h FIC FICI MOI Combination 0.19 15.62 0.25 0.24 0.49 Synergistic Alone 0.78 62.5 --- --- --- --- 31 SA --- Penicillin 6h PEN FIC 6h FIC FICI MOI Combination 25 31.25 0.5 0.25 0.75 Indifference Alone 50 125 --- --- --- --- 32 SA --- Norfloxacin 6h Nor. FIC 6h FIC FICI MOI Combination 1.56 7.81 0.5 0.06 0.56 Indifference Alone 3.12 125 --- --- --- --- 33 SE --- Penicillin 6h PEN FIC 6h FIC FICI MOI Combination 0.01 31.25 0.1 0.5 0.6 Indifference Alone 0.09 62.5 --- --- --- --- 34 SE --- Norfloxacin 6h Nor FIC 6h FIC FICI MOI Combination 0.39 31.25 0.5 0.5 1 Indifference Alone 0.78 62.5 --- --- --- --- 35 MS --- Rifampicin 6h RIF FIC 6h FIC FICI MOI Combination 0.15 62.5 0.24 0.5 0.74 Indifference Alone 0.625 125 --- --- --- --- 36 MS --- Gentamicin 6h GEN FIC 6h FIC FICI MOI Combination 2.08 62.5 0.5 0.5 1 Indifference Alone 4.16 125 --- --- --- --- 37 MRSA --- Penicillin 6h PEN FIC 6h FIC FICI MOI Combination 25 15.62 0.25 0.24 0.49 Synergistic Alone 100 62.5 --- --- --- --- 38 MRSA --- Norfloxacin 6h NOR FIC 6h FIC FICI MOI Combination 1.56 31.25 0.5 0.5 1 Indifference Alone 3.12 62.5 --- --- --- --- 39 MRSE --- Penicillin 6h PEN FIC 6h FIC FICI MOI Combination 12.5 31.25 0.25 0.5 0.75 Indifference Alone 50 62.5 --- --- --- --- 40 MRSE --- Norfloxacin 6h NOR FIC 6h FIC FICI MOI Combination 0.19 15.62 0.25 0.24 0.49 Synergistic Alone 0.78 62.5 --- --- --- --- SA : Staphylococcus aureus ; SE : Staphylococcus epidermidis ; MRSA : Methicillin-resistant Staphylococcus aureus; MRSE : Methicillin-resistant Staphylococcus epidermidis 2.8. Acute oral toxicity of compound 6h The acute oral toxicity was performed to find out various side effects of the 6h under investigation giving a single oral dose within 24 h in rodent model (Table 4 ). Four distinct concentrations of compound 6h i.e. (5 mg/kg, 50 mg/kg, 300 mg/kg, and 1000 mg/kg) were given to Swiss albino mice as single oral dose. Animals did not show any morbidity and mortality up to the dose level of 1000 mg/kg. Biochemical and hematological parameters showed non-significant changes. Gross pathological studies on animals showed no significant changes in any of the animal organs studies including their absolute and relative weight Fig. 4 . In higher doses ALP and creatinine level were high but these changes were non-significant. Results showed that it is absolutely safe up to 1000 mg/ kg dose. However, its sub-acute and chronic toxicity investigations should be undertaken before developing as a clinical drug to observe its effects on repeated exposure. Table 4 Effect of 6h as a single acute oral dose on body weight, haematological and serum biochemical parameters in Swiss albino mice (Mean ± SE; n = 6; Non significant changes were found compared to control, P < 0.05). Parameters Dose of 6h at mg/kg body weight as a single oral dose Control 5 mg/kg 50 mg/kg 300 mg/kg 1000 mg/kg Body weight Body weight (g) 28.15 ± 0.96 27.72 ± 1.52 24.47 ± 0.76 25.27 ± 0.85 25.82 ± 1.95 Haematalogical parameters Haemoglobin (g/dL) 12.40 ± 0.52 14.22 ± 0.77 12.14 ± 1.16 14.38 ± 0.87 13.30 ± 0.38 RBC (million/mm 3 ) 7.11 ± 0.40 7.05 ± 0.58 6.81 ± 0.42 5.88 ± 0.45 5.39 ± 0.10 WBC (1000*/mm 3 ) 4.49 ± 0.53 4.88 ± 1.03 4.15 ± 0.38 5.65 ± 1.04 4.19 ± 0.75 Liver function test ALP (U/L) 224.67 ± 9.24 219.85 ± 18.23 243.64 ± 22.19 257.52 ± 16.03 272.16 ± 15.18 SGOT (U/L) 26.33 ± 3.04 27.26 ± 5.33 28.98 ± 3.66 24.11 ± 3.47 24.37 ± 2.71 SGPT (U/L) 14.09 ± 1.16 19.77 ± 2.06 16.43 ± 1.85 13.61 ± 2.14 15.74 ± 2.12 Albumin (g/dL) 4.73 ± 0.31 5.76 ± 0.52 5.64 ± 0.31 5.29 ± 0.28 5.13 ± 0.36 Serum Protein (mg/ml) 7.02 ± 0.58 7.20 ± 0.76 5.91 ± 0.22 5.83 ± 0.36 6.27 ± 0.22 Bilirubin (mg/dL) 0.12 ± 0.01 0.10 ± 0.02 0.10 ± 0.02 0.09 ± 0.02 0.10 ± 0.01 Kidney Function test Creatinine (mg/dL) 0.38 ± 0.01 0.48 ± 0.04 0.44 ± 0.03 0.42 ± 0.02 0.46 ± 0.03 Lipid profile Triglycerides (mg/dL) 98.32 ± 9.85 85.38 ± 5.05 82.87 ± 7.12 89.10 ± 8.00 90.53 ± 9.31 Cholesterol (mg/dL) 174.82 ± 15.05 198.12 ± 16.94 185.61 ± 32.67 151.62 ± 16.03 131.56 ± 15.30 3. discussion Cancer and bacterial infections are two major health menaces. Leukemia is a type of cancer related to blood cells or bone marrow. Different types of leukemia have different treatment options and outlooks [ 8 ]. It is the most common type of cancer in children. In chemotherapy, vincristin sulphate, vinblastin sulphate, imatinib mesylate, doxorubicin, daunorubicin, and etoposide are used to cure various types of leukemia. However, these clinical drugs are associated with several serious side effects like loss of WBCs and blood platelets, gastrointestinal disorders, high BP, loss of hair, severe congestive heart failure etc. Their high cost and serious side effects make them undesirable for the treatment of leukemia. A key issue in the treatment of acute leukemia is the development of resistance to chemotherapeutic drugs [ 9 ]. In the present study the representative compound 6b exhibited significant cytotoxicity against leukemia cells K-562. Its antiproliferative effect was established via microtubule stabilization effect. Tubulin microtubule dynamics has become an attractive target for the development of cancer chemotherapeutics. The process of tubulin polymerisation and microtubules depolymerisation are in dynamic equilibrium. Any interruption created in this process disturbs this dynamic equilibrium and leads to cell cycle arrest at mitosis phase [ 6 ]. The disturbances may be created by destabilization of polymerisation process (Forward process) like colchicine, podophyllotoxin, 2-methoxyestradiol and combretastatin A4 etc. or by inducing destabilization effect in depolymerisation process (Backward process) like paclitaxel, epothilones etc. Compound 6b showed microtubule stabilization effects similar to paclitaxel. However, its effect was quite less than paclitaxel effect. Some of these Mannich bases also exhibited antibacterial activity. Compound 6h showed significant activity in disc diffusion method, and also in broth dilution method. In the checker board experiment 6h showed synergistic effect in combination of penicillin and also with norfloxacin, up to fourfold reduction of quantity of the antibiotic drug as bacteriostatic effects. We expected antibacterial effect due to involvement of Nuclear Division Cycle 80 (NDC80), loop region required for proper microtubule binding to kinetochores and loop mutant like ndc-80-21 displayed unstable kinetochore-microtubule interactions. The phenotype of NDC-80-21 could be partially released by over-expression of the microtubules-binding protein Dis-1, bacterial also expressed Dis-1 able to interact with NDC-80 [ 10 ]. NDC80 has become an important target for antibacterial drug development [ 11 ]. Safety is a necessary part of drug development [ 12 ]. It profoundly concentrates on unwanted drug outcomes. Nowadays, it is referred as ‘Pharmacovigilance’. According to World Health Organization, it focuses to increase safety and patient’s look-after in terms of use of medicine and to support public health programmes by providing authentic, relevant information for effective evaluation of risk-benefit profile of medicines [ 13 ]. Compound 6h did not show any significant adverse effects and may be regarded as LOAEL (Lowest observed adverse effect level). Acute oral toxicity is the most persistent experiment used to assess the preliminary toxicity of investigational bioactive candidates [ 14 ]. 4. CONCLUSION Present study demonstrated design and synthesis of several amino derivatives on diaryl propanone core by aza Michael addition. However, only five compounds exhibited significant antiproliferative activity. Compound 6b exhibited potential cytotoxicity against human leukemia cell line via microtubule stabilization effect. Another representative compound 6h showed significant antibacterial activity. Compound 6h was quite safe in rodent models in acute oral toxicity. The further optimization of both lead compounds of this series is underway in our research group. 5. MATERIALS AND METHODS 5.1. Chemistry The desired Aza Michael adducts were prepared as per scheme 1 . Synthesis of (E)-1, 3-bis (3, 4, 5-trimethoxyophenyl) prop-2-en 1- one (3) 3, 4, 5- trimethoxyacetophenone (2.1 g, 10 mmol) was taken in 7% aqueous- methanolic KOH (20 mL). To this 3,4,5- trimethoxybenzaldehyde (2.06 g, 10.5 mmol) was added and stirred for 2h at RT. Reaction mixture was acidified with dil. HCl (10%, 15 mL), extracted with ethyl acetate (3×20 mL), washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was refined through column chromatography (silica gel) eluting with hexane-ethyl acetate to get pure amorphous chalcone ( 3 ). Yield: 91% (3.65 g); M.p: 128–130˚C; 1 H NMR (CDCl 3 , 500 MHz): δ 3.89–3.91 (br s, 9H, 3×OCH 3 ), 3.93–3.94 (br s, 9H, 3×OCH 3 ), 6.85 (s, 2H, 2×CH, aromatic), 7.24 (s, 2H, 2×CH, aromatic), 7.30–7.33 (d, 1H, =CH, J = 15.5Hz), 7.69–7.72 (d, 1H, =CH, J = 15.5Hz); 13 C NMR (CDCl 3 , 125 MHz): δ 56.31, 56.52, 56.52, 61.01, 61.03, 105.79, 106.30, 121.35, 130.39, 133.63, 140.56, 142.57, 144.99, 153.18, 153.53, 189.46; ESI-TOF (HRMS) (MeOH): m/z [M + H] + for C 21 H 24 O 7 calcd. 389.1600 found 389.1578 Synthesis of 1, 3-bis (3, 4, 5-trimethoxyophenyl) propan-1-one (4) To a solution of hexamethoxychalcone 3 (500 mg, 1.28 mmol) in dry THF (10 mL), 5% palladium on carbon was added (100 mg) and stirred at RT for 2h with continuous supply of hydrogen gas using a balloon. On completion, it was filtered, washed with acetone and concentrated under vacuum. The residue was taken in ethyl acetate (30 mL), washed with water (20 mL), dried over anhydrous sodium sulphate and purified through column chromatography using hexane-ethyl acetate as mobile phase to get compound 4 . Yield: 82% (412 mg); M.p: 108–110˚C; 1 H NMR (CDCl 3 , 500 MHz): δ 2.98–3.016 (m, 2-CH 2 ), 3.23–3.26 (m, 3-CH 2 ), 3.86 (s, m, 9H, 3×OCH 3 ), 3.90 (s, m, 9H, 3×OCH 3 ), 6.46 (s, 2×CH, aromatic), 7.19 (s, 2H, 2×CH, aromatic); 13 C NMR (CDCl 3 , 125 MHz): δ 30.85, 40.51, 56.13, 56.34, 56.34, 56.53, 60.87, 60.96, 105.46, 105.46, 105.56, 105.56, 132.17, 136.41, 137.14, 142.66, 153.10, 153.10, 153.27, 153.27, 198.02; ESI-TOF (HRMS) (MeOH): m/z [M + H] + for C 21 H 26 O 7 calcd 391.1756 [M + H] + , found 391.1744 . Synthesis of 2- (3, 4, 5- trimethoxybenzyl)-1-(3, 4, 5- trimethoxyphenyl) prop-2-en-1-one (5) To a solution of reduced chalcone 4 (300 mg, 0.76 mmol) in glacial acetic acid (10 mL), formaldehyde (0.1 mL, 0.10 g, 3.63 mmol) was added and refluxed at 100˚C for 10 min. After 10 min, morpholine (0.2 mL, 0.19 g, 3.48 mmol) was added and further refluxed for 2 h. After completion, the solvent was evaporated and residue was taken in ethyl acetate and water. The organic layer was demoistened over anhydrous sodium sulphate, filtered and evaporated in vacuo. The crude mass was purified through silica gel column by eluting with hexane- ethyl acetate. The desired compound 5 was obtained as amorphous solid. Yield: 62% (192 mg); M.p: 129–130˚C; 1 H NMR (CDCl 3 , 500 MHz): δ 1.22 (s, CH 2 ), 3.07–3.75 (br m, 9H, 3×OCH 3 ), 3.83–3.87 (s, 9H, 3×OCH 3 ), 5.63 (s, 1H, =CH 2 ), 5.73 (s, 1H, =CH 2 ), 6.43 (s, 2H, 2×CH, aromatic), 6.98 (s, 2H, 2×CH, aromatic); 13 C NMR (CDCl 3 , 125 MHz): δ 39.38, 56.25, 56.87, 60.91, 106.08, 107.23, 125.15, 132.47, 134.31, 139.24, 142.15, 152.80, 153.23, 196.60; Electrospray mass (MeOH) for C 22 H 26 O 7 calcd for 403.1756 [M + H] + , found 403.1754 General procedure for the synthesis of compounds 6a-6h To a solution of arylbenzylpropenone 5 (50 mg, 0.1 mmol) and Na 2 CO 3 (60 mg) in 1:1 (water: acetonitrile, 12 mL). To this amine (0.2 mmol) was added and stirred with heating at 100˚C for 3h. On completion, reaction mixture was quenched by water and extracted with ethyl acetate (10 mL×3), washed with water (20 mL), dried over anhydrous sodium sulfate and evaporated in-vacuo . The residue was purified through column chromatography over silica gel (60–120 mesh) to get aza Michael adducts 6a - 6h in 38–57% yield. 3-(Ethylamino)-2-(3, 4, 5-trimethoxybenzyl)-1-(3, 4, 5-trimethoxyphenyl) propan-1-one (6a) Yield: 51% (14 mg); M.p: viscous; 1 H NMR (CDCl 3 , 500 MHz): δ 1.22–1.25 (t, 3H, CH 3 ), 2.79–2.80 (m, 4H, N -(CH 2 ) 2 ), 2.98-3.0 (m,1H,2-CH), 3.90 (m, 2H, CH 2 , benzylic), 4.03–4.07 (br m, 9H, 3×OCH 3 ), 4.05–4.10 (br m, 9H, 3×OCH 3 ), 6.5 (2×CH), 7.43 (2×CH). 13 C NMR (CDCl 3 , 125 MHz): δ 13.92, 34.21, 38.21, 44.30, 48.73, 51.48, 56.0, 56.09, 56.17, 56.27, 60.80, 60.92, 105.98, 105.08, 132.64, 135.20, 136.57, 139.28, 142.68, 152.95 153.12, 153.25, 202.40; ESI-TOF (HRMS) (MeOH) for C 24 H 33 NO 7 , calcd 448.2335 for [M + H] + , found 448.2319 3-(Propylamino)-2-(3, 4, 5-trimethoxybenzyl)-1-(3, 4, 5-trimethoxyphenyl) propan-1-one (6b) Yield: 43%; M.p: Viscous; 1 H NMR (CDCl 3 , 500 MHz): δ 0.84–0.87 (t, 3H, CH 3 ), 1.43–1.45 (m, 2H, CH 2 ), 1.98 (d, 2H, N -CH 2 ), 2.53–2.55 (m, 2H, N -CH 2 ), 2.79–2.81(bs,1H, N -H), 2.92–3.07(m, H, 2-CH), 3.73 (bs, 9H, 3×OCH 3 ), 3.80–3.85( bs, 9H, 3×OCH 3 ), 3.89 (bd, 2H, CH 2 , benzylic) 6.34 (s, 2H,CH,aromatic), 7.08 (s,2H, CH, aromatic); 13 C NMR (CDCl 3 , 125 MHz): δ 11.66, 22.92, 38.10, 48.96, 51.79, 52.02, 56.04, 56.10, 56.19, 60.81, 60.93, 105.86, 106.01, 132.75, 135.08, 136.57, 142.63, 152.96, 153.13, 202.50; ESI-TOF (HRMS) (MeOH) for C 25 H 35 NO 7 calcd 462.2491 for [M + H] + , found 462.2489. 3-(Butylamino)-2-(3, 4, 5-trimethoxybenzyl)-1-(3, 4, 5-trimethoxyphenyl) propan-1-one (6c) Yield: 49%; M.p: viscous; 1 H NMR (CDCl 3 , 500 MHz): δ 0.85–0.88 (t, 3H, CH 3 ), 1.42–1.43 (bs,4H, CH 2 -CH 2 ), 2.57–2.58 (m,4H, CH 2 - N -CH 2 -), 2.93–2.94 (m, 1H, 2-CH), 3.74 (br m, 9H, 3×OCH 3 ), 3.80 (br m, 9H, 3×OCH 3 ), 3.88 (s, 2H, CH 2 benzylic), 6.34 (s,2H, 2×CH, aromatic), 7.09 (s, 2H, 2×CH, aromatic); 13 C NMR (CDCl 3 , 125 MHz): δ 13.29, 20.34, 31.77, 38.13, 48.74, 49.76, 56.05, 56.11, 56.19, 60.80, 60.92, 105.89, 106.03, 132.69, 134.96, 152.97, 153.14, 202.45; ESI-TOF (HRMS) (MeOH) for C 26 H 37 NO 7 calcd 476.2648 for [M + H] + , found 476.2644 . 3-(Pyrrolidin-1-yl)-2-(3,4,5-trimethoxybenzyl)-1-(3,4,5-trimethoxyphenyl) propan-1-one (6d) Yield: 57%; M.p: 108–110˚C; 1 H NMR (CDCl 3 , 500 MHz): δ 1.71–2.49 (bs, 4H,-CH 2- CH 2 ), 2.86(m,1H, 2-CH), 2.88–2.94 (bm, 6H N -(CH 2 ) 3 ), 3.72–3.73 (br m, 9H, 3×OCH 3 ), 3.81(br m, 9H, 3×OCH 3 ), 3.89 (m,2H, CH 2 -Ph), 6.32 (s, 2H, 2×CH, aromatic), 7.02 (s,2H, 2×CH, aromatic); 13 C NMR (CDCl 3 , 125 MHz): δ 22.70, 38.65, 45.01, 54.59, 56.03, 56.17, 58.73, 60.79, 60.91, 105.68, 106.07, 133.16, 135.38, 136.47, 142.36, 152.87, 153.05, 202.62; ESI-TOF (HRMS) (MeOH) for C 26 H 35 NO 7 calcd 474.2491 for [M + H ] + 474.2476 . 3-(Piperidin-1-yl)-2-(3, 4, 5-trimethoxybenzyl)-1-(3, 4, 5-trimethoxyphenyl)-propan-1-one (6e) Yield: 43%; M.p: viscous; 1 H NMR (CDCl 3 , 500 MHz): δ 0.83–0.88 (bs, 2H, CH 2 ), 1.38 (m, 4H, 2xCH 2 ), 1.66 (s,2H, N -CH 2 ), 2.43–2.94 (m, 4H, N -(CH 2 ) 2 ), 3.73 (br m, 9H, 3×OCH 3 ), 3.84 (br m, 6H, 2×OCH 3 ), 3.93 (s, 3H, OCH 3 ) 4.90 (m, 1H, 2-CH), 6.30 (s,2H, CH-aromatic) 2H, 7.05(s, 2H,CH-aromatic); 13 C NMR (CDCl 3 , 125 MHz): δ 23.87, 30.32, 38.68, 46.47, 54.75, 56.01, 56.19, 60.90, 61.26, 105.77, 106.09, 114.07, 125.03, 133.12, 135.13, 142.35, 152.88, 202.60; ESI-TOF (HRMS) (MeOH) for C 27 H 37 NO 7 calcd 488.2648 for [M + H ] + , found 488.2650 . 3-Morpholino-2-(3, 4, 5-trimethoxybenzyl)-1-(3, 4, 5-trimethoxyphenyl) propan-1-one ( 6f ) Yield: 51%; M.p: 105–108˚C; 1 H NMR (CDCl 3 , 500 MHz): δ 2.43–2.44 (m, 4H, N (CH 2 ) 2 ), 2.85–2.58(m, 1H, CH), 2.80–2.95( bm, 2H, N -CH 2 ), 3.55–3.58 (bs, 4H, -CH 2 - O -CH 2 ), 3.70 (br m, 6H, 2×OCH 3 ), 3.73 (br m, 6H, 2×OCH 3 ), 3.79 (s, 3H,OCH 3 ), 3.89 (s,3H OCH 3 ), 6.32 (s, 2H×CH), 6.98 (s,1H, CH); 13 C NMR (CDCl 3 , 125 MHz): δ 38.17, 46.57, 53.97, 55.77, 56.30, 60.60, 61.52, 66.55, 105.33, 105.88, 133.42, 135.21, 136.58, 142.43, 152.49, 152.89, 153.80, 202.61; ESI-TOF (HRMS) (MeOH) for C 26 H 35 NO 8 calcd 488.2284 for [M-H] - , found 488.2296 . 3-(4-Methylpiperazin-1-yl)-2-(3,4,5-trimethoxybenzyl)-1-(3,4,5-trimethoxyphenyl)-propan-1- one (6g) Yield: 48%; M.p: viscous; 1 H NMR (CDCl 3 , 500 MHz): δ 2.22 (s, 3H, N -CH 3 ), 2.46–2.96 (m, 10H, N -(CH 2 ) 5 ), 3.73 (s, 9H, 3×OCH 3 ), 3.76 (s, 9H, 3×OCH 3 ), 3.80 (d,2H, Ph-CH 2 ), 3.88 (N-CH 2 ), 6.30 (2×CH), 6.96 (2×CH); 13 C NMR (CDCl 3 , 125 MHz): δ 38.20, 45.49, 46.86, 53.40, 55.05, 56.04, 56.12, 56.21, 60.80, 60.87, 60.93, 61.05, 105.44, 105.54, 105.78, 106.02 133.49, 135.39, 136.36, 136.47, 137.15, 153.07, 153.25, 202.82; ESI-TOF (HRMS) (MeOH) for C 27 H 38 N 2 O 7 calcd 503.2757 for [M + H] + , found 503.2751 . 3-(Octylamino)-2-(3, 4, 5-trimethoxybenzyl)-1-(3, 4, 5-trimethoxyphenyl)-propan-1-one (6h) Yield: 38%; M.p: viscous; 1 H NMR (CDCl 3 , 500 MHz): δ 0.7 (s, 3H, CH 3 ), 1.035–1.28 (bs, 14H, 7×CH 2 ) 2.69 (m,2H, N H- CH 2 ), 3.37(s,2H, N -CH 2 ), 3.63(br, m, 6H, 2×OCH 3 ), 3.72 (br, m, 6H, 2×OCH 3 ), 6.22 (s, CH- aromatic), 6.96 (s, CH-aromatic); 13 C NMR (CDCl 3 , 125 MHz): δ 14.98, 20.69, 26.16, 27.33, 27.33, 35.03, 35.47, 40.01, 48.86, 48.97, 90.90, 102.20, 111.79, 113.21, 120.83, 121.61, 122.38, 124.67, 130.71, 135.19, 140.63, 141.19, 190.09; ESI-TOF (HRMS) (MeOH) for C 30 H 45 NO 7 calcd 532.3274 for [M + H ] + , found 532.3257 5.2. Biological evaluation The detailed biological protocols are given in Supplementary information [Online Resource]. 5.2.1. Antiproliferative activity by SRB assay Sulphorhodamine B assay was performed as per reported method [ 15 ]. Doxorubicin and podophyllotoxin were used as positive controls. 5.2.2. Tubulin polymerisation assay Tubulin kinetics experiment was carried out using Cytoskeleton ‘assay kit’ (Inc. Denver, USA) [ 16 ]. The standard antimitotic agents, podophyllotoxin (as destabilizer) and paclitaxel (as stabilizer) were used as positive controls. 5.2.3. Anti-bacterial activity It was done by broth dilution method and disk diffusion assay. Penicillin-G was used as positive control. 5.2.4. Antimicrobial Activity Agar disc diffusion assay and broth dilution method were used as antimicrobial assays. Penicillin–G was used as standard drug. 5.2.5. Media and Bacterial strain culture preparation The Mueller Hinton Agar media for anti-TB activity was used. 5.2.6. Disc diffusion Assay The agar diffusion test or disc diffusion antibiotic sensitivity testing was done as per reported method [ 17 ]. 5.2.7. Broth dilution method Minimum inhibitory concentrations (MIC) and Minimum bactericidal concentration (MBC) were assessed as per reported method [ 18 ]. 5.2.8. Time kill assay It was performed as per reported protocol [ 18 ]. 5.2.9. Checkerboard Method Drug interaction was analyzed in 96-well microtiter plates using checkerboard micro-dilution method [ 19 ]. 5.2.10. Safety studies by acute oral toxicity Acute oral toxicity of the compound was performed in Swiss albino mice in accordance with the organization for Economic Co-operation and development (OECD) test guideline No. 423(1987) [ 14 ]. Study and number of animals used were approved via CIMAP/2016–2019/01 dated 09/02/2017 by Institutional Animal Ethics Committee of CSIR- CIMAP, Lucknow, India. Declarations Conflict of Interest The authors declare no conflict of interest, financial or otherwise. SUPPLEMENTARY INFORMATION Detailed biological protocols and Spectra of final compounds ( 6a - 6h ) are included as Online Resource. Acknowledgements All authors are thankful to Director, CSIR-CIMAP, Lucknow, India, for rendering essential research facilities and support. SS acknowledged the financial support from Department of Sciences & Technology (DST), India as RGNF (JRF/SRF). BT acknowledges DBT for her Junior Research Fellowship. References WHO. Antimicrobial resistance. Keyfacts. 21 Nov. 2023. https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance . Accessed 21March 2024. Privalsky TM, Soohoo AM, Wang J, Walsh CT, Wright GD, Gordon EM, Gray NS, Khosla C. Prospects for Antibacterial Discovery and Development. J Am Chem Soc. 2021; 143: 21127–42. WHO. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. 27 Feb 2017. https://www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed . Accessed 12 March 2024. Murray CW, Rees DC. The rise of fragment-based drug discovery. Nat Chem. 2009; 1: 187-92. Giordanetto F, Jin C, Willmore L, Feher M, Shaw DE (2019). Fragment Hits: What do They Look Like and How do They Bind? J Med Chem. 2019; 62: 3381−94. Negi AS, Gautam Y, Alam S, Chanda D, Luqman S, Sarkar J, Khan F, Konwar R. Natural antitubulin agents: Importance of 3, 4, 5-trimethoxyphenyl fragment. Bioorg Med Chem. 2015; 23: 373-89. Ustinov NB, Korshunoval AV, Gudimchuk NB. Protein Complex NDC80: Properties, Functions, and Possible Role in Pathophysiology of Cell Division. Biochem (Moscow). 2020; 85 (4): 448-62. Vos T, Allen C, Arora M, Barber RM, Bhutta ZA, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. The Lancet. 2016; 388(10053): 1545-1602. Zhang J, Gu Y, Chen B. Mechanisms of drug resistance in acute myeloid leukemia. Onco Targ Ther. 2019; 12: 1937-45. Hsu KS, Toda T. Ndc80 internal loop interacts with Dis1/TOG to ensure proper kinetochore-spindle attachment in fission yeast. Curr Biol. 2011; 21: 214-20. Field MC. The kinetochore and the origin of eukaryotic. chromosome segregation. Proc Natl Acad Sci. 2019; 116: 12596-8. Anadón A, Martínez-Larrañaga MR, Ares I, Martínez MA. Book: Chapter 38: Biomarkers of drug toxicity and safety evaluation. In: Biomarkers in Toxicology . 2nd ed. Academic Press: 2019 , pp655-691. Hoffmann E, Fouretier A, Vergne C, Bertram D. Pharmacovigilance regulatory requirements in Latin America. Pharm Med. 2012; 26(3): 153-64. Walum E. Acute oral toxicity. Env Health Persp. 1998; 106: 497-503. Orellana EA, Kasinski AL. Sulforhodamine B (SRB) assay in cell culture to investigate cell proliferation. Bio-Prot. 2006; 6(21): e1984. Shelanski ML, Gaskin F, Cantor, C.R. Microtubule assembly in the absence of added nucleotides. Proc Natl Acad Sci. 1973; 70(3): 765-68. Padalia RC, Verma RS, Chauhan A, Goswami P, Singh VR, et al. p-Menthenols chemotype of Cymbopogon distans from India: composition, antibacterial and antifungal activity of the essential oil against pathogens. J Essential Oil Res. 2018, 30, 40-6. Nyaa LBT, Tapondjou LA, Barboni L, Tamokou JDD, Kuiate JR, Tane P, Park HJ. NMR assignment and antimicrobial/antioxidant activities of 1β- hydroxyeuscaphic acid from the seeds of Butyrospermum parkii. Nat Prod Sci. 2009; 15: 76-82. Septama AW, Panichayupakaranant P. Synergistic effect of artocarpin on antibacterial activity of some antibiotics against methicillin-resistant Staphylococcus aureus , Pseudomonas aeruginosa , and Escherichia coli . Pharm Biol. 2016; 54: 686-91. Scheme 1 Scheme 1 is available in the Supplementary Files section. Supplementary Files Graphicalabstract.png Supplementaryinformation.docx scheme1.png Scheme 1 Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major Revision 03 May, 2024 Reviewers agreed at journal 09 Apr, 2024 Reviewers invited by journal 09 Apr, 2024 Editor assigned by journal 24 Mar, 2024 First submitted to journal 20 Mar, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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2","display":"","copyAsset":false,"role":"figure","size":41282,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of compound \u003cstrong\u003e6b\u003c/strong\u003e on tubulin kinetics\u003c/p\u003e\n\u003cp\u003e[Line below GTB blank indicates polymerisation inhibitory effect, while line above the GTB blank indicates stabilization effect.]\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4140948/v1/5631af391236f4a22a8a04c1.png"},{"id":54558149,"identity":"888da48f-a98c-4e42-900c-12c6e7c54d7a","added_by":"auto","created_at":"2024-04-12 09:06:47","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":24700,"visible":true,"origin":"","legend":"\u003cp\u003eAntibacterial effect of compound \u003cstrong\u003e6h\u003c/strong\u003e at different intervals\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4140948/v1/ffc02c0324440eeea32c5fe0.png"},{"id":54558151,"identity":"2bb7de34-c2ba-4f0d-abc5-dcac928a73f8","added_by":"auto","created_at":"2024-04-12 09:06:48","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":82509,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of compound \u003cstrong\u003e6h\u003c/strong\u003e as a single acute oral dose at 5, 50, 300 and 1000 mg/kg on absolute and relative organ weight in Swiss albino mice (Mean± SE; n=6)\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4140948/v1/4b70e86ee1242c9ceaf7404a.png"},{"id":54559149,"identity":"d174c733-ee91-481e-97c5-b7cd081a6c61","added_by":"auto","created_at":"2024-04-12 09:22:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1007395,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4140948/v1/3c3dd0a3-7436-49d3-8d80-922c5ee62dcb.pdf"},{"id":54557651,"identity":"3d185391-fa0f-4233-9adc-c267cc802063","added_by":"auto","created_at":"2024-04-12 08:58:47","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":105997,"visible":true,"origin":"","legend":"","description":"","filename":"Graphicalabstract.png","url":"https://assets-eu.researchsquare.com/files/rs-4140948/v1/52d1259150c0bd3c615036de.png"},{"id":54558665,"identity":"abff3de1-4dee-4042-8fea-c58e80ebd480","added_by":"auto","created_at":"2024-04-12 09:14:47","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1952728,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryinformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-4140948/v1/83ea16162be9331572a92e37.docx"},{"id":54557654,"identity":"0b3bb361-9a8b-40cb-81f7-483f82e0d170","added_by":"auto","created_at":"2024-04-12 08:58:48","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":42965,"visible":true,"origin":"","legend":"\u003cp\u003eScheme 1\u003c/p\u003e","description":"","filename":"scheme1.png","url":"https://assets-eu.researchsquare.com/files/rs-4140948/v1/70a3a94a9f78e188abbcfbec.png"}],"financialInterests":"","formattedTitle":"Gallic acid derived aza Michael adducts at diarylpropanone framework exhibit antiproliferative and synergistic antibacterial activities","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eAntimicrobial resistance has been identified as one of the top threats to public healthcare by WHO in 2023 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Most of the pathogens exhibit multidrug resistance (MDR) and extensive drug resistance (XDR). Some of the organisms like \u003cem\u003eStaphylococcus aureus\u003c/em\u003e, Methicillin resistant \u003cem\u003eS. aureus\u003c/em\u003e (MRSA), \u003cem\u003eStreptococcus pneumonia\u003c/em\u003e, \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e and \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e (MTb) have developed even pan-drug resistance (PDR) also known as \u0026lsquo;Superbugs\u0026rsquo; [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The WHO has released a list of such \u0026lsquo;priority pathogens\u0026rsquo; posing acute threat to human health [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The rising prevalence of multidrug resistant bacteria can best be tackled with developing newer antibacterial agents. Over the years, a diverse group of target oriented antibacterials have been developed to inhibit the biosynthesis of bacterial cell wall or biosynthesis of important macromolecule like DNA/RNA or any crucial protein. There are several worthy targets lacking good leads despite possessing druggable active sites. Perhaps \u0026ldquo;polypharmacology\u0026rdquo; approach may provide some new opportunities to researchers.\u003c/p\u003e \u003cp\u003eTubulin-microtubule dynamics is considered one of the most successful approaches to develop cancer chemotherapeutics. In our studies we designed an antitubulin pharmacophore using \u0026lsquo;Fragment Based Drug Discovery (FBDD)\u0026rsquo; approach. According to FBDD, a fragment is a small portion of a pharmacophore of molecular weight\u0026thinsp;~\u0026thinsp;150Da and has high quality (Crucial) interactions with the receptor protein [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. FBDD has become an established lead finding technology yielding encouraging results to pharma industry and also other researcher laboratories [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eInspired from some of the natural antitubulin agents, we kept a 3,4,5-trimethoxyphenyl fragment in the basic pharmacophore to induce antitubulin effect (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Further, recently protein complex NDC80 has been found a good target for the development of antibacterial agents. NDC80 is an important element of bacterial kinetochore that plays a crucial role in the attachment of microtubules to the chromosomes. NDC80 complex mediates interactions between the microtubules and chromosomes during mitosis [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In the present study, we incorporated two different 3,4,5-trimethoxyphenyl motifs at two different ends. One unit has restricted rotation due to ketone group while, another was kept flexible. Further, an amino alkyl unit was introduced \u003cem\u003evia\u003c/em\u003e aza Michael reaction to have better bioavailability of this pharmacophore. Eight diverse aza Michael adducts were prepared on a reduced chalcone unit as possible tubulin-microtubule dynamics modulators and evaluated for anticancer and antibacterial activities.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"2. results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Chemical synthesis\u003c/h2\u003e \u003cp\u003eThe synthetic strategy has been depicted in Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The basic core was prepared by the condensation of 3,4,5,-trimetheoxyacetophenone (\u003cb\u003e1\u003c/b\u003e) and 3, 4, 5- trimethoxybenzaldehyde (\u003cb\u003e2\u003c/b\u003e) in 7% KOH in aqueous-methanolic solution (1:9) to get the desired hexamethoxychalcone (\u003cb\u003e3\u003c/b\u003e) \u003cem\u003evia\u003c/em\u003e Claisen-Schmidt reaction in 95% yield. Chalcone \u003cb\u003e3\u003c/b\u003e was reduced with H\u003csub\u003e2\u003c/sub\u003e-Palladium charcoal (5%, Pd-C) to reduced chalcone \u003cb\u003e4\u003c/b\u003e in 82% yield. The reduced chalcone \u003cb\u003e4\u003c/b\u003e was treated with glacial acetic acid, formaldehyde and morpholine to afford compound \u003cb\u003e5\u003c/b\u003e in 62% yield. Compound \u003cb\u003e5\u003c/b\u003e was treated with various amines in Na\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e- water- acetonitrile system to get desired compounds \u003cb\u003e6a\u003c/b\u003e-\u003cb\u003e6h\u003c/b\u003e in 32\u0026ndash;57% yield \u003cem\u003evia\u003c/em\u003e Aza Michael reaction. All the intermediates and final products were confirmed by spectroscopy. Detailed spectral analysis in included in materials and method section.\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Antiproliferative activity\u003c/h2\u003e \u003cp\u003eAntiproliferative activity of compounds \u003cb\u003e6a\u003c/b\u003e-\u003cb\u003e6h\u003c/b\u003e was assessed by Sulphorhodamine assay as illustrated in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Among these only compounds \u003cb\u003e6b\u003c/b\u003e and \u003cb\u003e6g\u003c/b\u003e exhibited significant cytotoxicity against K562 cell line with IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;7.69 \u0026micro;M and 13.31 \u0026micro;M respectively.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cem\u003eIn- vitro\u003c/em\u003e cytoxicity of Micheal base derivatives against K-562 cell line and MDA-MB-231 cell line (IC\u003csub\u003e50\u003c/sub\u003e in \u0026micro;M).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eS. No.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCompd.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eCytotoxicity IC\u003csub\u003e50\u003c/sub\u003e (\u0026micro;M)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eS. No.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCompd.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eCytotoxicity IC\u003csub\u003e50\u003c/sub\u003e (\u0026micro;M)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eK562\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMDA-MB231\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eK562\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMDA-MB231\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e6a\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e˃100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e83.35\u0026thinsp;\u0026plusmn;\u0026thinsp;2.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6f\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e˃100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e71.11\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e6b\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.69\u0026thinsp;\u0026plusmn;\u0026thinsp;1.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e86.52\u0026thinsp;\u0026plusmn;\u0026thinsp;4.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6g\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e13.31\u0026thinsp;\u0026plusmn;\u0026thinsp;0.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e53.23\u0026thinsp;\u0026plusmn;\u0026thinsp;2.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e6c\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59.76\u0026thinsp;\u0026plusmn;\u0026thinsp;12.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e57.09\u0026thinsp;\u0026plusmn;\u0026thinsp;4.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e26.35\u0026thinsp;\u0026plusmn;\u0026thinsp;1.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e˃100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e6d\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e˃100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e63.26\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDOX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.77\u0026thinsp;\u0026plusmn;\u0026thinsp;0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9.18\u0026thinsp;\u0026plusmn;\u0026thinsp;2.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e6e\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45.65\u0026thinsp;\u0026plusmn;\u0026thinsp;0.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e56.73\u0026thinsp;\u0026plusmn;\u0026thinsp;3.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePDT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e86.11\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e*DOX\u0026thinsp;=\u0026thinsp;doxorubicin, PDT\u0026thinsp;=\u0026thinsp;Podophyllotoxin; ND\u0026thinsp;=\u0026thinsp;not determined\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Effect on tubulin polymerisation\u003c/h2\u003e \u003cp\u003eThe effect of compound \u003cb\u003e6b\u003c/b\u003e on tubulin polymerization was assessed as tubulin kinetics graph as depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Compound \u003cb\u003e6b\u003c/b\u003e enhanced microtubule polymerization, acting as microtubule stabilizer. Podophyllotoxin inhibited tubulin polymerisation while paclitaxel showed stabilization effect.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Antibacterial activity\u003c/h2\u003e \u003cp\u003eIn preliminary antibacterial evaluation against the \u003cem\u003eStaphylococcus aureus, Staphylococcus epidermidis\u003c/em\u003e, Methicillin-resistant \u003cem\u003eStaphylococcus aureus\u003c/em\u003e, Methicillin-resistant \u003cem\u003eStaphylococcus epidermidis\u003c/em\u003e strains, compounds \u003cb\u003e6e\u003c/b\u003e, \u003cb\u003e6f\u003c/b\u003e, and \u003cb\u003e6h\u003c/b\u003e showed significant activity. Compounds \u003cb\u003e6e\u003c/b\u003e and \u003cb\u003e6f\u003c/b\u003e exhibited antibacterial effect against \u003cem\u003eS. aureus\u003c/em\u003e strain, with zone of inhibition of 6 mm and 7 mm respectively. While \u003cb\u003e6h\u003c/b\u003e showed better antibacterial effect among all the four strains. It was also effective against methicillin resistance \u003cem\u003eStaphylococcus epidermis.\u003c/em\u003e But the antibacterial effect of all these compounds was much lower than the standard drug penicillin G (13\u0026ndash;44 mm). Results depicted in ST1 (Supplementary information).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5. Broth dilution method\u003c/h2\u003e \u003cp\u003eThe anti-bacterial activity was further confirmed by evaluating minimum inhibitory concentration against all the four strains. Among these \u003cb\u003e6e\u003c/b\u003e, \u003cb\u003e6f\u003c/b\u003e, and \u003cb\u003e6h\u003c/b\u003e exhibited significant antibacterial activity i.e. MIC\u0026thinsp;\u0026le;\u0026thinsp;500 \u0026micro;g/mL. However, \u003cb\u003e6h\u003c/b\u003e showed very good MIC i.e. (62.5\u0026ndash;125 \u0026micro;g/mL) further, minimum bacterial concentration was also evaluated. Compound \u003cb\u003e6h\u003c/b\u003e exhibited good MBC activity (125 \u0026micro;g/mL). Both MIC and MBC results are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMinimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) of Michael amines by Broth dilution method\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"13\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eS. No.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCompd.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c6\" namest=\"c3\"\u003e \u003cp\u003eMIC (\u0026micro;g/mL) against Bacterial strains\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eS. No.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCompd.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c13\" namest=\"c10\"\u003e \u003cp\u003eMBC (\u0026micro;g/mL) against Bacterial strains\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSE\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMRSA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMRSE\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eSE\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eMRSA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c13\"\u003e \u003cp\u003eMRSE\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e6e\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e6e\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e6f\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e6f\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e1000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e125\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e62.5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e62.5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e62.5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e250\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u003cb\u003e125\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u003cb\u003e125\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e125\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ePen.-G\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.097\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003ePen.-G\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.097\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRest were inactive up to 1000 \u0026micro;g/mL concentration.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6. Time kill assay\u003c/h2\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e Time-kill kinetics assay was performed to determine the bactericidal or bacteriostatic activity of compound \u003cb\u003e6h\u003c/b\u003e. The results are depicted in ST2 (Supplementary information). The same is expressed by plotting log\u003csub\u003e10\u003c/sub\u003e cfu/mL against time (h) in Fig.\u0026nbsp;3.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.7. Combination study by Checkerboard method\u003c/h2\u003e \u003cp\u003eCheckerboard method is used to determine the impact on potency of the combination of antibiotics in comparison to their individual activities. This comparison is then represented as the fractional inhibitory concentration index (FICI) value. At FICI value\u0026thinsp;\u0026le;\u0026thinsp;0 is synergism; FICI value\u0026thinsp;\u0026gt;\u0026thinsp;0.5\u0026ndash;4 is indifference; and FICI value\u0026thinsp;\u0026gt;\u0026thinsp;4 is antagonism. \u003cb\u003e6h\u003c/b\u003e was evaluated against 5 strains the SA-\u003cem\u003eStaphylococcus aureus\u003c/em\u003e (MTCC96), SE\u003cem\u003e-Staphylococcus epidermidis\u003c/em\u003e (MTCC435), MS\u003cem\u003e-Mycobacterium smegmatis\u003c/em\u003e (UDSC mc\u003csup\u003e2\u003c/sup\u003e 155), MR\u003cem\u003eSA-\u003c/em\u003e Methicillin-resistant \u003cem\u003eStaphylococcus aureus\u003c/em\u003e (ATCC33591), MRSE\u003cem\u003e-\u003c/em\u003eMethicillin-resistant \u003cem\u003eStaphylococcus epidermidis\u003c/em\u003e (ATCC51625) for combination study against bacterial strains with known antibacterial drugs. Among all the combination \u003cb\u003e6h\u003c/b\u003e showed synergistic effect with penicillin in MRSA Strain and with norfloxacin was shown synergistic effect with norfloxacin in MRSE Strain. Results are shown in Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMIC (\u0026micro;g/mL) of \u003cb\u003e6h\u003c/b\u003e against Bacterial strains alone and in combination.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eType\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDrugs\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTime\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eRemark\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePenicillin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePEN FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNorfloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNor. FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePenicillin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePEN FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNorfloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNor FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRifampicin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRIF FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.625\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGentamicin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGEN FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e7\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMRSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePenicillin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePEN FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSynergistic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMRSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNorfloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNOR FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e9\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMRSE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePenicillin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePEN FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMRSE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNorfloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNOR FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSynergistic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e11\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePenicillin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePEN FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e12\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNorfloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNor. FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e13\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePenicillin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePEN FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e14\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNorfloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNor FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e15\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRifampicin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRIF FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.625\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e16\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGentamicin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGEN FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e17\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMRSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePenicillin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePEN FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSynergistic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e18\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMRSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNorfloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNOR FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e19\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMRSE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePenicillin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePEN FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e20\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMRSE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNorfloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNOR FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSynergistic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e21\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePenicillin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePEN FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e22\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNorfloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNor. FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e23\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePenicillin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePEN FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e24\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNorfloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNor FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e25\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRifampicin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRIF FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.625\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e26\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGentamicin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGEN FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e27\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMRSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePenicillin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePEN FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSynergistic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e28\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMRSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNorfloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNOR FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e29\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMRSE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePenicillin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePEN FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e30\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMRSE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNorfloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNOR FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSynergistic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e31\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePenicillin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePEN FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e32\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNorfloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNor. FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e33\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePenicillin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePEN FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e34\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNorfloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNor FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e35\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRifampicin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRIF FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.625\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e36\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGentamicin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGEN FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e37\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMRSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePenicillin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePEN FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSynergistic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e38\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMRSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNorfloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNOR FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e39\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMRSE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePenicillin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePEN FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndifference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e40\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMRSE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNorfloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNOR FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e FIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMOI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSynergistic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003cb\u003eSA\u003c/b\u003e: \u003cem\u003eStaphylococcus aureus\u003c/em\u003e; \u003cb\u003eSE\u003c/b\u003e: \u003cem\u003eStaphylococcus epidermidis\u003c/em\u003e; \u003cb\u003eMRSA\u003c/b\u003e: Methicillin-resistant \u003cem\u003eStaphylococcus aureus;\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003cb\u003eMRSE\u003c/b\u003e: Methicillin-resistant \u003cem\u003eStaphylococcus epidermidis\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e2.8. Acute oral toxicity of compound 6h\u003c/h2\u003e \u003cp\u003eThe acute oral toxicity was performed to find out various side effects of the \u003cb\u003e6h\u003c/b\u003e under investigation giving a single oral dose within 24 h in rodent model (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Four distinct concentrations of compound \u003cb\u003e6h\u003c/b\u003e i.e. (5 mg/kg, 50 mg/kg, 300 mg/kg, and 1000 mg/kg) were given to Swiss albino mice as single oral dose. Animals did not show any morbidity and mortality up to the dose level of 1000 mg/kg. Biochemical and hematological parameters showed non-significant changes. Gross pathological studies on animals showed no significant changes in any of the animal organs studies including their absolute and relative weight Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e. In higher doses ALP and creatinine level were high but these changes were non-significant.\u003c/p\u003e \u003cp\u003eResults showed that it is absolutely safe up to 1000 mg/ kg dose. However, its sub-acute and chronic toxicity investigations should be undertaken before developing as a clinical drug to observe its effects on repeated exposure.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEffect of \u003cb\u003e6h\u003c/b\u003e as a single acute oral dose on body weight, haematological and serum biochemical parameters in Swiss albino mice (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SE; n\u0026thinsp;=\u0026thinsp;6; Non significant changes were found compared to control, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c7\" namest=\"c3\"\u003e \u003cp\u003eDose of 6h at mg/kg body weight as a single oral dose\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eControl\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e5 mg/kg\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e50 mg/kg\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e300 mg/kg\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e1000 mg/kg\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBody weight\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eBody weight (g)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27.72\u0026thinsp;\u0026plusmn;\u0026thinsp;1.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24.47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e25.27\u0026thinsp;\u0026plusmn;\u0026thinsp;0.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e25.82\u0026thinsp;\u0026plusmn;\u0026thinsp;1.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eHaematalogical parameters\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eHaemoglobin (g/dL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.40\u0026thinsp;\u0026plusmn;\u0026thinsp;0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.22\u0026thinsp;\u0026plusmn;\u0026thinsp;0.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.14\u0026thinsp;\u0026plusmn;\u0026thinsp;1.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e13.30\u0026thinsp;\u0026plusmn;\u0026thinsp;0.38\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eRBC (million/mm\u003c/b\u003e\u003csup\u003e\u003cb\u003e3\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e5.39\u0026thinsp;\u0026plusmn;\u0026thinsp;0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eWBC (1000*/mm\u003c/b\u003e\u003csup\u003e\u003cb\u003e3\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.88\u0026thinsp;\u0026plusmn;\u0026thinsp;1.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.65\u0026thinsp;\u0026plusmn;\u0026thinsp;1.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e4.19\u0026thinsp;\u0026plusmn;\u0026thinsp;0.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"5\" rowspan=\"6\"\u003e \u003cp\u003e\u003cb\u003eLiver function test\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eALP (U/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e224.67\u0026thinsp;\u0026plusmn;\u0026thinsp;9.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e219.85\u0026thinsp;\u0026plusmn;\u0026thinsp;18.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e243.64\u0026thinsp;\u0026plusmn;\u0026thinsp;22.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e257.52\u0026thinsp;\u0026plusmn;\u0026thinsp;16.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e272.16\u0026thinsp;\u0026plusmn;\u0026thinsp;15.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eSGOT (U/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.33\u0026thinsp;\u0026plusmn;\u0026thinsp;3.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27.26\u0026thinsp;\u0026plusmn;\u0026thinsp;5.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28.98\u0026thinsp;\u0026plusmn;\u0026thinsp;3.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24.11\u0026thinsp;\u0026plusmn;\u0026thinsp;3.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e24.37\u0026thinsp;\u0026plusmn;\u0026thinsp;2.71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eSGPT (U/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14.09\u0026thinsp;\u0026plusmn;\u0026thinsp;1.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19.77\u0026thinsp;\u0026plusmn;\u0026thinsp;2.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16.43\u0026thinsp;\u0026plusmn;\u0026thinsp;1.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13.61\u0026thinsp;\u0026plusmn;\u0026thinsp;2.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e15.74\u0026thinsp;\u0026plusmn;\u0026thinsp;2.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eAlbumin (g/dL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.73\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.76\u0026thinsp;\u0026plusmn;\u0026thinsp;0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.29\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e5.13\u0026thinsp;\u0026plusmn;\u0026thinsp;0.36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eSerum Protein (mg/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.02\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.91\u0026thinsp;\u0026plusmn;\u0026thinsp;0.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.83\u0026thinsp;\u0026plusmn;\u0026thinsp;0.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e6.27\u0026thinsp;\u0026plusmn;\u0026thinsp;0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eBilirubin (mg/dL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.09\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e0.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKidney Function test\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eCreatinine (mg/dL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.48\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.44\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eLipid profile\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eTriglycerides (mg/dL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e98.32\u0026thinsp;\u0026plusmn;\u0026thinsp;9.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e85.38\u0026thinsp;\u0026plusmn;\u0026thinsp;5.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e82.87\u0026thinsp;\u0026plusmn;\u0026thinsp;7.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e89.10\u0026thinsp;\u0026plusmn;\u0026thinsp;8.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e90.53\u0026thinsp;\u0026plusmn;\u0026thinsp;9.31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eCholesterol (mg/dL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e174.82\u0026thinsp;\u0026plusmn;\u0026thinsp;15.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e198.12\u0026thinsp;\u0026plusmn;\u0026thinsp;16.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e185.61\u0026thinsp;\u0026plusmn;\u0026thinsp;32.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e151.62\u0026thinsp;\u0026plusmn;\u0026thinsp;16.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e131.56\u0026thinsp;\u0026plusmn;\u0026thinsp;15.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"3. discussion","content":"\u003cp\u003eCancer and bacterial infections are two major health menaces. Leukemia is a type of cancer related to blood cells or bone marrow. Different types of leukemia have different treatment options and outlooks [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. It is the most common type of cancer in children. In chemotherapy, vincristin sulphate, vinblastin sulphate, imatinib mesylate, doxorubicin, daunorubicin, and etoposide are used to cure various types of leukemia. However, these clinical drugs are associated with several serious side effects like loss of WBCs and blood platelets, gastrointestinal disorders, high BP, loss of hair, severe congestive heart failure etc. Their high cost and serious side effects make them undesirable for the treatment of leukemia. A key issue in the treatment of acute leukemia is the development of resistance to chemotherapeutic drugs [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In the present study the representative compound \u003cb\u003e6b\u003c/b\u003e exhibited significant cytotoxicity against leukemia cells K-562. Its antiproliferative effect was established \u003cem\u003evia\u003c/em\u003e microtubule stabilization effect. Tubulin microtubule dynamics has become an attractive target for the development of cancer chemotherapeutics. The process of tubulin polymerisation and microtubules depolymerisation are in dynamic equilibrium. Any interruption created in this process disturbs this dynamic equilibrium and leads to cell cycle arrest at mitosis phase [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The disturbances may be created by destabilization of polymerisation process (Forward process) like colchicine, podophyllotoxin, 2-methoxyestradiol and combretastatin A4 etc. or by inducing destabilization effect in depolymerisation process (Backward process) like paclitaxel, epothilones etc. Compound \u003cb\u003e6b\u003c/b\u003e showed microtubule stabilization effects similar to paclitaxel. However, its effect was quite less than paclitaxel effect.\u003c/p\u003e \u003cp\u003eSome of these Mannich bases also exhibited antibacterial activity. Compound \u003cb\u003e6h\u003c/b\u003e showed significant activity in disc diffusion method, and also in broth dilution method. In the checker board experiment \u003cb\u003e6h\u003c/b\u003e showed synergistic effect in combination of penicillin and also with norfloxacin, up to fourfold reduction of quantity of the antibiotic drug as bacteriostatic effects. We expected antibacterial effect due to involvement of Nuclear Division Cycle 80 (NDC80), loop region required for proper microtubule binding to kinetochores and loop mutant like ndc-80-21 displayed unstable kinetochore-microtubule interactions. The phenotype of NDC-80-21 could be partially released by over-expression of the microtubules-binding protein Dis-1, bacterial also expressed Dis-1 able to interact with NDC-80 [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. NDC80 has become an important target for antibacterial drug development [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSafety is a necessary part of drug development [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. It profoundly concentrates on unwanted drug outcomes. Nowadays, it is referred as \u0026lsquo;Pharmacovigilance\u0026rsquo;. According to World Health Organization, it focuses to increase safety and patient\u0026rsquo;s look-after in terms of use of medicine and to support public health programmes by providing authentic, relevant information for effective evaluation of risk-benefit profile of medicines [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Compound \u003cb\u003e6h\u003c/b\u003e did not show any significant adverse effects and may be regarded as LOAEL (Lowest observed adverse effect level). Acute oral toxicity is the most persistent experiment used to assess the preliminary toxicity of investigational bioactive candidates [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e"},{"header":"4. CONCLUSION","content":"\u003cp\u003ePresent study demonstrated design and synthesis of several amino derivatives on diaryl propanone core by aza Michael addition. However, only five compounds exhibited significant antiproliferative activity. Compound \u003cb\u003e6b\u003c/b\u003e exhibited potential cytotoxicity against human leukemia cell line \u003cem\u003evia\u003c/em\u003e microtubule stabilization effect. Another representative compound \u003cb\u003e6h\u003c/b\u003e showed significant antibacterial activity. Compound \u003cb\u003e6h\u003c/b\u003e was quite safe in rodent models in acute oral toxicity. The further optimization of both lead compounds of this series is underway in our research group.\u003c/p\u003e"},{"header":"5. MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e5.1. Chemistry\u003c/h2\u003e \u003cp\u003eThe desired Aza Michael adducts were prepared as per scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSynthesis of (E)-1, 3-bis (3, 4, 5-trimethoxyophenyl) prop-2-en 1- one (3)\u003c/b\u003e \u003c/p\u003e \u003cp\u003e3, 4, 5- trimethoxyacetophenone (2.1 g, 10 mmol) was taken in 7% aqueous- methanolic KOH (20 mL). To this 3,4,5- trimethoxybenzaldehyde (2.06 g, 10.5 mmol) was added and stirred for 2h at RT. Reaction mixture was acidified with dil. HCl (10%, 15 mL), extracted with ethyl acetate (3\u0026times;20 mL), washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was refined through column chromatography (silica gel) eluting with hexane-ethyl acetate to get pure amorphous chalcone (\u003cb\u003e3\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eYield: 91% (3.65 g); M.p: 128\u0026ndash;130˚C; \u003csup\u003e1\u003c/sup\u003eH NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 500 MHz): δ 3.89\u0026ndash;3.91 (br s, 9H, 3\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 3.93\u0026ndash;3.94 (br s, 9H, 3\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 6.85 (s, 2H, 2\u0026times;CH, aromatic), 7.24 (s, 2H, 2\u0026times;CH, aromatic), 7.30\u0026ndash;7.33 (d, 1H, =CH, J\u0026thinsp;=\u0026thinsp;15.5Hz), 7.69\u0026ndash;7.72 (d, 1H, =CH, J\u0026thinsp;=\u0026thinsp;15.5Hz); \u003csup\u003e13\u003c/sup\u003eC NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 125 MHz): δ 56.31, 56.52, 56.52, 61.01, 61.03, 105.79, 106.30, 121.35, 130.39, 133.63, 140.56, 142.57, 144.99, 153.18, 153.53, 189.46; ESI-TOF (HRMS) (MeOH): m/z [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e for C\u003csub\u003e21\u003c/sub\u003eH\u003csub\u003e24\u003c/sub\u003eO\u003csub\u003e7\u003c/sub\u003e calcd. 389.1600 found 389.1578\u003c/p\u003e \u003cp\u003e \u003cb\u003eSynthesis of 1, 3-bis (3, 4, 5-trimethoxyophenyl) propan-1-one (4)\u003c/b\u003e \u003c/p\u003e \u003cp\u003eTo a solution of hexamethoxychalcone \u003cb\u003e3\u003c/b\u003e (500 mg, 1.28 mmol) in dry THF (10 mL), 5% palladium on carbon was added (100 mg) and stirred at RT for 2h with continuous supply of hydrogen gas using a balloon. On completion, it was filtered, washed with acetone and concentrated under vacuum. The residue was taken in ethyl acetate (30 mL), washed with water (20 mL), dried over anhydrous sodium sulphate and purified through column chromatography using hexane-ethyl acetate as mobile phase to get compound \u003cb\u003e4\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eYield: 82% (412 mg); M.p: 108\u0026ndash;110˚C; \u003csup\u003e1\u003c/sup\u003eH NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 500 MHz): δ 2.98\u0026ndash;3.016 (m, 2-CH\u003csub\u003e2\u003c/sub\u003e), 3.23\u0026ndash;3.26 (m, 3-CH\u003csub\u003e2\u003c/sub\u003e), 3.86 (s, m, 9H, 3\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 3.90 (s, m, 9H, 3\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 6.46 (s, 2\u0026times;CH, aromatic), 7.19 (s, 2H, 2\u0026times;CH, aromatic); \u003csup\u003e13\u003c/sup\u003eC NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 125 MHz): δ 30.85, 40.51, 56.13, 56.34, 56.34, 56.53, 60.87, 60.96, 105.46, 105.46, 105.56, 105.56, 132.17, 136.41, 137.14, 142.66, 153.10, 153.10, 153.27, 153.27, 198.02; ESI-TOF (HRMS) (MeOH): m/z [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e for C\u003csub\u003e21\u003c/sub\u003eH\u003csub\u003e26\u003c/sub\u003eO\u003csub\u003e7\u003c/sub\u003e calcd 391.1756 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e, found 391.1744 .\u003c/p\u003e \u003cp\u003e \u003cb\u003eSynthesis of 2- (3, 4, 5- trimethoxybenzyl)-1-(3, 4, 5- trimethoxyphenyl) prop-2-en-1-one (5)\u003c/b\u003e \u003c/p\u003e \u003cp\u003eTo a solution of reduced chalcone \u003cb\u003e4\u003c/b\u003e (300 mg, 0.76 mmol) in glacial acetic acid (10 mL), formaldehyde (0.1 mL, 0.10 g, 3.63 mmol) was added and refluxed at 100˚C for 10 min. After 10 min, morpholine (0.2 mL, 0.19 g, 3.48 mmol) was added and further refluxed for 2 h. After completion, the solvent was evaporated and residue was taken in ethyl acetate and water. The organic layer was demoistened over anhydrous sodium sulphate, filtered and evaporated \u003cem\u003ein vacuo.\u003c/em\u003e The crude mass was purified through silica gel column by eluting with hexane- ethyl acetate. The desired compound \u003cb\u003e5\u003c/b\u003e was obtained as amorphous solid.\u003c/p\u003e \u003cp\u003eYield: 62% (192 mg); M.p: 129\u0026ndash;130˚C; \u003csup\u003e1\u003c/sup\u003eH NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 500 MHz): δ 1.22 (s, CH\u003csub\u003e2\u003c/sub\u003e), 3.07\u0026ndash;3.75 (br m, 9H, 3\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 3.83\u0026ndash;3.87 (s, 9H, 3\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 5.63 (s, 1H, =CH\u003csub\u003e2\u003c/sub\u003e), 5.73 (s, 1H, =CH\u003csub\u003e2\u003c/sub\u003e), 6.43 (s, 2H, 2\u0026times;CH, aromatic), 6.98 (s, 2H, 2\u0026times;CH, aromatic); \u003csup\u003e13\u003c/sup\u003eC NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 125 MHz): δ 39.38, 56.25, 56.87, 60.91, 106.08, 107.23, 125.15, 132.47, 134.31, 139.24, 142.15, 152.80, 153.23, 196.60; Electrospray mass (MeOH) for C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e26\u003c/sub\u003eO\u003csub\u003e7\u003c/sub\u003e calcd for 403.1756 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e, found 403.1754\u003c/p\u003e \u003cp\u003e \u003cb\u003eGeneral procedure for the synthesis of compounds 6a-6h\u003c/b\u003e \u003c/p\u003e \u003cp\u003eTo a solution of arylbenzylpropenone \u003cb\u003e5\u003c/b\u003e (50 mg, 0.1 mmol) and Na\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e (60 mg) in 1:1 (water: acetonitrile, 12 mL). To this amine (0.2 mmol) was added and stirred with heating at 100˚C for 3h. On completion, reaction mixture was quenched by water and extracted with ethyl acetate (10 mL\u0026times;3), washed with water (20 mL), dried over anhydrous sodium sulfate and evaporated \u003cem\u003ein-vacuo\u003c/em\u003e. The residue was purified through column chromatography over silica gel (60\u0026ndash;120 mesh) to get aza Michael adducts \u003cb\u003e6a\u003c/b\u003e-\u003cb\u003e6h\u003c/b\u003e in 38\u0026ndash;57% yield.\u003c/p\u003e \u003cp\u003e \u003cb\u003e3-(Ethylamino)-2-(3, 4, 5-trimethoxybenzyl)-1-(3, 4, 5-trimethoxyphenyl) propan-1-one (6a)\u003c/b\u003e Yield: 51% (14 mg); M.p: viscous; \u003csup\u003e1\u003c/sup\u003eH NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 500 MHz): δ 1.22\u0026ndash;1.25 (t, 3H, CH\u003csub\u003e3\u003c/sub\u003e), 2.79\u0026ndash;2.80 (m, 4H, \u003cem\u003eN\u003c/em\u003e-(CH\u003csub\u003e2\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003e), 2.98-3.0 (m,1H,2-CH), 3.90 (m, 2H, CH\u003csub\u003e2\u003c/sub\u003e, benzylic), 4.03\u0026ndash;4.07 (br m, 9H, 3\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 4.05\u0026ndash;4.10 (br m, 9H, 3\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 6.5 (2\u0026times;CH), 7.43 (2\u0026times;CH). \u003csup\u003e13\u003c/sup\u003eC NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 125 MHz): δ 13.92, 34.21, 38.21, 44.30, 48.73, 51.48, 56.0, 56.09, 56.17, 56.27, 60.80, 60.92, 105.98, 105.08, 132.64, 135.20, 136.57, 139.28, 142.68, 152.95 153.12, 153.25, 202.40; ESI-TOF (HRMS) (MeOH) for C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e33\u003c/sub\u003eNO\u003csub\u003e7 ,\u003c/sub\u003e calcd 448.2335 for [M\u0026thinsp;+\u0026thinsp;H] \u003csup\u003e+\u003c/sup\u003e, found 448.2319\u003c/p\u003e \u003cp\u003e \u003cb\u003e3-(Propylamino)-2-(3, 4, 5-trimethoxybenzyl)-1-(3, 4, 5-trimethoxyphenyl) propan-1-one (6b)\u003c/b\u003e Yield: 43%; M.p: Viscous; \u003csup\u003e1\u003c/sup\u003eH NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 500 MHz): δ 0.84\u0026ndash;0.87 (t, 3H, CH\u003csub\u003e3\u003c/sub\u003e), 1.43\u0026ndash;1.45 (m, 2H, CH\u003csub\u003e2\u003c/sub\u003e), 1.98 (d, 2H, \u003cem\u003eN\u003c/em\u003e-CH\u003csub\u003e2\u003c/sub\u003e), 2.53\u0026ndash;2.55 (m, 2H, \u003cem\u003eN\u003c/em\u003e-CH\u003csub\u003e2\u003c/sub\u003e), 2.79\u0026ndash;2.81(bs,1H,\u003cem\u003eN\u003c/em\u003e-H), 2.92\u0026ndash;3.07(m, H, 2-CH), 3.73 (bs, 9H, 3\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 3.80\u0026ndash;3.85( bs, 9H, 3\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 3.89 (bd, 2H, CH\u003csub\u003e2\u003c/sub\u003e, benzylic) 6.34 (s, 2H,CH,aromatic), 7.08 (s,2H, CH, aromatic); \u003csup\u003e13\u003c/sup\u003eC NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 125 MHz): δ 11.66, 22.92, 38.10, 48.96, 51.79, 52.02, 56.04, 56.10, 56.19, 60.81, 60.93, 105.86, 106.01, 132.75, 135.08, 136.57, 142.63, 152.96, 153.13, 202.50; ESI-TOF (HRMS) (MeOH) for C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e35\u003c/sub\u003eNO\u003csub\u003e7\u003c/sub\u003e calcd 462.2491 for [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e, found 462.2489.\u003c/p\u003e \u003cp\u003e \u003cb\u003e3-(Butylamino)-2-(3, 4, 5-trimethoxybenzyl)-1-(3, 4, 5-trimethoxyphenyl) propan-1-one (6c)\u003c/b\u003e Yield: 49%; M.p: viscous; \u003csup\u003e1\u003c/sup\u003eH NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 500 MHz): δ 0.85\u0026ndash;0.88 (t, 3H, CH\u003csub\u003e3\u003c/sub\u003e), 1.42\u0026ndash;1.43 (bs,4H, CH\u003csub\u003e2\u003c/sub\u003e-CH\u003csub\u003e2\u003c/sub\u003e), 2.57\u0026ndash;2.58 (m,4H, CH\u003csub\u003e2\u003c/sub\u003e-\u003cem\u003eN\u003c/em\u003e-CH\u003csub\u003e2\u003c/sub\u003e-), 2.93\u0026ndash;2.94 (m, 1H, 2-CH), 3.74 (br m, 9H, 3\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 3.80 (br m, 9H, 3\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 3.88 (s, 2H, CH\u003csub\u003e2\u003c/sub\u003e benzylic), 6.34 (s,2H, 2\u0026times;CH, aromatic), 7.09 (s, 2H, 2\u0026times;CH, aromatic); \u003csup\u003e13\u003c/sup\u003eC NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 125 MHz): δ 13.29, 20.34, 31.77, 38.13, 48.74, 49.76, 56.05, 56.11, 56.19, 60.80, 60.92, 105.89, 106.03, 132.69, 134.96, 152.97, 153.14, 202.45; ESI-TOF (HRMS) (MeOH) for C\u003csub\u003e26\u003c/sub\u003eH\u003csub\u003e37\u003c/sub\u003eNO\u003csub\u003e7\u003c/sub\u003e calcd 476.2648 for [M\u0026thinsp;+\u0026thinsp;H] \u003csup\u003e+\u003c/sup\u003e, found 476.2644 .\u003cb\u003e3-(Pyrrolidin-1-yl)-2-(3,4,5-trimethoxybenzyl)-1-(3,4,5-trimethoxyphenyl) propan-1-one (6d)\u003c/b\u003e Yield: 57%; M.p: 108\u0026ndash;110˚C; \u003csup\u003e1\u003c/sup\u003eH NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 500 MHz): δ 1.71\u0026ndash;2.49 (bs, 4H,-CH\u003csub\u003e2-\u003c/sub\u003eCH\u003csub\u003e2\u003c/sub\u003e), 2.86(m,1H, 2-CH), 2.88\u0026ndash;2.94 (bm, 6H \u003cem\u003eN\u003c/em\u003e-(CH\u003csub\u003e2\u003c/sub\u003e)\u003csub\u003e3\u003c/sub\u003e), 3.72\u0026ndash;3.73 (br m, 9H, 3\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 3.81(br m, 9H, 3\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 3.89 (m,2H, CH\u003csub\u003e2\u003c/sub\u003e-Ph), 6.32 (s, 2H, 2\u0026times;CH, aromatic), 7.02 (s,2H, 2\u0026times;CH, aromatic); \u003csup\u003e13\u003c/sup\u003eC NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 125 MHz): δ 22.70, 38.65, 45.01, 54.59, 56.03, 56.17, 58.73, 60.79, 60.91, 105.68, 106.07, 133.16, 135.38, 136.47, 142.36, 152.87, 153.05, 202.62; ESI-TOF (HRMS) (MeOH) for C\u003csub\u003e26\u003c/sub\u003eH\u003csub\u003e35\u003c/sub\u003eNO\u003csub\u003e7\u003c/sub\u003e calcd 474.2491 for [M\u0026thinsp;+\u0026thinsp;H ]\u003csup\u003e+\u003c/sup\u003e 474.2476 .\u003c/p\u003e \u003cp\u003e \u003cb\u003e3-(Piperidin-1-yl)-2-(3, 4, 5-trimethoxybenzyl)-1-(3, 4, 5-trimethoxyphenyl)-propan-1-one (6e)\u003c/b\u003e Yield: 43%; M.p: viscous; \u003csup\u003e1\u003c/sup\u003eH NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 500 MHz): δ 0.83\u0026ndash;0.88 (bs, 2H, CH\u003csub\u003e2\u003c/sub\u003e), 1.38 (m, 4H, 2xCH\u003csub\u003e2\u003c/sub\u003e), 1.66 (s,2H, \u003cem\u003eN\u003c/em\u003e-CH\u003csub\u003e2\u003c/sub\u003e), 2.43\u0026ndash;2.94 (m, 4H, \u003cem\u003eN\u003c/em\u003e-(CH\u003csub\u003e2\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003e), 3.73 (br m, 9H, 3\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 3.84 (br m, 6H, 2\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 3.93 (s, 3H, OCH\u003csub\u003e3\u003c/sub\u003e) 4.90 (m, 1H, 2-CH), 6.30 (s,2H, CH-aromatic) 2H, 7.05(s, 2H,CH-aromatic); \u003csup\u003e13\u003c/sup\u003eC NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 125 MHz): δ 23.87, 30.32, 38.68, 46.47, 54.75, 56.01, 56.19, 60.90, 61.26, 105.77, 106.09, 114.07, 125.03, 133.12, 135.13, 142.35, 152.88, 202.60; ESI-TOF (HRMS) (MeOH) for C\u003csub\u003e27\u003c/sub\u003eH\u003csub\u003e37\u003c/sub\u003eNO\u003csub\u003e7\u003c/sub\u003e calcd 488.2648 for [M\u0026thinsp;+\u0026thinsp;H ]\u003csup\u003e+\u003c/sup\u003e, found 488.2650 .\u003c/p\u003e \u003cp\u003e \u003cb\u003e3-Morpholino-2-(3, 4, 5-trimethoxybenzyl)-1-(3, 4, 5-trimethoxyphenyl) propan-1-one\u003c/b\u003e \u003cem\u003e(\u003c/em\u003e\u003cb\u003e6f\u003c/b\u003e\u003cem\u003e)\u003c/em\u003e Yield: 51%; M.p: 105\u0026ndash;108˚C; \u003csup\u003e1\u003c/sup\u003eH NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 500 MHz): δ 2.43\u0026ndash;2.44 (m, 4H, \u003cem\u003eN\u003c/em\u003e (CH\u003csub\u003e2\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003e), 2.85\u0026ndash;2.58(m, 1H, CH), 2.80\u0026ndash;2.95( bm, 2H, \u003cem\u003eN\u003c/em\u003e-CH\u003csub\u003e2\u003c/sub\u003e), 3.55\u0026ndash;3.58 (bs, 4H, -CH\u003csub\u003e2\u003c/sub\u003e-\u003cem\u003eO\u003c/em\u003e-CH\u003csub\u003e2\u003c/sub\u003e), 3.70 (br m, 6H, 2\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 3.73 (br m, 6H, 2\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 3.79 (s, 3H,OCH\u003csub\u003e3\u003c/sub\u003e), 3.89 (s,3H OCH\u003csub\u003e3\u003c/sub\u003e), 6.32 (s, 2H\u0026times;CH), 6.98 (s,1H, CH); \u003csup\u003e13\u003c/sup\u003eC NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 125 MHz): δ 38.17, 46.57, 53.97, 55.77, 56.30, 60.60, 61.52, 66.55, 105.33, 105.88, 133.42, 135.21, 136.58, 142.43, 152.49, 152.89, 153.80, 202.61; ESI-TOF (HRMS) (MeOH) for C\u003csub\u003e26\u003c/sub\u003eH\u003csub\u003e35\u003c/sub\u003eNO\u003csub\u003e8\u003c/sub\u003e calcd 488.2284 for [M-H]\u003csup\u003e-\u003c/sup\u003e, found 488.2296 .\u003c/p\u003e \u003cp\u003e \u003cb\u003e3-(4-Methylpiperazin-1-yl)-2-(3,4,5-trimethoxybenzyl)-1-(3,4,5-trimethoxyphenyl)-propan-1- one (6g)\u003c/b\u003e Yield: 48%; M.p: viscous; \u003csup\u003e1\u003c/sup\u003eH NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 500 MHz): δ 2.22 (s, 3H, \u003cem\u003eN\u003c/em\u003e-CH\u003csub\u003e3\u003c/sub\u003e), 2.46\u0026ndash;2.96 (m, 10H, \u003cem\u003eN\u003c/em\u003e-(CH\u003csub\u003e2\u003c/sub\u003e)\u003csub\u003e5\u003c/sub\u003e), 3.73 (s, 9H, 3\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 3.76 (s, 9H, 3\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 3.80 (d,2H, Ph-CH\u003csub\u003e2\u003c/sub\u003e), 3.88 (N-CH\u003csub\u003e2\u003c/sub\u003e), 6.30 (2\u0026times;CH), 6.96 (2\u0026times;CH); \u003csup\u003e13\u003c/sup\u003eC NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 125 MHz): δ 38.20, 45.49, 46.86, 53.40, 55.05, 56.04, 56.12, 56.21, 60.80, 60.87, 60.93, 61.05, 105.44, 105.54, 105.78, 106.02 133.49, 135.39, 136.36, 136.47, 137.15, 153.07, 153.25, 202.82; ESI-TOF (HRMS) (MeOH) for C\u003csub\u003e27\u003c/sub\u003eH\u003csub\u003e38\u003c/sub\u003eN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e7\u003c/sub\u003e calcd 503.2757 for [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e, found 503.2751 .\u003c/p\u003e \u003cp\u003e \u003cb\u003e3-(Octylamino)-2-(3, 4, 5-trimethoxybenzyl)-1-(3, 4, 5-trimethoxyphenyl)-propan-1-one (6h)\u003c/b\u003e Yield: 38%; M.p: viscous; \u003csup\u003e1\u003c/sup\u003eH NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 500 MHz): δ 0.7 (s, 3H, CH\u003csub\u003e3\u003c/sub\u003e), 1.035\u0026ndash;1.28 (bs, 14H, 7\u0026times;CH\u003csub\u003e2\u003c/sub\u003e) 2.69 (m,2H, \u003cem\u003eN\u003c/em\u003eH- CH\u003csub\u003e2\u003c/sub\u003e), 3.37(s,2H, \u003cem\u003eN\u003c/em\u003e-CH\u003csub\u003e2\u003c/sub\u003e), 3.63(br, m, 6H, 2\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 3.72 (br, m, 6H, 2\u0026times;OCH\u003csub\u003e3\u003c/sub\u003e), 6.22 (s, CH- aromatic), 6.96 (s, CH-aromatic); \u003csup\u003e13\u003c/sup\u003eC NMR (CDCl\u003csub\u003e3\u003c/sub\u003e, 125 MHz): δ 14.98, 20.69, 26.16, 27.33, 27.33, 35.03, 35.47, 40.01, 48.86, 48.97, 90.90, 102.20, 111.79, 113.21, 120.83, 121.61, 122.38, 124.67, 130.71, 135.19, 140.63, 141.19, 190.09; ESI-TOF (HRMS) (MeOH) for C\u003csub\u003e30\u003c/sub\u003eH\u003csub\u003e45\u003c/sub\u003eNO\u003csub\u003e7\u003c/sub\u003e calcd 532.3274 for [M\u0026thinsp;+\u0026thinsp;H ]\u003csup\u003e+\u003c/sup\u003e, found 532.3257\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e5.2. Biological evaluation\u003c/h2\u003e \u003cp\u003eThe detailed biological protocols are given in Supplementary information [Online Resource].\u003c/p\u003e \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e \u003ch2\u003e5.2.1. Antiproliferative activity by SRB assay\u003c/h2\u003e \u003cp\u003eSulphorhodamine B assay was performed as per reported method [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Doxorubicin and podophyllotoxin were used as positive controls.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section3\"\u003e \u003ch2\u003e5.2.2. Tubulin polymerisation assay\u003c/h2\u003e \u003cp\u003eTubulin kinetics experiment was carried out using Cytoskeleton \u0026lsquo;assay kit\u0026rsquo; (Inc. Denver, USA) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The standard antimitotic agents, podophyllotoxin (as destabilizer) and paclitaxel (as stabilizer) were used as positive controls.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section3\"\u003e \u003ch2\u003e5.2.3. Anti-bacterial activity\u003c/h2\u003e \u003cp\u003eIt was done by broth dilution method and disk diffusion assay. Penicillin-G was used as positive control.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section3\"\u003e \u003ch2\u003e5.2.4. Antimicrobial Activity\u003c/h2\u003e \u003cp\u003eAgar disc diffusion assay and broth dilution method were used as antimicrobial assays. Penicillin\u0026ndash;G was used as standard drug.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section3\"\u003e \u003ch2\u003e5.2.5. Media and Bacterial strain culture preparation\u003c/h2\u003e \u003cp\u003eThe Mueller Hinton Agar media for anti-TB activity was used.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section3\"\u003e \u003ch2\u003e5.2.6. Disc diffusion Assay\u003c/h2\u003e \u003cp\u003eThe agar diffusion test or disc diffusion antibiotic sensitivity testing was done as per reported method [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section3\"\u003e \u003ch2\u003e5.2.7. Broth dilution method\u003c/h2\u003e \u003cp\u003eMinimum inhibitory concentrations (MIC) and Minimum bactericidal concentration (MBC) were assessed as per reported method [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003e5.2.8. Time kill assay\u003c/h2\u003e \u003cp\u003eIt was performed as per reported protocol [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section3\"\u003e \u003ch2\u003e5.2.9. Checkerboard Method\u003c/h2\u003e \u003cp\u003eDrug interaction was analyzed in 96-well microtiter plates using checkerboard micro-dilution method [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003e5.2.10. Safety studies by acute oral toxicity\u003c/h2\u003e \u003cp\u003eAcute oral toxicity of the compound was performed in Swiss albino mice in accordance with the organization for Economic Co-operation and development (OECD) test guideline No. 423(1987) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Study and number of animals used were approved \u003cem\u003evia\u003c/em\u003e CIMAP/2016\u0026ndash;2019/01 dated 09/02/2017 by Institutional Animal Ethics Committee of CSIR- CIMAP, Lucknow, India.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eConflict of Interest\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest, financial or otherwise.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSUPPLEMENTARY INFORMATION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDetailed biological protocols and Spectra of final compounds (\u003cstrong\u003e6a\u003c/strong\u003e-\u003cstrong\u003e6h\u003c/strong\u003e) are included as\u0026nbsp;Online Resource.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eAll authors are thankful to Director, CSIR-CIMAP, Lucknow, India, for rendering essential research facilities and support. SS acknowledged the financial support from Department of Sciences \u0026amp; Technology (DST), India as RGNF (JRF/SRF). \u0026nbsp;BT acknowledges DBT for her Junior Research Fellowship.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWHO. Antimicrobial resistance. Keyfacts. 21 Nov. 2023. https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance . Accessed 21March 2024.\u003c/li\u003e\n\u003cli\u003ePrivalsky TM, Soohoo AM, Wang J, Walsh CT, Wright GD, Gordon EM, Gray NS, Khosla C. Prospects for Antibacterial Discovery and Development. J Am Chem Soc. 2021; 143: 21127\u0026ndash;42.\u003c/li\u003e\n\u003cli\u003eWHO. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. 27 Feb 2017. https://www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed . Accessed 12 March 2024.\u003c/li\u003e\n\u003cli\u003eMurray CW, Rees DC. The rise of fragment-based drug discovery. Nat Chem. 2009; 1: 187-92.\u003c/li\u003e\n\u003cli\u003eGiordanetto F, Jin C, Willmore L, Feher M, Shaw DE (2019). Fragment Hits: What do They Look Like and How do They Bind? J Med Chem. 2019; 62: 3381\u0026minus;94.\u003c/li\u003e\n\u003cli\u003eNegi AS, Gautam Y, Alam S, Chanda D, Luqman S, Sarkar J, Khan F, Konwar R. Natural antitubulin agents: Importance of 3, 4, 5-trimethoxyphenyl fragment. Bioorg Med Chem. 2015; 23: 373-89.\u003c/li\u003e\n\u003cli\u003eUstinov NB, Korshunoval AV, Gudimchuk NB. Protein Complex NDC80: Properties, Functions, and Possible Role in Pathophysiology of Cell Division. Biochem (Moscow). 2020; 85 (4): 448-62.\u003c/li\u003e\n\u003cli\u003eVos T, Allen C, Arora M, Barber RM, Bhutta ZA, \u003cem\u003eet al.\u003c/em\u003e Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990\u0026ndash;2015: a systematic analysis for the Global Burden of Disease Study 2015. The Lancet. 2016; 388(10053): 1545-1602.\u003c/li\u003e\n\u003cli\u003eZhang J, Gu Y, Chen B. Mechanisms of drug resistance in acute myeloid leukemia. Onco Targ Ther. 2019; 12: 1937-45.\u003c/li\u003e\n\u003cli\u003eHsu KS, Toda T. Ndc80 internal loop interacts with Dis1/TOG to ensure proper kinetochore-spindle attachment in fission yeast. Curr Biol. 2011; 21: 214-20.\u003c/li\u003e\n\u003cli\u003eField MC. The kinetochore and the origin of eukaryotic. chromosome segregation. Proc Natl Acad Sci. 2019; 116: 12596-8.\u003c/li\u003e\n\u003cli\u003eAnad\u0026oacute;n A, Mart\u0026iacute;nez-Larra\u0026ntilde;aga MR, Ares I, Mart\u0026iacute;nez MA. Book: Chapter 38: Biomarkers of drug toxicity and safety evaluation. In: \u003cem\u003eBiomarkers in Toxicology\u003c/em\u003e. 2nd ed. Academic Press: 2019\u003cem\u003e \u003c/em\u003e, pp655-691.\u003c/li\u003e\n\u003cli\u003eHoffmann E, Fouretier A, Vergne C, Bertram D. Pharmacovigilance regulatory requirements in Latin America. Pharm Med. 2012; 26(3): 153-64.\u003c/li\u003e\n\u003cli\u003eWalum E. Acute oral toxicity. Env Health Persp. 1998; 106: 497-503.\u003c/li\u003e\n\u003cli\u003eOrellana EA, Kasinski AL. Sulforhodamine B (SRB) assay in cell culture to investigate cell proliferation. Bio-Prot. 2006; 6(21): e1984.\u003c/li\u003e\n\u003cli\u003eShelanski ML, Gaskin F, Cantor, C.R. Microtubule assembly in the absence of added nucleotides. Proc Natl Acad Sci. 1973; 70(3): 765-68.\u003c/li\u003e\n\u003cli\u003ePadalia RC, Verma RS, Chauhan A, Goswami P, Singh VR, et al. p-Menthenols chemotype of \u003cem\u003eCymbopogon distans\u003c/em\u003e from India: composition, antibacterial and antifungal activity of the essential oil against pathogens. J Essential Oil Res. 2018, 30, 40-6.\u003c/li\u003e\n\u003cli\u003eNyaa LBT, Tapondjou LA, Barboni L, Tamokou JDD, Kuiate JR, Tane P, Park HJ. NMR assignment and antimicrobial/antioxidant activities of 1\u0026beta;- hydroxyeuscaphic acid from the seeds of Butyrospermum parkii. Nat Prod Sci. 2009; 15: 76-82.\u003c/li\u003e\n\u003cli\u003eSeptama AW, Panichayupakaranant P. Synergistic effect of artocarpin on antibacterial activity of some antibiotics against methicillin-resistant \u003cem\u003eStaphylococcus aureus\u003c/em\u003e, \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e, and \u003cem\u003eEscherichia coli\u003c/em\u003e. Pharm Biol. 2016; 54: 686-91.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Scheme 1","content":"\u003cp\u003eScheme 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"medicinal-chemistry-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mcre","sideBox":"Learn more about [Medicinal Chemistry Research](https://www.springer.com/journal/44)","snPcode":"44","submissionUrl":"https://submission.nature.com/new-submission/44/3","title":"Medicinal Chemistry Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Aza Michael adducts, antibacterial, anticancer, acute oral toxicity","lastPublishedDoi":"10.21203/rs.3.rs-4140948/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4140948/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eDevelopment of resistance against most of the clinical antibiotics is a menace to their use in future. Present study aimed at design and synthesis of some microtubule dynamics modulators as antibacterial and anticancer agents. Eight diverse Aza Michael adducts were prepared at diarylpropenone core with desired motifs in 38\u0026ndash;57% yields. Compound \u003cb\u003e6b\u003c/b\u003e showed significant antiproliferative activity against leukemic cell line K562. While compound \u003cb\u003e6h\u003c/b\u003e exhibited potent antibacterial activity against methicillin resistant \u003cem\u003eStaphylococcus aureus\u003c/em\u003e and methicillin resistant \u003cem\u003eS. epidermidis\u003c/em\u003e. In the checker board experiment \u003cb\u003e6h\u003c/b\u003e showed synergistic effect in combination of penicillin and also with norfloxacin, up to four-fold reduction in quantity of the antibiotic drug. Its effect was bacteriostatic as evident from time kill assay. The 3,4,5-trimethoxyphenyl motif induces antitubulin effect in Aza Michael adduct \u003cb\u003e6b\u003c/b\u003e for anticancer activity. Both the leads can further be optimized for better efficacy in future.\u003c/p\u003e","manuscriptTitle":"Gallic acid derived aza Michael adducts at diarylpropanone framework exhibit antiproliferative and synergistic antibacterial activities","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-12 08:58:41","doi":"10.21203/rs.3.rs-4140948/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revision","date":"2024-05-03T05:41:27+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-04-09T11:44:20+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-09T08:20:24+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-25T02:25:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"Medicinal Chemistry Research","date":"2024-03-21T01:49:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"medicinal-chemistry-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mcre","sideBox":"Learn more about [Medicinal Chemistry Research](https://www.springer.com/journal/44)","snPcode":"44","submissionUrl":"https://submission.nature.com/new-submission/44/3","title":"Medicinal Chemistry Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3241fbcd-9ca0-484d-9362-31615b6468ae","owner":[],"postedDate":"April 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-06-03T15:04:21+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-12 08:58:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4140948","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4140948","identity":"rs-4140948","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}