Multicomponent Reaction for Synthesis, Molecular Docking and Anti-inflammatory Evaluation of Novel Indole-Thiazole Hybrid Derivatives

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Abdelaziz, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4659163/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Aug, 2024 Read the published version in Molecular Diversity → Version 1 posted 12 You are reading this latest preprint version Abstract In this article, novel thiazol-indolin-2-one derivatives 4a-f have been synthesized via treatment of thiosemicarbazide ( 1 ) with some isatin derivative 2a-f and N -(4-(2-bromoacetyl)phenyl)-4-tolyl-sulfonamide ( 3) under reflux in ethanol in the presence of triethyl amine (TEA). The structures of new products were elucidated by elemental and spectral analyses. Moreover, all compounds were investigated for their in vivo anti-inflammatory activity using celecoxib as a reference drug. The target comound 4b was the most active anti-inflammatory candidate and exhibited higher edema inhibition (EI = 38.50 %) than that recorded by celecoxib (EI = 34.58%) after 3h. Furthermore, the most active compounds 4b and 4f were subjected to molecular docking study inside COX-2 enzyme to show their binding interactions . Both compounds 4b and 2f showed good fitting into COX-2 binding site with docking energy scores -11.45 kcal/mol and -10.48kcal/mol,respectively which indicated that compound 4b revealed the most promising and effective anti-inflammatory potential. Indole derivatives Thiazole Multicomponent reaction Anti-inflammatory activity Histopathological examination Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Inflammation is a biological reaction to a distrubtion in tissue homeostasis and body defence chemicals in which cells penetrate the affected tissue causing increasing blood flow, vascular permeability and vasodilatation [ 1 , 2 ]. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly used medications for relieving pain and inflammation by inhibiting Cyclooxygenase (COX) enzymes [ 3 , 4 ]. The constitutive COX-1 performs numerous physiological activities as protecting gastric mucosa, vascular homeostasis and platelet aggregation, while the other isoform, the inducible COX-2 is concerned with prostaglandins that promote inflammation and modulate pain [ 5 – 7 ]. The use of traditional NSAIDs as aspirin, indomethacin and phenazone causes gastrointestinal side effects due to the inhibition of both COX isoforms [ 8 – 10 ]. Selective COX-2 inhibitor medications as celecoxib, valdecoxib and rofecoxib have been prepared to avoid the side effects produced by traditional NSAIDs [ 11 , 12 ]. Unfortunately, rofecoxib and valdecoxib were taken off the market due to their cardiovascular side effects including myocardial infarction and the occurrence of high blood pressure [ 13 – 15 ]. So, there is a great demand for selective COX-2 inhibitors with diminished side effects. Indole is one of the most widely used scaffolds in a broad range of anti-inflammatory agents [ 16 – 18 ]. Many research investigations have focused on indole-based NSAIDs such as indomethacin ( I ) to enhance their COX-2 selectivity and decrease the ulcerogenic adverse effects that linked to their strong COX-1 selectivity and drug , s acidic properties [ 19 – 21 ]. Knaus and co-workers synthesized a new set of indole derivatives substituted at N-1 and C-3 [ 22 ]. From the prepared indole derivatives, compound II was the most selective (SI > 312) and potent (COX-2 IC 50 = 0.32 µM) COX-2 inhibitor. In 2021, new indole derivatives having thiosemicarbazone moiety were prepared and screened for their anti-inflammatory effect using carrageenan-induced paw edema assay [ 23 ]. Compound III recorded superior COX-2 selectivity (SI = 23.06) than displayed by celecoxib (SI = 11.88). Thiazole is a five membered heterocyclic ring with many pharmacological utility as anticancer [ 24 , 25 ], antioxidant [ 26 , 27 ], antimicrobial [ 28 , 29 ], antidiabetic [ 30 ], anthelmintic [ 31 ] and anti-inflammatory [ 32 – 34 ]. For example, the thiazole derivative IV significantly inhibited edema (60.82%) in the carrageenan-induced edema compared with indomethacin (53.21%) [ 35 ]. Also, thiazole derivative V recorded comparable edema inhibition (EI = 87%) to that registered by indomethacin (EI = 91%) after 4 hours [ 36 ]. Considering the aforesaid data and as an extension and development of our previous studies [ 37 – 45 ], we present the design and construction of novel indole-thiazole hybrids and biologically screened for their anti-inflammatory effect. The aim of this work is to get new compounds with selective COX-2 inhibition, favorable anti-inflammatory potential and minimized gastric side effects. This aim has been achieved by hybridization the privileged indole ring with the thiazole nucleus in one chemical entity (Fig. 1 ). Result and Discussion 2.1. Chemistry In this work, treatment of thiosemicarbazide ( 1 ) with isatin derivatives 2a-f and 4-(bromoacetyl)- N -(4-methylphenyl)benzenesulfonamide ( 3) via three-component reaction under reflux in ethanol / tiethyl amine (TEA). Firstly, compound 1 was allowed to react with some isatin derivatives 2a-f namely; isatin ( 2a ), 5-chloro-isatin ( 2b ), 5-nitro-isatin ( 2c ), N -methyl-isatin ( 2d ), 5-chloro- N -methyl-isatin ( 2e ), 5-nitro- N -methyl-isatin ( 2f ), then compound 3 was added until the reaction completed (TLC), to obtain thiazol-indolin-2-one derivatives 4a-f ( Scheme 1 ). Scheme 1. Synthesis of indole-thiazole hybrid derivatives 4a-f The chemical structure of compounds 4a-f was determined using different elemental and spectroscopic analysis such as 1 H-NMR, 13 CNMR, as well as infrared spectroscopy. Their infrared spectra revealed the existence of new bands in the range 3363 − 3124 cm − 1 corresponding to NH. groups. 1 H NMR spectra showed, as well as the aromatic signals, new singlet signals in the region δ 13.30–9.03 ppm for NH groups. The N-CH 3 proton in compounds 4d-f appeared as a singlet signal in the range δ 3.73–3.84 ppm, respectively. Moreover, their 13 C NMR spectra matched the accurate chemical structure which showed the carbonyl groups in the range 190.03 -160.85 ppm and the N-CH 3 groups in compounds 4d - f appeared in the region δ 46.40-35.15 ppm, and the CH 3 groups at range δ 21.42–21.01 ppm, respectively. Furthermore, elemental analyses of thiazoles 4a - f provided the correct structure of the new products (cf. experimental). 2.2 Anti-inflammatory activity The anti-inflammaory potential of indol-3-ylidenehydrazino-1,3-thiazole derivatives 4a-f was estimated applying the carrageenan-induced rat paw edema method using celecoxib as a standard. Each target compound was taken immediately before inflammation induction by carrageenan injection. The anti-inflammatory potential was recoded according to paw volume changes after 1, 3 and 5 hours as displayed in Table 1 . The obtained outcomes disclosed that 4-{2-[2-(5-chloro-2-oxo-1,2-dihydro-3 H -indol-3-ylidene)hydrazino]-1,3-thiazol-4-yl}- N -phenyl-4-tolylsulfonamide ( 4b ) was the most active candidate with edema inhibition percent equal to 12.72–45.63%. Furthermore, this compound 4b showed higher edema inhibition (EI = 38.50%) than that exhibited by celecoxib (EI = 34.58%) after 3h. Moreover, compound 4f revealed comparable edema inhibition (3h; EI = 31.94%, 5h; EI = 41.84%) to that recorded by celecoxib (3h; EI = 34.58%, 5h; EI = 49.30%). In addition, within 1 H -indole derivatives 4a-c , the 5-chloroindole derivative ( 4b ) was the most active anti-inflammatory candidate (3h; EI = 38.50%, 5h; EI = 45.63%) followed by 5-nitro analogue ( 4c ) (3h; EI = 23.33%, 5h; EI = 39.19%) while compound 4a with no substitution at positions 1 and 5 of indole moiety exhibited the least anti-inflammatory activity (3h; EI = 18.05%, 5h; EI = 12.76%). In case of N -methylindole derivatives ( 4d-f ), the 5-nitroindole candidate ( 4f ) showed the highest edema inhibition percent (3h; EI = 31.94%, 5h; EI = 41.84%) followed by compound 4d (3h; EI = 15.41%, 5h; EI = 23.76%) then the 5-chloro analogue ( 4e ) (3h; EI = 5.69%, 5h; EI = 8.72%). From the recorded data in (Table 1 and Fig. 2 ), it is clear that compound 4b has the most promising anti-inflammatory potential in comparison with celecoxib. Table 1 Anti-inflammatory potential of test compounds (4a-f) using celecoxib reference drug. Diameter inflammation (mm) % Edema inhibition Compound 1h 3h 5h 1h 3h 5h Control 3.90 ± 0.14 3.90 ± 0.14 3.90 ± 0.14 -------- -------- -------- Carrageenan 5.76 ± 0.08 7.20 ± 0.08 7.91 ± 0.15 -------- -------- -------- Celecoxib 4.09 ± 0.06 4.71 ± 0.18 4.01 ± 0.14 28.99 34.58 49.30 4a 5.70 ± 0.14 5.90 ± 0.12 6.90 ± 0.15 01.04 18.05 12.76 4b 4.90 ± 0.51 4.46 ± 0.23 4.30 ± 0.33 12.72 38.50 45.63 4c 5.53 ± 0.08 5.52 ± 0.09 4.81 ± 0.23 03.99 23.33 39.19 4d 5.60 ± 0.96 6.09 ± 0.22 6.03 ± 0.59 02.77 15.41 23.76 4e 5.74 ± 0.23 6.79 ± 0.19 7.22 ± 0.23 0.34 5.69 8.72 4f 5.36 ± 0.30 4.90 ± 0.20 4.60 ± 0.06 6.94 31.94 41.84 2.3. Histological investigation The impact of compound 4b on paw tissue after carrageenan injection, comparing the results to those observed with indomethacin. It has found that is compound 4b has the most effective of the tested products. As shown in Figure (3), the paw tissues of control rats (2, A) are not inflamed. The carrageenan model demonstrated neutrophil migration in addition to acute inflammation (black arrow) and hemorrhagic edema (black star) (2, B). Nevertheless, the rats given Celecoxib showed a notable decrease in inflammation (2, C). Figures (2, D) demonstrated the impact of test chemical 4b on paw tissue inflammation, demonstrating a notable reduction in inflammatory cells and edema. 3. Molecular docking study. To gain insights into the fundamental mechanism of action of newly prepared indol-3-ylidenehydrazino-1,3-thiazole derivatives, molecular docking of the most active candidates ( 4b and 4f ) was conducted inside COX-2 active region. The results of docking including docking score (Kcal/mol), types of interactions and the binded amino acids are listed in Table 2 and Figs. 4 & 5 . Compound 4b revealed good binding within COX-2 with binding energy score = -11.45 kcal/mol. Conventional hydrogen bonds with ARG376, TRP139, ASP229 and GLY235 amino acids were detected (Fig. 4 ). In addition, this compound 4b displayed other Pi-Cation interactions with LYS333, Pi-Alkyl binding with LEU145, PRO538; Amide-Pi Stacked with LEU224 and Van der Waals interactions with SER143 and ASN375 (Fig. 4 ). Furthermore, compound 4f exhibited three hydrogen bonding interactions qith ARG44, CYS41 and GLY135 amino acids with binding energy score equal to -10.48 kcal/mol. also, other binding interactions were registered as Pi-Alkyl binding with LYS468, PRO153 and ALA156; Amide-Pi binding with VAL155 and Van der Waals interaction with ASN34, ALA156 and ARG469 (Fig. 5 ). Table 2 Outcomes of docking study for target candidates 4b and 4f inside COX-2 enzyme. Compound NO. Docking score Kcal/mol Number of bonds Type of interactions Amino acids Function group 4b -11.45 11 H-bond H-bond H-bond H-bond Amide-Pi Pi-Cation Pi-Cation Pi-Alkyl Pi-Alkyl Van der Waal Van der Waal ARG376 TRP139 ASP229 GLY235 LEU224 LYS333 LYS333 LEU145 PRO538 SER143 ASN375 SO 2 =N NH Indole NH Thiazole Indole Indole Phenyl Methyl =N Phenyl 2f -10.48 13 H-bond H-bond H-bond Pi-Alkyl Pi-Alkyl Pi-Alkyl Pi-Alkyl Pi-Alkyl Pi-Alky Amide-Pi Van der Waal Van der Waal Van der Waal CYS41 ARG44 GLY135 LYS468 LYS468 CYS36 PRO153 ALA156 ALA156 VAL155 ARG469 ALA156 ASN34 NH SO 2 NO 2 Phenyl Methyl Thiazole Thiazole Indole Indole Indole SO 2 NO 2 Indole EXPERIMENTAL Chemistry All melting points were recorded on Melt-Temp II melting point apparatus. IR spectra were measured as KBr pellets on a Shimadzu DR-8001 spectrometer. 1 H NMR and 13 C NMR spectra were recorded on a Bruker at 400 MHz and 100 MHz using TMS as an internal reference, DMSO- d 6 as solvent. The elemental analyses were carried out on a Perkin-Elmer 240C Micro analyzer. All compounds were checked for their purity on TLC plates. General Procedure for the Synthesis of thiazole derivatives 4a-f: An equimolar mixture of thiosemicarbazide (1) (0.01 mol, 0.91 g) with the appropriate isatin derivative ( 2a-f ) (0.01 mol) was allowed to reflux in ethanol/ TEA until the reaction (TLC) (10 min). Then added 4-(bromoacetyl)-N-(4-methylphenyl)benzenesulfonamide (3) to the reaction mixture, and continued refluxing for 20–30 min., until the reaction completed (TLC) to afford the corresponding thiazole derivatives ( 4a-f ). The reaction mixture was allowed to cool to room temperature and the solid precipitate was filtrated, and recrystallized from ethanol. 4 -{2-[2-(2-Oxo-1,2-dihydro-1H-indol-3-ylidene)hydrazino]-1,3-thiazol-4-yl}- N -phenyl-4-tolyl sulfonamide (4a) Mp 235°C; IR cm − 1 : 3363, 3178, 3120 (3NH), 3064 (C–H arom .), 1682 (C = O), 1 H NMR δ 13.30 (br,1H, NH), 11.20 ( s, 1H, NH), 10.29 ( s, 1H, NH), 7.76–6.85 (m, 13H, CH arom .), 2.33 (s, 3H, -CH 3 ); 13 C NMR; 166.53 (C = O), 150.95, 143.82, 141.71, 137.93, 137.07, 132.53, 130.95, 130.32, 130.20, 130.14, 127.19, 125.03, 122.90, 120.46, 120.28, 120.19, 111.54, 106.41, 21.37; Anal. Calcd. For C 24 H 19 N 5 O 3 S 2 (489.56) C (58.88%), H (3.91%), N (14.31%), S (13.10%); Found C (58.95%), H (3.98%), N (14.26%), S (13.16%). 4 -{2-[2-(5-Chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-1,3-thiazol-4-yl}- N -phenyl- tolylsulfonamide (4b) Mp 241°C; IR cm − 1 : 3308, 3124 (3NH), 3061 (CH arom.), 1671 (C = O), 1 H NMR δ 13.24 (s,1H, NH), 11.26 ( s, 1H, NH), 10.29 ( s, 1H, NH), 8.39–6.81 (m, 12H, CH arom .), 2.33 (s, 3H, -CH 3 ); 13 C NMR δ (ppm): 163.39 (C = O), 150.99, 143.97, 143.82, 141.03, 140.23, 138.72, 137.94, 137.06, 131.30, 130.21, 129.92, 127.19, 127.08, 127.03, 125.87, 121.88, 120.44, 120.11, 119.41, 21.37; Anal. Calcd. For C 24 H 18 ClN 5 O 3 S 2 (524.01) C (55.01%), H (3.46%), N (13.36%), S (12.24%); Found; C (54.98%), H (3.39%), N (13.29%), S (12.18%). 4 -{2-[2-(5-Nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-1,3-thiazol-4-yl}-N-phenyl- tolysulfonamide (4c) Mp 228°C; IR cm − 1 : 3247 − 3154 (3NH), 3085 (C–H arom .), 1654 (C = O), 1 H NMR δ 10.28 (s,1H, NH), 9.14 ( s, 1H, NH), 8.64–7.11 (m, 13H, CH arom + NH.), 2.32 (s, 3H, CH 3 ), 13 C NMR δ (ppm): 164.76 (C = O), 147.14, 144.84, 142.67, 140.28, 139.36, 138.94, 137.15, 136.03, 135.97, 135.80, 132.56, 128.37, 124.21, 123.98, 120.38, 117.46, 116.09, 112.45, 21.42; Anal. Calcd. For C 24 H 18 N 6 O 5 S 2 (534.56); C (53.92%), H (3.39%), N (15.72%), S (12.00%) Found: C (53.86%), H (3.46%), N (15.65%), S (12.06%) (4-(2-(2-(1-methyl-2-oxoindolin-3-ylidene)hydrazinyl)thiazol-4-yl)-N-(p-tolyl) benzene sulfonamide (4d) Mp 268°C; IR cm − 1 : 3217, 3161 (2NH), 3078 (C–H arom .), 1658 (C = O), 1 H NMR δ 13.16 (br,1H, NH), 10.45 (s, 1H, NH), 7.75–7.02 (m, 13H, CH arom .), 3.73 (s, 3H, N-CH 3 ), 2.30 (s, 3H, CH 3 ); 13 C NMR δ (ppm): 160.85 (C = O), 143.84, 141.56, 138.94, 137.04, 135.57, 133.94, 132.06, 131.03, 128.05, 127.20, 123.33, 122.46, 121.55, 121.47, 119.59, 119.37, 115.67, 110.28, 45.66, 21.38; Anal. Calcd. For C 25 H 21 N 5 O 3 S 2 C (59.62%), H (4.20%), N (13.91%), S (12.73%) Found; C (59.69%), H (4.16%), N (13.84%), S (12.85%). 4 -{2-[2-(5-Chloro-2-oxo-1,2-dihydro-N-methyl-3H-indol-3-ylidene)hydrazino]-1,3-thiazol-4-yl}-N-phenyl-4 tolylsulfonamide (4e) Mp 216°C; IR cm − 1 : 3190, 3167 (2NH), 3047 (C–H arom .), 1661 (C = O), 1 H NMR δ 12.27 (s,1H, NH), 10.33 ( s, 1H, NH), 7.79–6.99 (m, 12H, CH arom .), 3.75 (s, 3H, N-CH 3 ), 2.33 (s, 3H, CH 3 ), 13 C NMR δ (ppm): 190.03 (C = O), 143.92, 140.47, 139.93, 137.08, 136.42, 134.57, 132.76, 131.02, 130.81, 127.20, 127.05, 126.14, 124.43, 123.03, 120.43, 120.16, 119.59, 46.40, 21.35; Anal. Calcd. For C 25 H 20 ClN 5 O 3 S 2 (538.04) C (55.81%), H (3.75%), N (13.02%), S (11.92%) Found C (55.86%), H (3.83%), N (12.97%), S (11.86%) 4 -{2-[2-(5-Nitro-2-oxo- N-methyl − 3-ylidene)hydrazino]-1,3-thiazol-4-yl}-N-phenyl-4-tolyl sulfonamide (4f) Mp 290°C; IR cm − 1 : 3251, 3126 (2NH), 3085 (C–H arom .), 1654 (C = O), 1 H NMR δ 9.18 (s,1H, NH), 9.03 (s, 1H, NH), 8.64–7.11 (m, 12H, CH arom .), 3.84 (s, 3H, N-CH 3 ), 2.34 (s, 3H, CH 3 ), 13 C NMR δ (ppm): 179.46 (C = O), 147.79, 143.57, 142.90, 140.54, 139.65, 138.82, 134.96, 130.24, 129.31, 128.60, 127.22, 124.42, 121.84, 120.63, 117.36, 116.61, 110.50, 109.25, 35.13, 21.01 ; Anal. Calcd. For C 25 H 20 N 6 O 5 S 2 (548.59); C (54.73%), H (3.67%), N (15.32%), S (11.69%) Found: C (54.69%), H (3.73%), N (15.26%), S (11.78%). Anti-inflammatory activity In vivo estimation the anti-inflammatory effects of test compounds on rats via carrageenan-induced paw edema model. For the in vivo assessment of the test compounds' anti-inflammatory activity, male Wister rats weighing 180 ± 10 grams each were employed, with celecoxib serving as the reference drug. All animals had to acclimate to the criteria set by the Institutional Animals Ethics Committee (IAEC) of the Faculty of Medicine at Sohag University for at least one week prior to the investigations (permit No; ). For this in vivo evaluation, 40 adult male Westar rats (n = 4) were randomly assigned. The selected agents were suspended in 1% newly prepared carboxy methyl cellulose (CMC) prior to being administered orally by gavage. Following a sub plantar injection of 100 µL of freshly prepared carrageenan gel (1% distilled water) into each rat's left hind paw, changes in paw thickness were observed [ 46 ]. Rats were administered test compounds orally via gavage one hour before the injection of carrageenan. Paw thickness was measured one, three, and five hours after the development of inflammation. The test compound's effects were quantified as a percentage of edema inhibition. The anti-inflammatory potential is expressed as a percentage suppression of paw edema and quantified [ 47 ]. Histopathological analysis of the tissues in the paws Prior to being embedded in paraffin, the tissues from the paws were stored in a 10% formalin-neutral buffer. Hematoxylin and eosin (H&E) were used to stain the slides after thin sections of 5–6 µm were cut using a microtome. The slides that were made with a light microscope exhibit pathological changes in them. Docking study The crystal structure of COX-2 was downloaded from Protein Data Bank (PDB:1CX2) and the molecular docking was performed following our previously reported work [ 48 ]. Statistical analysis The obtained data were statistically analyzed using GraphPad Prism version 9, and the mean values and standard deviations (mean ± SD) were presented as a result. The significance of mean differences was evaluated using the Tukey-Kramer test and one-way analysis of variance (ANOVA), with p-values of less than 0.05 being considered statistically significant. Conclusion New series of novel indole-thiazole hybrids derivatives 4a-f were synthesized via multi-components of thiosemicarbazide with some isatine derivatives ( 2a-f ) and N -(4-(2-bromoacetyl)phenyl)-4-methylbenzenesulfonamide ( 3 ) under reflux in ethanol. The chemical structures of novel compounds were elucidated by elemental and spectral analyses. All newly compounds have been screened for their anti-inflammatory activity using celecoxib as a reference drug. It has been found that compound 4b (3h; EI = 38.50%, 5h; EI = 45.63%) has the most promising and effective anti-inflammatory potential. Furthermore, Molecular dockingstudyof compounds 4b and 4f displayed that these compoundsfitted into the COX-2binding site with good docking energy scores Declarations Supporting Information Summary The data that support the findings of this article are available in the supplementary material of this article. Conflict of Interest The authors declare no conflict of interest Ethics approval This study has been carried on rats and the authors take personal responsibility for knowing their statutory responsibility under the Animal (Scientific Procedures) Act 1986, under the acceptance of Committee for Scientific Research Ethics (CSRE), code no. (CSRE-23-24)-Sohag University Acknowledgments The authors gratefully acknowledge to Najran University, Faculty of Science and Arts at Sharurah, 68342; Sohag University, Egypt; Minia University, Egypt and Tabuk University Faculty of Science, Tabuk 71491. 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Djukic M, Fesatidou M, Xenikakis I, Geronikaki A, Angelova VT, Savic V, Pasic M, Krilovic B, Djukic D, Gobeljic B. (2018) In vitro antioxidant activity of thiazolidinone derivatives of 1, 3-thiazole and 1, 3, 4-thiadiazole, Chemico-biological interactions 286: 119-131. Muluk M, Patil PS, Kasare SL, Kulkarni RS, Dixit PP, Choudhary P, Haval, KP. (2020) Synthesis and molecular docking studies of novel pyridine-thiazole-hydrazone conjugates as antimicrobial and antioxidant agents, European Chemical Bulletin 9: 184-192. Borcea A-M, IonuÈ I, CriÈan O, Oniga, O. (2021) An overview of the synthesis and antimicrobial, antiprotozoal, and antitumor activity of thiazole and bisthiazole derivatives, Molecules 26: 624. Mishra I, Mishra R, Mujwar S, Chandra P, Sachan, N. (2020) A retrospect on antimicrobial potential of thiazole scaffold, Journal of Heterocyclic Chemistry 57: 2304-2329. Khatik GL, Datusalia AK, Ahsan W, Kaur P, Vyas M, Mittal A, Nayak SK. (2018) A retrospect study on thiazole derivatives as the potential antidiabetic agents in drug discovery and developments, Current drug discovery technologies 15: 163-177. Amnerkar ND, Bhusari KP. (2011) Synthesis of some thiazolyl aminobenzothiazole derivatives as potential antibacterial, antifungal and anthelmintic agents, Journal of enzyme inhibition and medicinal chemistry 26: 22-28. Kamat V, Santosh R, Poojary B, Nayak SP, Kumar BK, Sankaranarayanan M, Faheem Khanapure S, Barretto DA, Vootla SK. (2020) Pyridine-and thiazole-based hydrazides with promising anti-inflammatory and antimicrobial activities along with their in silico studies, ACS omega 5: 25228-25239. Pattan SR, Hullolikar R, Dighe NS, Ingalagi B, Hole M, Gaware V, Chavan P. (2009) Synthesis and evaluation of some new phenyl thiazole derivatives for their anti-inflammatory activities, Journal of Pharmaceutical Sciences and Research 1: 96. Tratrat C, Haroun M, Tsolaki E, Petrou A, Gavalas A, Geronikaki A. (2021) Thiazole-based chalcone derivatives as potential anti-inflammatory agents: Biological evaluation and molecular modelling, Current Topics in Medicinal Chemistry 21: 257-268. Manju S. (2020) Identification and development of thiazole leads as COX-2/5-LOX inhibitors through in-vitro and in-vivo biological evaluation for anti-inflammatory activity, Bioorganic chemistry 100: 103882. Helal M, Salem M, El-Gaby M, (2013) Aljahdali M. Synthesis and biological evaluation of some novel thiazole compounds as potential anti-inflammatory agents, European Journal of Medicinal Chemistry 65: 517-526. Elkanzi NA, Abdelhamid AA, Ali, AM. (2022) Designing and Anti-Inflammatory Effectiveness of Novel Phenytoin Derivatives via One Pot Multicomponent Reaction, ChemistrySelect 7: e202201293. Abdelgawad MA, Bakr RB, El-Gendy AO, Kamel GM, Azouz AA, Bukhari, SNA. (2017) Discovery of a COX-2 selective inhibitor hit with anti-inflammatory activity and gastric ulcer protective effect, Future medicinal chemistry 9: 1899-1912. Abdelgawad MA, Elkanzi NA, Musa A, Ghoneim MM, Ahmad W, Elmowafy M, Ali AM, Abdelazeem AH, Bukhari SN, El-Sherbiny M. (2022) Optimization of pyrazolo [1, 5-a] pyrimidine based compounds with pyridine scaffold: Synthesis, biological evaluation and molecular modeling study, Arabian Journal of Chemistry 15: 104015. Abdelgawad MA, Al-Sanea MM, Musa A, Elmowafy M, El-Damasy AK, Azouz AA, Ghoneim, MM, and Bakr, RB. (2022) Docking study, synthesis, and anti-inflammatory potential of some new pyridopyrimidine-derived compounds, Journal of Inflammation Research: 451-463. Elkanzi NA, AlHazmi AKG, Bakr RB, Gad, MA, Abd ElLateef HM, Ali, AM. (2023) Design and synthesis of pyridine and thiazole derivatives as ecofriendly insecticidal to control olive pests, Chemistry & Biodiversity 20: e202300559. Shaker ME, Goma HA, Alsalahat I, Elkanzi NA, Azouz AA, Abdel-Bakky MS, Ghoneim MM, Hazem SH, El-Mesery ME, Farouk F. (2023), A. Design and construction of novel pyridine-pyrimidine hybrids as selective COX-2 suppressors: anti-inflammatory potential, ulcerogenic profile, molecular modeling and ADME/Tox studies, Journal of Biomolecular Structure and Dynamics: 1-14. Shaker ME, Goma,HA, Alsalahat I, Elkanzi NA, Azouz AA, Abdel-Bakky MS, Ghoneim MM, Hazem SH, El-Mesery ME, Farouk, A. (2023) Design and construction of novel pyridine-pyrimidine hybrids as selective COX-2 suppressors: anti-inflammatory potential, ulcerogenic profile, molecular modeling and ADME/Tox studies, Journal of Biomolecular Structure and Dynamics: 1-14. Khodairy A, Ali AM, ElWassimy M. (2018) Synthesis and reactions of new thiazoles and pyrimidines containing sulfonate moiety, Journal of Heterocyclic Chemistry 55: 964-970. Elkanzi NA, Kadry AM, Ryad RM, Bakr RB, Ali El-Remaily, MAEAA, Ali, AM. Efficient and recoverable bio-organic catalyst cysteine for synthesis, docking study, and antifungal activity of new bio-active 3, 4-dihydropyrimidin-2 (1 H)-ones/thiones under microwave irradiation, ACS omega 7: 22839-22849. Winter C.A, E.A. Risley, G.W. Nuss, (1962) Carrageenin-induced edema in hind paw of the rat as an assay for antiinflammatory drugs. Proceedings of the society for experimental biology and medicine 111(3): p. 544-547 . Arooj, B., (2023) Anti-inflammatory mechanisms of eucalyptol rich Eucalyptus globulus essential oil alone and in combination with flurbiprofen. Inflammopharmacology, 2023. 31(4): p. 1849-1862 . Ghoneim MM, Abdelgawad MA, Elkanzi NA, Parambi, DGT, Alsalahat, I, Farouk, A, and Bakr, RB. (2024) A literature review on pharmacological aspects, docking studies, and synthetic approaches of quinazoline and quinazolinone derivatives, Archiv der Pharmazie: e2400057. Scheme Scheme 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files supplementarymaterial.docx GraphicalAbstract.png Scheme1.png Scheme 1. Synthesis of indole-thiazole hybrid derivatives 4a-f Cite Share Download PDF Status: Published Journal Publication published 15 Aug, 2024 Read the published version in Molecular Diversity → Version 1 posted Editorial decision: Revision requested 12 Jul, 2024 Reviews received at journal 12 Jul, 2024 Reviews received at journal 11 Jul, 2024 Reviews received at journal 11 Jul, 2024 Reviewers agreed at journal 03 Jul, 2024 Reviewers agreed at journal 02 Jul, 2024 Reviewers agreed at journal 30 Jun, 2024 Reviewers agreed at journal 30 Jun, 2024 Reviewers invited by journal 30 Jun, 2024 Editor assigned by journal 29 Jun, 2024 Submission checks completed at journal 29 Jun, 2024 First submitted to journal 29 Jun, 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4659163","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":326033576,"identity":"74c18b63-143f-4abf-8747-4d34075ef2db","order_by":0,"name":"Faeza Alkorbi","email":"","orcid":"","institution":"Najran University","correspondingAuthor":false,"prefix":"","firstName":"Faeza","middleName":"","lastName":"Alkorbi","suffix":""},{"id":326033577,"identity":"e7ffd037-d16e-41ed-bf9c-bb3e19665688","order_by":1,"name":"Shareefa Ahmed Alshareef","email":"","orcid":"","institution":"University of Tabuk","correspondingAuthor":false,"prefix":"","firstName":"Shareefa","middleName":"Ahmed","lastName":"Alshareef","suffix":""},{"id":326033578,"identity":"47fcf4b7-68c9-4527-a433-aa460f17e964","order_by":2,"name":"Mahmoud A. Abdelaziz","email":"","orcid":"","institution":"University of Tabuk","correspondingAuthor":false,"prefix":"","firstName":"Mahmoud","middleName":"A.","lastName":"Abdelaziz","suffix":""},{"id":326033579,"identity":"272785a6-4a80-4c77-bc3f-1cd499001c68","order_by":3,"name":"Noha Omer","email":"","orcid":"","institution":"University of Tabuk","correspondingAuthor":false,"prefix":"","firstName":"Noha","middleName":"","lastName":"Omer","suffix":""},{"id":326033580,"identity":"68421553-53f6-4c4b-aa88-90350815f2bc","order_by":4,"name":"Rasha Jame","email":"","orcid":"","institution":"University of Tabuk","correspondingAuthor":false,"prefix":"","firstName":"Rasha","middleName":"","lastName":"Jame","suffix":""},{"id":326033581,"identity":"75851f33-a44b-4de7-9f9c-271caeed20c0","order_by":5,"name":"Ibrahim Saleem Alatawi","email":"","orcid":"","institution":"University of Tabuk","correspondingAuthor":false,"prefix":"","firstName":"Ibrahim","middleName":"Saleem","lastName":"Alatawi","suffix":""},{"id":326033582,"identity":"26b1bb99-7117-4604-8aa8-7014a561a6db","order_by":6,"name":"Ali M. Ali","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtklEQVRIiWNgGAWjYDACdjBpw8AgQbQWZjCZRrqWwyRo4Wdmf/zh547zif2zmw8+YKixiSaoRbKZx0yy98ztxBl3jiUbMBxLy20gpMXgMA8bA2/b7cSGGzlmEowNhwlrsT/M/vjj37ZzifOJ1mLAzGAgzdt2IHED0VokDvOYScu2JRtvvJGWbJBAjF/429sff3zbZic770bywQcfamwIa4EBR7DKBGKVg4A9KYpHwSgYBaNghAEAIqQ+ouNj2NEAAAAASUVORK5CYII=","orcid":"","institution":"Sohag University","correspondingAuthor":true,"prefix":"","firstName":"Ali","middleName":"M.","lastName":"Ali","suffix":""},{"id":326033583,"identity":"511fbb60-67e0-4897-a2f0-d0992b98fb41","order_by":7,"name":"Omran A. Omran","email":"","orcid":"","institution":"Sohag University","correspondingAuthor":false,"prefix":"","firstName":"Omran","middleName":"A.","lastName":"Omran","suffix":""},{"id":326033584,"identity":"721867f2-1df7-49db-bea4-e9bdd8e8153b","order_by":8,"name":"Rania B. Bakr","email":"","orcid":"","institution":"Beni-Suef University","correspondingAuthor":false,"prefix":"","firstName":"Rania","middleName":"B.","lastName":"Bakr","suffix":""}],"badges":[],"createdAt":"2024-06-29 11:53:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4659163/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4659163/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11030-024-10969-8","type":"published","date":"2024-08-15T15:58:14+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60908144,"identity":"3988533a-b44c-4318-9c68-8d6d492a6137","added_by":"auto","created_at":"2024-07-23 12:20:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":31456,"visible":true,"origin":"","legend":"\u003cp\u003eExamples of some reported indoles\u003cstrong\u003e (I-III) \u003c/strong\u003eand thiazoles\u003cstrong\u003e (IV, V) \u003c/strong\u003eand the rationale for design of target compounds\u003cstrong\u003e 4a-f.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4659163/v1/2bc26db76402f126c491a30a.png"},{"id":60908632,"identity":"2719918c-21c5-4e5e-b105-c91028c9f360","added_by":"auto","created_at":"2024-07-23 12:28:15","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":22496,"visible":true,"origin":"","legend":"\u003cp\u003eThe % of edema inhibition in response to test compounds.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4659163/v1/cf2a5a0d338e2152d2728299.png"},{"id":60908634,"identity":"fb6f7a5f-544f-42e5-86db-bdf6e1a8a6aa","added_by":"auto","created_at":"2024-07-23 12:28:15","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":551869,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMicroscopic examination of the impact of 4b on paw tissues following carrageenan injection.A\u003c/strong\u003e); control group with normal paw tissue, \u003cstrong\u003eB\u003c/strong\u003e); carrageenan group disclosed an acute inflammation (\u003cstrong\u003eblack arrow\u003c/strong\u003e) with edema (\u003cstrong\u003eblack star\u003c/strong\u003e), C); Celecoxib group with remarkable attenuation of edema and neutrophils migration, \u003cstrong\u003eD\u003c/strong\u003e); compound \u003cstrong\u003e4b\u003c/strong\u003e treated group with significant attenuation of inflammation and edema. Sections stained with H\u0026amp;E, (×200).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4659163/v1/4fb92522cb1cc23d70d549ed.png"},{"id":60908149,"identity":"6c25ca13-7dac-4cf1-a685-7647106c96da","added_by":"auto","created_at":"2024-07-23 12:20:15","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":285838,"visible":true,"origin":"","legend":"\u003cp\u003eThe proposed binding mode of compound\u003cstrong\u003e 4b \u003c/strong\u003ewithin COX-2 enzyme. A) 2D binding form, B) 3D binding form.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4659163/v1/b6b63fbd38ff936f7fa1bc01.png"},{"id":60909077,"identity":"b341db1f-0f5f-4694-a4a9-fcc55bee6d2d","added_by":"auto","created_at":"2024-07-23 12:36:15","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":241683,"visible":true,"origin":"","legend":"\u003cp\u003eThe proposed binding mode of compound\u003cstrong\u003e 4f \u003c/strong\u003ewithin COX-2 enzyme. A) 2D binding form, B) 3D binding form.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4659163/v1/877d62569722cec0151e9810.png"},{"id":63071774,"identity":"f2d23621-dd6e-41d2-9018-e1a02c8c863c","added_by":"auto","created_at":"2024-08-22 20:09:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1935583,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4659163/v1/f71aa9ac-3b24-41de-ab88-7fcec2ccf163.pdf"},{"id":60908147,"identity":"3281e27e-27b1-4a57-a8b7-364512babc4f","added_by":"auto","created_at":"2024-07-23 12:20:15","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":885462,"visible":true,"origin":"","legend":"","description":"","filename":"supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-4659163/v1/8b058667a2e8a813c73facf2.docx"},{"id":60908145,"identity":"03207c4f-b9db-45e9-9c99-37153d16a4d7","added_by":"auto","created_at":"2024-07-23 12:20:15","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":101887,"visible":true,"origin":"","legend":"","description":"","filename":"GraphicalAbstract.png","url":"https://assets-eu.researchsquare.com/files/rs-4659163/v1/95ec4fbd6bdc1ba6e9a50178.png"},{"id":60908152,"identity":"ba7acafe-6393-4dbe-a8a5-66c0c6698fa6","added_by":"auto","created_at":"2024-07-23 12:20:16","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":62809,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 1. Synthesis of indole-thiazole hybrid derivatives 4a-f\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Scheme1.png","url":"https://assets-eu.researchsquare.com/files/rs-4659163/v1/79f99c36225477a25df98873.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Multicomponent Reaction for Synthesis, Molecular Docking and Anti-inflammatory Evaluation of Novel Indole-Thiazole Hybrid Derivatives","fulltext":[{"header":"Introduction","content":"\u003cp\u003eInflammation is a biological reaction to a distrubtion in tissue homeostasis and body defence chemicals in which cells penetrate the affected tissue causing increasing blood flow, vascular permeability and vasodilatation [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e]. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly used medications for relieving pain and inflammation by inhibiting Cyclooxygenase (COX) enzymes [\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]. The constitutive COX-1 performs numerous physiological activities as protecting gastric mucosa, vascular homeostasis and platelet aggregation, while the other isoform, the inducible COX-2 is concerned with prostaglandins that promote inflammation and modulate pain [\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eThe use of traditional NSAIDs as aspirin, indomethacin and phenazone causes gastrointestinal side effects due to the inhibition of both COX isoforms [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]. Selective COX-2 inhibitor medications as celecoxib, valdecoxib and rofecoxib have been prepared to avoid the side effects produced by traditional NSAIDs [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]. Unfortunately, rofecoxib and valdecoxib were taken off the market due to their cardiovascular side effects including myocardial infarction and the occurrence of high blood pressure [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]. So, there is a great demand for selective COX-2 inhibitors with diminished side effects. Indole is one of the most widely used scaffolds in a broad range of anti-inflammatory agents [\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]. Many research investigations have focused on indole-based NSAIDs such as indomethacin (\u003cstrong\u003eI\u003c/strong\u003e) to enhance their COX-2 selectivity and decrease the ulcerogenic adverse effects that linked to their strong COX-1 selectivity and drug\u003csup\u003e,\u003c/sup\u003es acidic properties [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. Knaus and co-workers synthesized a new set of indole derivatives substituted at N-1 and C-3 [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]. From the prepared indole derivatives, compound \u003cstrong\u003eII\u003c/strong\u003e was the most selective (SI\u0026thinsp;\u0026gt;\u0026thinsp;312) and potent (COX-2 IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.32 \u0026micro;M) COX-2 inhibitor. In 2021, new indole derivatives having thiosemicarbazone moiety were prepared and screened for their anti-inflammatory effect using carrageenan-induced paw edema assay [\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]. Compound \u003cstrong\u003eIII\u003c/strong\u003e recorded superior COX-2 selectivity (SI\u0026thinsp;=\u0026thinsp;23.06) than displayed by celecoxib (SI\u0026thinsp;=\u0026thinsp;11.88).\u003c/p\u003e\n\u003cp\u003eThiazole is a five membered heterocyclic ring with many pharmacological utility as anticancer [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e], antioxidant [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e], antimicrobial [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e], antidiabetic [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e], anthelmintic [\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e] and anti-inflammatory [\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e]. For example, the thiazole derivative \u003cstrong\u003eIV\u003c/strong\u003e significantly inhibited edema (60.82%) in the carrageenan-induced edema compared with indomethacin (53.21%) [\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e]. Also, thiazole derivative \u003cstrong\u003eV\u003c/strong\u003e recorded comparable edema inhibition (EI\u0026thinsp;=\u0026thinsp;87%) to that registered by indomethacin (EI\u0026thinsp;=\u0026thinsp;91%) after 4 hours [\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eConsidering the aforesaid data and as an extension and development of our previous studies [\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e], we present the design and construction of novel indole-thiazole hybrids and biologically screened for their anti-inflammatory effect. The aim of this work is to get new compounds with selective COX-2 inhibition, favorable anti-inflammatory potential and minimized gastric side effects. This aim has been achieved by hybridization the privileged indole ring with the thiazole nucleus in one chemical entity (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e"},{"header":"Result and Discussion","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003e2.1. Chemistry\u003c/h2\u003e\n \u003cp\u003eIn this work, treatment of thiosemicarbazide (\u003cstrong\u003e1\u003c/strong\u003e) with isatin derivatives \u003cstrong\u003e2a-f\u003c/strong\u003e and 4-(bromoacetyl)-\u003cem\u003eN\u003c/em\u003e-(4-methylphenyl)benzenesulfonamide (\u003cstrong\u003e3)\u003c/strong\u003e \u003cem\u003evia\u003c/em\u003e three-component reaction under reflux in ethanol / tiethyl amine (TEA). Firstly, compound \u003cstrong\u003e1\u003c/strong\u003e was allowed to react with some isatin derivatives \u003cstrong\u003e2a-f\u003c/strong\u003e namely; isatin (\u003cstrong\u003e2a\u003c/strong\u003e), 5-chloro-isatin (\u003cstrong\u003e2b\u003c/strong\u003e), 5-nitro-isatin (\u003cstrong\u003e2c\u003c/strong\u003e), \u003cem\u003eN\u003c/em\u003e-methyl-isatin (\u003cstrong\u003e2d\u003c/strong\u003e), 5-chloro-\u003cem\u003eN\u003c/em\u003e-methyl-isatin (\u003cstrong\u003e2e\u003c/strong\u003e), 5-nitro-\u003cem\u003eN\u003c/em\u003e-methyl-isatin (\u003cstrong\u003e2f\u003c/strong\u003e), then compound \u003cstrong\u003e3\u003c/strong\u003e was added until the reaction completed (TLC), to obtain thiazol-indolin-2-one derivatives \u003cstrong\u003e4a-f\u003c/strong\u003e (\u003cstrong\u003eScheme 1\u003c/strong\u003e).\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eScheme 1. Synthesis of indole-thiazole hybrid derivatives 4a-f\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eThe chemical structure of compounds \u003cstrong\u003e4a-f\u003c/strong\u003e was determined using different elemental and spectroscopic analysis such as \u003csup\u003e1\u003c/sup\u003eH-NMR, \u003csup\u003e13\u003c/sup\u003eCNMR, as well as infrared spectroscopy.\u003c/p\u003e\n \u003cp\u003eTheir infrared spectra revealed the existence of new bands in the range 3363\u0026thinsp;\u0026minus;\u0026thinsp;3124 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e corresponding to NH. groups. \u003csup\u003e1\u003c/sup\u003eH NMR spectra showed, as well as the aromatic signals, new singlet signals in the region \u0026delta; 13.30\u0026ndash;9.03 ppm for NH groups. The N-CH\u003csub\u003e3\u003c/sub\u003e proton in compounds \u003cstrong\u003e4d-f\u003c/strong\u003e appeared as a singlet signal in the range \u0026delta; 3.73\u0026ndash;3.84 ppm, respectively. Moreover, their \u003csup\u003e13\u003c/sup\u003eC NMR spectra matched the accurate chemical structure which showed the carbonyl groups in the range 190.03 -160.85 ppm and the N-CH\u003csub\u003e3\u003c/sub\u003e groups in compounds \u003cstrong\u003e4d\u003c/strong\u003e-\u003cstrong\u003ef\u003c/strong\u003e appeared in the region \u0026delta; 46.40-35.15 ppm, and the CH\u003csub\u003e3\u003c/sub\u003e groups at range \u0026delta; 21.42\u0026ndash;21.01 ppm, respectively. Furthermore, elemental analyses of thiazoles \u003cstrong\u003e4a\u003c/strong\u003e-\u003cstrong\u003ef\u003c/strong\u003e provided the correct structure of the new products (cf. experimental).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003e2.2 Anti-inflammatory activity\u003c/h2\u003e\n \u003cp\u003eThe anti-inflammaory potential of indol-3-ylidenehydrazino-1,3-thiazole derivatives \u003cstrong\u003e4a-f\u003c/strong\u003e was estimated applying the carrageenan-induced rat paw edema method using celecoxib as a standard. Each target compound was taken immediately before inflammation induction by carrageenan injection. The anti-inflammatory potential was recoded according to paw volume changes after 1, 3 and 5 hours as displayed in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The obtained outcomes disclosed that 4-{2-[2-(5-chloro-2-oxo-1,2-dihydro-3\u003cem\u003eH\u003c/em\u003e-indol-3-ylidene)hydrazino]-1,3-thiazol-4-yl}-\u003cem\u003eN\u003c/em\u003e-phenyl-4-tolylsulfonamide (\u003cstrong\u003e4b\u003c/strong\u003e) was the most active candidate with edema inhibition percent equal to 12.72\u0026ndash;45.63%. Furthermore, this compound \u003cstrong\u003e4b\u003c/strong\u003e showed higher edema inhibition (EI\u0026thinsp;=\u0026thinsp;38.50%) than that exhibited by celecoxib (EI\u0026thinsp;=\u0026thinsp;34.58%) after 3h. Moreover, compound \u003cstrong\u003e4f\u003c/strong\u003e revealed comparable edema inhibition (3h; EI\u0026thinsp;=\u0026thinsp;31.94%, 5h; EI\u0026thinsp;=\u0026thinsp;41.84%) to that recorded by celecoxib (3h; EI\u0026thinsp;=\u0026thinsp;34.58%, 5h; EI\u0026thinsp;=\u0026thinsp;49.30%). In addition, within 1\u003cem\u003eH\u003c/em\u003e-indole derivatives \u003cstrong\u003e4a-c\u003c/strong\u003e, the 5-chloroindole derivative (\u003cstrong\u003e4b\u003c/strong\u003e) was the most active anti-inflammatory candidate (3h; EI\u0026thinsp;=\u0026thinsp;38.50%, 5h; EI\u0026thinsp;=\u0026thinsp;45.63%) followed by 5-nitro analogue (\u003cstrong\u003e4c\u003c/strong\u003e) (3h; EI\u0026thinsp;=\u0026thinsp;23.33%, 5h; EI\u0026thinsp;=\u0026thinsp;39.19%) while compound \u003cstrong\u003e4a\u003c/strong\u003e with no substitution at positions 1 and 5 of indole moiety exhibited the least anti-inflammatory activity (3h; EI\u0026thinsp;=\u0026thinsp;18.05%, 5h; EI\u0026thinsp;=\u0026thinsp;12.76%). In case of \u003cem\u003eN\u003c/em\u003e-methylindole derivatives (\u003cstrong\u003e4d-f\u003c/strong\u003e), the 5-nitroindole candidate (\u003cstrong\u003e4f\u003c/strong\u003e) showed the highest edema inhibition percent (3h; EI\u0026thinsp;=\u0026thinsp;31.94%, 5h; EI\u0026thinsp;=\u0026thinsp;41.84%) followed by compound \u003cstrong\u003e4d\u003c/strong\u003e (3h; EI\u0026thinsp;=\u0026thinsp;15.41%, 5h; EI\u0026thinsp;=\u0026thinsp;23.76%) then the 5-chloro analogue (\u003cstrong\u003e4e\u003c/strong\u003e) (3h; EI\u0026thinsp;=\u0026thinsp;5.69%, 5h; EI\u0026thinsp;=\u0026thinsp;8.72%). From the recorded data in (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e), it is clear that compound \u003cstrong\u003e4b\u003c/strong\u003e has the most promising anti-inflammatory potential in comparison with celecoxib.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eAnti-inflammatory potential of test compounds (4a-f) using celecoxib reference drug.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"7\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eDiameter inflammation (mm)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e% Edema inhibition\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCompound\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5h\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e--------\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e--------\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e--------\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCarrageenan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.76\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.91\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e--------\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e--------\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e--------\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCelecoxib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.09\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.71\u0026thinsp;\u0026plusmn;\u0026thinsp;0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49.30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e4a\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.70\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e01.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.76\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e4b\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.30\u0026thinsp;\u0026plusmn;\u0026thinsp;0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45.63\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e4c\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.53\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.52\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e03.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39.19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e4d\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.60\u0026thinsp;\u0026plusmn;\u0026thinsp;0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.09\u0026thinsp;\u0026plusmn;\u0026thinsp;0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e02.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.76\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e4e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.74\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.79\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.22\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e4f\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.60\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41.84\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003ch3\u003e2.3. Histological investigation\u003c/h3\u003e\n\u003cp\u003eThe impact of compound \u003cstrong\u003e4b\u003c/strong\u003e on paw tissue after carrageenan injection, comparing the results to those observed with indomethacin. It has found that is compound \u003cstrong\u003e4b\u003c/strong\u003e has the most effective of the tested products. As shown in Figure (3), the paw tissues of control rats (2, A) are not inflamed. The carrageenan model demonstrated neutrophil migration in addition to acute inflammation (black arrow) and hemorrhagic edema (black star) (2, B). Nevertheless, the rats given Celecoxib showed a notable decrease in inflammation (2, C). Figures (2, D) demonstrated the impact of test chemical \u003cstrong\u003e4b\u003c/strong\u003e on paw tissue inflammation, demonstrating a notable reduction in inflammatory cells and edema.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. Molecular docking study.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo gain insights into the fundamental mechanism of action of newly prepared indol-3-ylidenehydrazino-1,3-thiazole derivatives, molecular docking of the most active candidates (\u003cstrong\u003e4b\u003c/strong\u003e and \u003cstrong\u003e4f\u003c/strong\u003e) was conducted inside COX-2 active region. The results of docking including docking score (Kcal/mol), types of interactions and the binded amino acids are listed in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and Figs. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e \u0026amp; \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eCompound \u003cstrong\u003e4b\u003c/strong\u003e revealed good binding within COX-2 with binding energy score = -11.45 kcal/mol. Conventional hydrogen bonds with ARG376, TRP139, ASP229 and GLY235 amino acids were detected (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). In addition, this compound \u003cstrong\u003e4b\u003c/strong\u003e displayed other Pi-Cation interactions with LYS333, Pi-Alkyl binding with LEU145, PRO538; Amide-Pi Stacked with LEU224 and Van der Waals interactions with SER143 and ASN375 (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eFurthermore, compound \u003cstrong\u003e4f\u003c/strong\u003e exhibited three hydrogen bonding interactions qith ARG44, CYS41 and GLY135 amino acids with binding energy score equal to -10.48 kcal/mol. also, other binding interactions were registered as Pi-Alkyl binding with LYS468, PRO153 and ALA156; Amide-Pi binding with VAL155 and Van der Waals interaction with ASN34, ALA156 and ARG469 (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eOutcomes of docking study for target candidates \u003cstrong\u003e4b\u003c/strong\u003e and \u003cstrong\u003e4f\u003c/strong\u003e inside COX-2 enzyme.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"7\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCompound NO.\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eDocking score\u003c/p\u003e\n \u003cp\u003eKcal/mol\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNumber of bonds\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eType of interactions\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAmino acids\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFunction group\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e4b\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-11.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eH-bond\u003c/p\u003e\n \u003cp\u003eH-bond\u003c/p\u003e\n \u003cp\u003eH-bond\u003c/p\u003e\n \u003cp\u003eH-bond\u003c/p\u003e\n \u003cp\u003eAmide-Pi\u003c/p\u003e\n \u003cp\u003ePi-Cation\u003c/p\u003e\n \u003cp\u003ePi-Cation\u003c/p\u003e\n \u003cp\u003ePi-Alkyl\u003c/p\u003e\n \u003cp\u003ePi-Alkyl\u003c/p\u003e\n \u003cp\u003eVan der Waal\u003c/p\u003e\n \u003cp\u003eVan der Waal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eARG376\u003c/p\u003e\n \u003cp\u003eTRP139\u003c/p\u003e\n \u003cp\u003eASP229\u003c/p\u003e\n \u003cp\u003eGLY235\u003c/p\u003e\n \u003cp\u003eLEU224\u003c/p\u003e\n \u003cp\u003eLYS333\u003c/p\u003e\n \u003cp\u003eLYS333\u003c/p\u003e\n \u003cp\u003eLEU145\u003c/p\u003e\n \u003cp\u003ePRO538\u003c/p\u003e\n \u003cp\u003eSER143\u003c/p\u003e\n \u003cp\u003eASN375\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003e=N\u003c/p\u003e\n \u003cp\u003eNH\u003c/p\u003e\n \u003cp\u003eIndole NH\u003c/p\u003e\n \u003cp\u003eThiazole\u003c/p\u003e\n \u003cp\u003eIndole\u003c/p\u003e\n \u003cp\u003eIndole\u003c/p\u003e\n \u003cp\u003ePhenyl\u003c/p\u003e\n \u003cp\u003eMethyl\u003c/p\u003e\n \u003cp\u003e=N\u003c/p\u003e\n \u003cp\u003ePhenyl\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e2f\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-10.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eH-bond\u003c/p\u003e\n \u003cp\u003eH-bond\u003c/p\u003e\n \u003cp\u003eH-bond\u003c/p\u003e\n \u003cp\u003ePi-Alkyl\u003c/p\u003e\n \u003cp\u003ePi-Alkyl\u003c/p\u003e\n \u003cp\u003ePi-Alkyl\u003c/p\u003e\n \u003cp\u003ePi-Alkyl\u003c/p\u003e\n \u003cp\u003ePi-Alkyl\u003c/p\u003e\n \u003cp\u003ePi-Alky\u003c/p\u003e\n \u003cp\u003eAmide-Pi\u003c/p\u003e\n \u003cp\u003eVan der Waal\u003c/p\u003e\n \u003cp\u003eVan der Waal\u003c/p\u003e\n \u003cp\u003eVan der Waal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCYS41\u003c/p\u003e\n \u003cp\u003eARG44\u003c/p\u003e\n \u003cp\u003eGLY135\u003c/p\u003e\n \u003cp\u003eLYS468\u003c/p\u003e\n \u003cp\u003eLYS468\u003c/p\u003e\n \u003cp\u003eCYS36\u003c/p\u003e\n \u003cp\u003ePRO153\u003c/p\u003e\n \u003cp\u003eALA156\u003c/p\u003e\n \u003cp\u003eALA156\u003c/p\u003e\n \u003cp\u003eVAL155\u003c/p\u003e\n \u003cp\u003eARG469\u003c/p\u003e\n \u003cp\u003eALA156\u003c/p\u003e\n \u003cp\u003eASN34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNH\u003c/p\u003e\n \u003cp\u003eSO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003eNO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003ePhenyl\u003c/p\u003e\n \u003cp\u003eMethyl\u003c/p\u003e\n \u003cp\u003eThiazole\u003c/p\u003e\n \u003cp\u003eThiazole\u003c/p\u003e\n \u003cp\u003eIndole\u003c/p\u003e\n \u003cp\u003eIndole\u003c/p\u003e\n \u003cp\u003eIndole\u003c/p\u003e\n \u003cp\u003eSO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003eNO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003eIndole\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"EXPERIMENTAL","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eChemistry\u003c/h2\u003e \u003cp\u003eAll melting points were recorded on Melt-Temp II melting point apparatus. IR spectra were measured as KBr pellets on a Shimadzu DR-8001 spectrometer. \u003csup\u003e1\u003c/sup\u003eH NMR and \u003csup\u003e13\u003c/sup\u003eC NMR spectra were recorded on a Bruker at 400 MHz and 100 MHz using TMS as an internal reference, DMSO-\u003cem\u003ed\u003c/em\u003e\u003csub\u003e\u003cem\u003e6\u003c/em\u003e\u003c/sub\u003e as solvent. The elemental analyses were carried out on a Perkin-Elmer 240C Micro analyzer. All compounds were checked for their purity on TLC plates.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eGeneral Procedure for the Synthesis of thiazole derivatives 4a-f:\u003c/h2\u003e \u003cp\u003eAn equimolar mixture of thiosemicarbazide (1) (0.01 mol, 0.91 g) with the appropriate isatin derivative (\u003cb\u003e2a-f\u003c/b\u003e) (0.01 mol) was allowed to reflux in ethanol/ TEA until the reaction (TLC) (10 min). Then added 4-(bromoacetyl)-N-(4-methylphenyl)benzenesulfonamide (3) to the reaction mixture, and continued refluxing for 20\u0026ndash;30 min., until the reaction completed (TLC) to afford the corresponding thiazole derivatives (\u003cb\u003e4a-f\u003c/b\u003e). The reaction mixture was allowed to cool to room temperature and the solid precipitate was filtrated, and recrystallized from ethanol.\u003c/p\u003e \u003cp\u003e4\u003cb\u003e-{2-[2-(2-Oxo-1,2-dihydro-1H-indol-3-ylidene)hydrazino]-1,3-thiazol-4-yl}-\u003c/b\u003e\u003cb\u003eN\u003c/b\u003e\u003cb\u003e-phenyl-4-tolyl sulfonamide (4a)\u003c/b\u003e\u003c/p\u003e \u003cp\u003eMp 235\u0026deg;C; IR cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3363, 3178, 3120 (3NH), 3064 (C\u0026ndash;H\u003csub\u003earom\u003c/sub\u003e.), 1682 (C\u0026thinsp;=\u0026thinsp;O), \u003csup\u003e1\u003c/sup\u003eH NMR \u003cem\u003eδ\u003c/em\u003e 13.30 (br,1H, NH), 11.20 ( s, 1H, NH), 10.29 ( s, 1H, NH), 7.76\u0026ndash;6.85 (m, 13H, CH\u003csub\u003earom\u003c/sub\u003e.), 2.33 (s, 3H, -CH\u003csub\u003e3\u003c/sub\u003e); \u003csup\u003e13\u003c/sup\u003eC NMR; 166.53 (C\u0026thinsp;=\u0026thinsp;O), 150.95, 143.82, 141.71, 137.93, 137.07, 132.53, 130.95, 130.32, 130.20, 130.14, 127.19, 125.03, 122.90, 120.46, 120.28, 120.19, 111.54, 106.41, 21.37; Anal. Calcd. For C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS\u003csub\u003e2\u003c/sub\u003e (489.56) C (58.88%), H (3.91%), N (14.31%), S (13.10%); Found C (58.95%), H (3.98%), N (14.26%), S (13.16%).\u003c/p\u003e \u003cp\u003e4\u003cb\u003e-{2-[2-(5-Chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-1,3-thiazol-4-yl}-\u003c/b\u003e\u003cb\u003eN\u003c/b\u003e\u003cb\u003e-phenyl- tolylsulfonamide (4b)\u003c/b\u003e\u003c/p\u003e \u003cp\u003eMp 241\u0026deg;C; IR cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3308, 3124 (3NH), 3061 (CH arom.), 1671 (C\u0026thinsp;=\u0026thinsp;O), \u003csup\u003e1\u003c/sup\u003eH NMR \u003cem\u003eδ\u003c/em\u003e 13.24 (s,1H, NH), 11.26 ( s, 1H, NH), 10.29 ( s, 1H, NH), 8.39\u0026ndash;6.81 (m, 12H, CH\u003csub\u003earom\u003c/sub\u003e.), 2.33 (s, 3H, -CH\u003csub\u003e3\u003c/sub\u003e); \u003csup\u003e13\u003c/sup\u003eC NMR δ (ppm): 163.39 (C\u0026thinsp;=\u0026thinsp;O), 150.99, 143.97, 143.82, 141.03, 140.23, 138.72, 137.94, 137.06, 131.30, 130.21, 129.92, 127.19, 127.08, 127.03, 125.87, 121.88, 120.44, 120.11, 119.41, 21.37; Anal. Calcd. For C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eClN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS\u003csub\u003e2\u003c/sub\u003e (524.01) C (55.01%), H (3.46%), N (13.36%), S (12.24%); Found; C (54.98%), H (3.39%), N (13.29%), S (12.18%).\u003c/p\u003e \u003cp\u003e4\u003cb\u003e-{2-[2-(5-Nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-1,3-thiazol-4-yl}-N-phenyl- tolysulfonamide (4c)\u003c/b\u003e\u003c/p\u003e \u003cp\u003eMp 228\u0026deg;C; IR cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3247\u0026thinsp;\u0026minus;\u0026thinsp;3154 (3NH), 3085 (C\u0026ndash;H\u003csub\u003earom\u003c/sub\u003e.), 1654 (C\u0026thinsp;=\u0026thinsp;O), \u003csup\u003e1\u003c/sup\u003eH NMR \u003cem\u003eδ\u003c/em\u003e 10.28 (s,1H, NH), 9.14 ( s, 1H, NH), 8.64\u0026ndash;7.11 (m, 13H, CH\u003csub\u003earom\u003c/sub\u003e+ NH.), 2.32 (s, 3H, CH\u003csub\u003e3\u003c/sub\u003e), \u003csup\u003e13\u003c/sup\u003eC NMR δ (ppm): 164.76 (C\u0026thinsp;=\u0026thinsp;O), 147.14, 144.84, 142.67, 140.28, 139.36, 138.94, 137.15, 136.03, 135.97, 135.80, 132.56, 128.37, 124.21, 123.98, 120.38, 117.46, 116.09, 112.45, 21.42; Anal. Calcd. For C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eN\u003csub\u003e6\u003c/sub\u003eO\u003csub\u003e5\u003c/sub\u003eS\u003csub\u003e2\u003c/sub\u003e (534.56); C (53.92%), H (3.39%), N (15.72%), S (12.00%) Found: C (53.86%), H (3.46%), N (15.65%), S (12.06%)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e(4-(2-(2-(1-methyl-2-oxoindolin-3-ylidene)hydrazinyl)thiazol-4-yl)-N-(p-tolyl) benzene sulfonamide (4d)\u003c/h2\u003e \u003cp\u003eMp 268\u0026deg;C; IR cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3217, 3161 (2NH), 3078 (C\u0026ndash;H\u003csub\u003earom\u003c/sub\u003e.), 1658 (C\u0026thinsp;=\u0026thinsp;O), \u003csup\u003e1\u003c/sup\u003eH NMR \u003cem\u003eδ\u003c/em\u003e 13.16 (br,1H, NH), 10.45 (s, 1H, NH), 7.75\u0026ndash;7.02 (m, 13H, CH\u003csub\u003earom\u003c/sub\u003e.), 3.73 (s, 3H, N-CH\u003csub\u003e3\u003c/sub\u003e), 2.30 (s, 3H, CH\u003csub\u003e3\u003c/sub\u003e); \u003csup\u003e13\u003c/sup\u003eC NMR δ (ppm): 160.85 (C\u0026thinsp;=\u0026thinsp;O), 143.84, 141.56, 138.94, 137.04, 135.57, 133.94, 132.06, 131.03, 128.05, 127.20, 123.33, 122.46, 121.55, 121.47, 119.59, 119.37, 115.67, 110.28, 45.66, 21.38; Anal. Calcd. For C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e21\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS\u003csub\u003e2\u003c/sub\u003e C (59.62%), H (4.20%), N (13.91%), S (12.73%) Found; C (59.69%), H (4.16%), N (13.84%), S (12.85%).\u003c/p\u003e \u003cp\u003e4\u003cb\u003e-{2-[2-(5-Chloro-2-oxo-1,2-dihydro-N-methyl-3H-indol-3-ylidene)hydrazino]-1,3-thiazol-4-yl}-N-phenyl-4 tolylsulfonamide (4e)\u003c/b\u003e\u003c/p\u003e \u003cp\u003eMp 216\u0026deg;C; IR cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3190, 3167 (2NH), 3047 (C\u0026ndash;H\u003csub\u003earom\u003c/sub\u003e.), 1661 (C\u0026thinsp;=\u0026thinsp;O), \u003csup\u003e1\u003c/sup\u003eH NMR \u003cem\u003eδ\u003c/em\u003e 12.27 (s,1H, NH), 10.33 ( s, 1H, NH), 7.79\u0026ndash;6.99 (m, 12H, CH\u003csub\u003earom\u003c/sub\u003e.), 3.75 (s, 3H, N-CH\u003csub\u003e3\u003c/sub\u003e), 2.33 (s, 3H, CH\u003csub\u003e3\u003c/sub\u003e), \u003csup\u003e13\u003c/sup\u003eC NMR δ (ppm): 190.03 (C\u0026thinsp;=\u0026thinsp;O), 143.92, 140.47, 139.93, 137.08, 136.42, 134.57, 132.76, 131.02, 130.81, 127.20, 127.05, 126.14, 124.43, 123.03, 120.43, 120.16, 119.59, 46.40, 21.35; Anal. Calcd. For C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e20\u003c/sub\u003eClN\u003csub\u003e5\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003eS\u003csub\u003e2\u003c/sub\u003e(538.04) C (55.81%), H (3.75%), N (13.02%), S (11.92%) Found C (55.86%), H (3.83%), N (12.97%), S (11.86%)\u003c/p\u003e \u003cp\u003e4\u003cb\u003e-{2-[2-(5-Nitro-2-oxo- N-methyl \u0026minus;\u0026thinsp;3-ylidene)hydrazino]-1,3-thiazol-4-yl}-N-phenyl-4-tolyl sulfonamide (4f)\u003c/b\u003e\u003c/p\u003e \u003cp\u003eMp 290\u0026deg;C; IR cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3251, 3126 (2NH), 3085 (C\u0026ndash;H\u003csub\u003earom\u003c/sub\u003e.), 1654 (C\u0026thinsp;=\u0026thinsp;O), \u003csup\u003e1\u003c/sup\u003eH NMR \u003cem\u003eδ\u003c/em\u003e 9.18 (s,1H, NH), 9.03 (s, 1H, NH), 8.64\u0026ndash;7.11 (m, 12H, CH\u003csub\u003earom\u003c/sub\u003e.), 3.84 (s, 3H, N-CH\u003csub\u003e3\u003c/sub\u003e), 2.34 (s, 3H, CH\u003csub\u003e3\u003c/sub\u003e), \u003csup\u003e13\u003c/sup\u003eC NMR δ (ppm): 179.46 (C\u0026thinsp;=\u0026thinsp;O), 147.79, 143.57, 142.90, 140.54, 139.65, 138.82, 134.96, 130.24, 129.31, 128.60, 127.22, 124.42, 121.84, 120.63, 117.36, 116.61, 110.50, 109.25, 35.13, 21.01 ; Anal. Calcd. For C\u003csub\u003e25\u003c/sub\u003eH\u003csub\u003e20\u003c/sub\u003eN\u003csub\u003e6\u003c/sub\u003eO\u003csub\u003e5\u003c/sub\u003eS\u003csub\u003e2\u003c/sub\u003e (548.59); C (54.73%), H (3.67%), N (15.32%), S (11.69%) Found: C (54.69%), H (3.73%), N (15.26%), S (11.78%).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eAnti-inflammatory activity\u003c/h2\u003e \u003cp\u003e \u003cb\u003eIn vivo\u003c/b\u003e \u003cb\u003eestimation the anti-inflammatory effects of test compounds on rats via carrageenan-induced paw edema model.\u003c/b\u003e\u003c/p\u003e \u003cp\u003eFor the \u003cem\u003ein vivo\u003c/em\u003e assessment of the test compounds' anti-inflammatory activity, male Wister rats weighing 180\u0026thinsp;\u0026plusmn;\u0026thinsp;10 grams each were employed, with celecoxib serving as the reference drug. All animals had to acclimate to the criteria set by the Institutional Animals Ethics Committee (IAEC) of the Faculty of Medicine at Sohag University for at least one week prior to the investigations (permit No; ). For this in vivo evaluation, 40 adult male Westar rats (n\u0026thinsp;=\u0026thinsp;4) were randomly assigned. The selected agents were suspended in 1% newly prepared carboxy methyl cellulose (CMC) prior to being administered orally by gavage. Following a sub plantar injection of 100 \u0026micro;L of freshly prepared carrageenan gel (1% distilled water) into each rat's left hind paw, changes in paw thickness were observed [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. Rats were administered test compounds orally via gavage one hour before the injection of carrageenan. Paw thickness was measured one, three, and five hours after the development of inflammation. The test compound's effects were quantified as a percentage of edema inhibition. The anti-inflammatory potential is expressed as a percentage suppression of paw edema and quantified [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eHistopathological analysis of the tissues in the paws\u003c/h2\u003e \u003cp\u003ePrior to being embedded in paraffin, the tissues from the paws were stored in a 10% formalin-neutral buffer. Hematoxylin and eosin (H\u0026amp;E) were used to stain the slides after thin sections of 5\u0026ndash;6 \u0026micro;m were cut using a microtome. The slides that were made with a light microscope exhibit pathological changes in them.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eDocking study\u003c/h2\u003e \u003cp\u003eThe crystal structure of COX-2 was downloaded from Protein Data Bank (PDB:1CX2) and the molecular docking was performed following our previously reported work [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe obtained data were statistically analyzed using GraphPad Prism version 9, and the mean values and standard deviations (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD) were presented as a result. The significance of mean differences was evaluated using the Tukey-Kramer test and one-way analysis of variance (ANOVA), with p-values of less than 0.05 being considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eNew series of novel indole-thiazole hybrids derivatives\u0026nbsp;\u003cstrong\u003e4a-f\u003c/strong\u003e were synthesized \u003cem\u003evia\u003c/em\u003e multi-components of thiosemicarbazide with some isatine derivatives (\u003cstrong\u003e2a-f\u003c/strong\u003e) and \u003cem\u003eN\u003c/em\u003e-(4-(2-bromoacetyl)phenyl)-4-methylbenzenesulfonamide (\u003cstrong\u003e3\u003c/strong\u003e)\u0026nbsp;under reflux in ethanol. The chemical structures of novel compounds were elucidated by elemental and spectral analyses. All newly compounds have been screened for their anti-inflammatory activity using celecoxib as a reference drug. It has been found that compound \u003cstrong\u003e4b\u003c/strong\u003e (3h; EI = 38.50%, 5h; EI = 45.63%) has the most promising and effective anti-inflammatory potential. Furthermore, Molecular dockingstudyof\u0026nbsp;compounds \u003cstrong\u003e4b\u0026nbsp;\u003c/strong\u003eand \u003cstrong\u003e4f\u0026nbsp;\u003c/strong\u003edisplayed that these compoundsfitted into the COX-2binding site with good docking energy scores\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp dir=\"LTR\"\u003e\u003cstrong\u003eSupporting Information Summary\u003c/strong\u003e\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eThe data that support the findings of this article are available in the supplementary material of this article.\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u0026nbsp;The authors declare no conflict of interest\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has been carried on rats and the authors take personal responsibility for knowing\u003c/p\u003e\n\u003cp\u003etheir statutory responsibility under the Animal (Scientific Procedures) Act 1986, under the\u003c/p\u003e\n\u003cp\u003eacceptance of Committee for Scientific Research Ethics (CSRE), code no. (CSRE-23-24)-Sohag University\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eThe authors gratefully acknowledge to Najran University, Faculty of Science and Arts at Sharurah, 68342; Sohag University, Egypt; Minia University, Egypt and Tabuk University Faculty of Science, Tabuk 71491.\u0026nbsp;\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper..\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSilva L. A. (2015) literature review of inflammation and its relationship with the oral cavity. Glob J Infect Dis Clin Res 1: 21-27.\u003c/li\u003e\n \u003cli\u003eAbdellatif K.R.A., Abdelall, E KE, and Bakr, R. B. 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(2023) Design and construction of novel pyridine-pyrimidine hybrids as selective COX-2 suppressors: anti-inflammatory potential, ulcerogenic profile, molecular modeling and ADME/Tox studies, Journal of Biomolecular Structure and Dynamics: 1-14.\u003c/li\u003e\n \u003cli\u003eKhodairy A, Ali AM, ElWassimy M. (2018) Synthesis and reactions of new thiazoles and pyrimidines containing sulfonate moiety, Journal of Heterocyclic Chemistry 55: 964-970.\u003c/li\u003e\n \u003cli\u003eElkanzi NA, Kadry AM, Ryad RM, Bakr RB, Ali El-Remaily, MAEAA, Ali, AM. Efficient and recoverable bio-organic catalyst cysteine for synthesis, docking study, and antifungal activity of new bio-active 3, 4-dihydropyrimidin-2 (1 H)-ones/thiones under microwave irradiation, ACS omega 7: 22839-22849.\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Winter C.A, E.A. Risley, G.W. Nuss, (1962) Carrageenin-induced edema in hind paw of the rat as an assay for antiinflammatory drugs. Proceedings of the society for experimental biology and medicine 111(3): p. 544-547\u003cspan dir=\"RTL\"\u003e.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Arooj, B., (2023) Anti-inflammatory mechanisms of eucalyptol rich Eucalyptus globulus essential oil alone and in combination with flurbiprofen. Inflammopharmacology, 2023. 31(4): p. 1849-1862\u003cspan dir=\"RTL\"\u003e.\u003c/span\u003e\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eGhoneim MM, Abdelgawad MA, Elkanzi NA, Parambi, DGT, Alsalahat, I, Farouk, A, and Bakr, RB. (2024) A literature review on pharmacological aspects, docking studies, and synthetic approaches of quinazoline and quinazolinone derivatives, Archiv der Pharmazie: e2400057.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Scheme","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":"molecular-diversity","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"modi","sideBox":"Learn more about [Molecular Diversity](http://link.springer.com/journal/11030)","snPcode":"11030","submissionUrl":"https://submission.nature.com/new-submission/11030/3","title":"Molecular Diversity","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Indole derivatives, Thiazole, Multicomponent reaction, Anti-inflammatory activity, Histopathological examination","lastPublishedDoi":"10.21203/rs.3.rs-4659163/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4659163/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn this article, novel thiazol-indolin-2-one derivatives \u003cstrong\u003e4a-f\u003c/strong\u003e have been synthesized \u003cem\u003evia\u003c/em\u003e treatment of thiosemicarbazide (\u003cstrong\u003e1\u003c/strong\u003e) with some isatin derivative \u003cstrong\u003e2a-f\u003c/strong\u003e and \u003cem\u003eN\u003c/em\u003e-(4-(2-bromoacetyl)phenyl)-4-tolyl-sulfonamide (\u003cstrong\u003e3)\u003c/strong\u003e under reflux in ethanol in the presence of triethyl amine (TEA). The structures of new products were elucidated by elemental and spectral analyses. Moreover, all compounds were investigated for their\u003cem\u003e in vivo\u003c/em\u003e anti-inflammatory activity using celecoxib as a reference drug. \u0026nbsp;The target comound \u003cstrong\u003e4b\u003c/strong\u003e was the most active anti-inflammatory candidate and exhibited higher edema inhibition (EI = 38.50 %) than that recorded by celecoxib (EI = 34.58%) after 3h. Furthermore, the most active compounds \u003cstrong\u003e4b\u003c/strong\u003eand \u003cstrong\u003e4f\u003c/strong\u003e were subjected to molecular docking\u003cstrong\u003e \u003c/strong\u003estudy inside COX-2 enzyme to show their binding interactions\u003cstrong\u003e. \u003c/strong\u003eBoth compounds \u003cstrong\u003e4b \u003c/strong\u003eand\u003cstrong\u003e 2f \u003c/strong\u003eshowed good fitting into COX-2\u003cem\u003e\u003cstrong\u003e \u003c/strong\u003e\u003c/em\u003ebinding site with docking energy scores -11.45 kcal/mol and -10.48kcal/mol,respectively which indicated that compound \u003cstrong\u003e4b\u003c/strong\u003e revealed the most promising and effective anti-inflammatory potential.\u003c/p\u003e","manuscriptTitle":"Multicomponent Reaction for Synthesis, Molecular Docking and Anti-inflammatory Evaluation of Novel Indole-Thiazole Hybrid Derivatives","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-23 12:20:11","doi":"10.21203/rs.3.rs-4659163/v1","editorialEvents":[{"type":"communityComments","content":1},{"type":"decision","content":"Revision requested","date":"2024-07-12T08:07:43+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-12T04:31:42+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-11T11:58:13+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-11T11:18:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"319824781418433427344893564891322943178","date":"2024-07-03T05:16:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"87381153162392912760205418924889881759","date":"2024-07-02T14:41:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"129171102898341039803473821498485665098","date":"2024-06-30T22:26:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"194876556883722602712020890991572248559","date":"2024-06-30T08:45:58+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-30T08:40:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-29T15:40:08+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-29T14:22:51+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular Diversity","date":"2024-06-29T11:40:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-diversity","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"modi","sideBox":"Learn more about [Molecular Diversity](http://link.springer.com/journal/11030)","snPcode":"11030","submissionUrl":"https://submission.nature.com/new-submission/11030/3","title":"Molecular Diversity","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3205d9f9-405d-4c90-bc7a-aa6ea4ed4250","owner":[],"postedDate":"July 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-22T19:47:29+00:00","versionOfRecord":{"articleIdentity":"rs-4659163","link":"https://doi.org/10.1007/s11030-024-10969-8","journal":{"identity":"molecular-diversity","isVorOnly":false,"title":"Molecular Diversity"},"publishedOn":"2024-08-15 15:58:14","publishedOnDateReadable":"August 15th, 2024"},"versionCreatedAt":"2024-07-23 12:20:11","video":"","vorDoi":"10.1007/s11030-024-10969-8","vorDoiUrl":"https://doi.org/10.1007/s11030-024-10969-8","workflowStages":[]},"version":"v1","identity":"rs-4659163","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4659163","identity":"rs-4659163","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}