Structure–Activity Relationship and ADME-Guided Optimization of 4H-Chromene-3-Carbonitrile Derivatives as Promising Antimicrobial Agents

Structure–Activity Relationship and ADME-Guided Optimization of 4H-Chromene-3-Carbonitrile Derivatives as Promising Antimicrobial Agents | 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 Structure–Activity Relationship and ADME-Guided Optimization of 4H-Chromene-3-Carbonitrile Derivatives as Promising Antimicrobial Agents Dr. Shweta Patel This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8718836/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract The wide range of biological activities and advantageous pharmacological characteristics of 4H-chromene derivatives have drawn a lot of attention. In this work, a variety of 4 H -chromene-3-carbonitrile derivatives were synthesized under ideal conditions using an environmentally friendly and effective multicomponent process. High yields, quicker reaction times, and less environmental effect were provided by the synthetic protocol. Several derivatives with significant antibacterial and antifungal properties were found when the synthetic compounds' antimicrobial activity was assessed. ADME prediction experiments also showed appropriate pharmacokinetic behavior, excellent drug-likeness, and oral bioavailability. All things considered, the findings point to these 4H-chromene derivatives as viable options for more medicinal chemistry research. 4H-chromene-3-carbonitrile Green synthesis Multicomponent reaction Optimization Antimicrobial activity ADME study Bioactive heterocycles Figures Figure 1 Introduction Multicomponent reactions (MCRs) have emerged as powerful synthetic strategies in modern organic chemistry due to their ability to construct structurally complex and diverse molecules in a single operational step [ 1 ]. These reactions offer remarkable advantages such as atom economy, operational simplicity, reduced reaction time, and minimal waste generation, making them highly compatible with the principles of green chemistry [ 2 , 3 ]. In recent years, the emphasis on sustainable and eco-friendly synthesis has accelerated the use of MCRs for generating biologically active heterocycles with improved efficiency and reduced environmental impact [ 4 ]. Among the wide variety of heterocyclic scaffolds obtained through green multicomponent methodologies, 4H-chromene derivatives represent an exceptionally important class of compounds. They are widely recognized for their diverse pharmacological activities including antimicrobial, antioxidant, anticancer, anti-inflammatory, and enzyme inhibitory properties [ 5 , 6 ]. The presence of the chromene core, in combination with suitable electron-withdrawing or electron-donating substituents, allows for extensive structural modification, which can significantly enhance biological potency and drug-likeness [ 7 ]. In particular, 4H-chromene-3-carbonitrile derivatives have gained significant attention due to their broad-spectrum antimicrobial activity and potential utility as lead molecules in medicinal chemistry [ 8 ]. To develop efficient therapeutic candidates, optimization of reaction conditions is essential for maximizing yield, selectivity, and purity in synthetic pathways. Optimization studies not only refine the synthetic process but also enhance reproducibility and scalability, which are crucial for drug development [ 9 , 10 ]. Additionally, modern drug discovery relies heavily on computational approaches, particularly ADME (Absorption, Distribution, Metabolism, and Excretion) analyses, to predict pharmacokinetic behavior and identify compounds with favorable biological profiles prior to in-vivo studies [ 11 – 14 ]. ADME screening serves as a powerful filter to eliminate compounds with poor pharmacokinetic characteristics at an early stage, thereby accelerating identification of promising drug-like molecules [ 15 ]. Considering the biological importance of chromene scaffolds and the growing demand for sustainable synthetic methodologies, the development of green, multicomponent approaches for synthesizing 4H-chromene derivatives, followed by comprehensive optimization and ADME evaluation, holds significant potential. Moreover, the chromene nucleus has demonstrated a broad spectrum of biological applications—such as anticancer, antioxidant, anti-inflammatory, antimicrobial, and enzyme inhibitory activities—making it a highly valuable pharmacophore in medicinal chemistry [ 16 – 20 ]. The present work focuses on the eco-friendly synthesis of novel 4H-chromene-3-carbonitrile derivatives, optimization of reaction parameters, and assessment of their pharmacokinetic and antimicrobial properties. This integrated approach aims to identify potent, multifunctional, and drug-like chromene-based candidates that may contribute to future therapeutic and antimicrobial drug discovery efforts. Materials and Method Sdfine Chemicals, LOBA Chemie, and Merk Ltd. provided all of the chemicals and solvents needed for the synthesis. The melting points shown here are uncorrected and were determined using the open-end capillary method. Merk supplied the TLC plates (TLC silica gel 60 F254) that were utilized to track the reaction's completion. Bruker FT-IR alpha-t (ATR) was used to measure the infrared spectrum data. The Bruker spectrophotometer-400 MHz was utilized to get the 1 H and 13 C NMR, with TMS serving as the reference and DMSO-d6 serving as the solvent. A Shimadzu mass spectrophotometer was used to perform the mass spectral analysis. The Perkin-Elmer 2400 CHN Analyzer was used to do the elemental analysis. Result and discussion Ultrasound irradiation for the synthesis of 1,8- naphthyridine-3-carbonitrile A mixture of 3-methylphenol (10 mmol, 1.08 g), malononitrile (10 mmol, 0.66 g), and benzaldehyde (10 mmol, 1.06 g, 1.01 mL) was suspended in water (10 mL). Morpholine (5 mmol, 0.44 g, ca. 0.43 mL) was added, and the reaction mixture was subjected to ultrasonic irradiation (33 kHz) at 40°C. Reaction progress was monitored by TLC using ethyl acetate/n-hexane (20:80, v/v) as eluent. After completion, the solid product was filtered, washed with water (5 mL), dried, and purified by recrystallization from ethanol to afford the desired 4H-chromene-3-carbonitrile derivative. Table 1 Synthesis of 4 H -chromene − 3-carbonitrile derivatives in both sonication and non-sonication conditions. No. Compound - R Ultrasonic irradiation Conventional method Time (min) Yield (%) Time (min) Yield (%) 1 4a -H 04 88 120 50 2 4b 4-Cl 03 93 180 59 3 4c 3-Cl 03 90 120 54 4 4d 2-Cl 04 84 90 41 5 4e 2-OH 03 83 110 50 6 4f 3-OH 04 84 180 50 7 4g 4-OH 04 85 120 34 8 4h 4-NO2 03 81 180 45 9 4i Furfural 04 80 150 54 10 4j Indole-3-carbaldehyde 04 82 160 59 Comparison of solvents 4 H -chromene-3-carbonitrile and its derivatives were produced utilizing 3-Methyl phenol, Malononitrile and various substituted aldehyde in 1:1:1 stoichiometric ratio. Water is employed as a green solvent and morpholine (5 mmol) as a catalyst. The reaction is taking place due of the ultrasonic irradiation method. A reaction was constructed as a model in order to figure out the ideal solvent which is illustrate in Table no.1 Table 2 The use of different solvents for the reaction of 3-Methyl phenol 1, Malononitrile 2, and 4-chlorobenzaldehyde 3 to afford 2-amino-4-(4-chlorophenyl)-7-methyl-4 H -chromene-3-carbonitrile(4c) No. Solvent Time(min) Yield% 1 Solvent free 06 None 2 Water 03 93 3 Ethanol 06 86 4 Methanol 06 76 5 Acetone 10 61 6 n-Hexane 19 59 7 Toluene 20 - Comparison of ultrasonic irradiation and conventional methods: Enhanced sound is used in ultrasonic irradiation to observe how ultrasound influences a certain reaction. When the reaction was conducted in the usual fashion, it produced low product yields and took longer to complete, but when it was executed under the presence of ultrasonic irradiation, it yielded good product yields in a short reaction time. Ultrasonic irradiation was proven to be superior to the standard approach in terms of yield, reagents, and yield of 4H-chromene-3-carbonitrile derivatives. Table 3 Effect of amount of catalyst in the synthesis of the product 4b No. Amount of morpholine Time(min) Yield % 1 Trace 02 Trace 2 5 03 93 3 10 04 87 4 15 05 82 5 20 06 79 6 25 05 76 7 30 06 72 Table 4 In the synthesis of product 4b, the effect of time is considerable. No. Solvent Time(min) Yield% 1 Water 03 93 2 Water 05 8 3 Water 10 80 4 Water 15 77 5 Water 20 73 Table 5 Temperature Effect on product 4b synthesis No. Solvent Temperature(˚C) Time(min) Yield% 1 Water 30 03 93 2 Water 40 05 87 3 Water 50 05 83 4 Water 60 06 79 5 water 70 06 74 Pharmacology Antibacterial activity Gram-positive bacteria Bacillus subtilis and gram-negative bacteria Escherichia coli were used for antimicrobial activity testing of the newly synthesized compounds 4a-j at different concentrations, with chloramphenicol used as a standard drug for comparison of antibacterial activity of the synthesised novel compounds. In comparison to the standard drug chloramphenicol, only four derivatives (4b (4-Cl), 4h (4-NO 2 ), 4i (Furfural) and 4j (Indole-3-carbaldehyde) demonstrated very good activity against gram positive bacteria Bacillus subtilis at concentrations of 1000, 500, and 250 µg/ml. In comparison to the standard drugs, the compounds 4a (H), and 4e (2-OH) had poor activity against the gram-positive bacteria Bacillus subtilis . Other derivatives performed good against gram-positive bacteria when compared to the standard, as shown in Table 6 . The novel synthesised compounds were tested against gram-negative bacteria Escherichia coli at different concentrations of 1000, 500, 250 µg/ml, and only four compounds (4b (4-Cl), 4h (4-NO 2 ), 4i (Furfural) and 4j (Indole-3-carbaldehyde) were found to have good activity against gram-negative bacteria Escherichia coli when compared to standard drug. When compared to standard drug chloramphenicol, the compounds 4a (H), and 4e (2-OH) had poor activity against gram-negative bacteria Escherichia coli . Other derivatives performed good against gram negative bacteria when compared to the standard, as shown in Table 6 . Antifungal activity The newly synthesized compounds were tested for antifungal activity against Aspergillus niger at concentrations of 1000, 500, 250 µg/ml. Fluconazole was used as a control drug to compare and assess the antifungal activity of the synthesized compounds. At different concentrations, compounds compounds (4b (4-Cl), 4h (4-NO 2 ), 4i (Furfural) and 4j (Indole-3-carbaldehyde) demonstrated excellent activity when compared to the standard drug. Only two derivatives, 4a (H), and 4e (2-OH) demonstrated significant activity against the standard. Othe derivatives performed good against the standard drug fluconazole reported in Table 6 . SAR study-Structure Activity Relationship The synthetic 4H-chromene-3-carbonitrile derivatives' antibacterial assessment demonstrated a distinct structure–activity connection determined by the structural and electronic characteristics of the aldehyde substituents. The strongest antibacterial and antifungal activity was consistently shown by compounds with strong electron-withdrawing groups, such as 4b (4-Cl) and 4h (4-NO₂). This suggests that electron-deficient aromatic rings improve membrane penetration and reinforce binding contacts with microbial targets. Similar to this, the heterocyclic aldehyde derivatives 4i (furfural) and 4j (indole-3-carbaldehyde) showed exceptional broad-spectrum activity, perhaps as a result of increased structural flexibility, hydrogen bonding, and π–π stacking within the enzyme active sites. Conversely, compounds with electron-donating groups like 2-OH (4e) or those without substituents (4a) showed little activity, indicating that higher electron density reduces antimicrobial interactions. Overall, the SAR analysis demonstrates that heterocyclic moieties and para-EWG substitution are essential for boosting antibacterial activity in this series. Table 6 Zone of Inhibition (ZOI) Values of Newly Synthesized Compounds 4 a-j -R (Derivatives) Zone of Inhibition (mm) B. subtilis (Gram-positive bacteria) E. coli (Gram-negative bacteria) A.niger (Fungi) 1000 µg/ml 500 µg/ml 250 µg/ml 1000 µg/ml 500 µg/ml 250 µg/ml 1000 µg/ml 500 µg/ml 250 µg/ml 4a 17 15 10 16 10 8 11 9 6 4b 22 18 14 19 17 14 18 15 12 4c 19 14 12 18 16 12 17 14 10 4d 18 14 12 17 15 12 14 11 9 4e 17 15 - 16 10 - 11 9 - 4f 21 16 13 15 13 11 15 13 11 4g 21 15 13 20 17 14 18 15 12 4h 22 15 13 16 14 11 15 12 10 4i 23 16 14 16 14 11 15 12 10 4j 22 15 13 16 14 11 15 12 10 Fluconazole 22 22 21 Chloramphenicol 30 28 27 30 28 27 ADME and drug-likeness study. The ADME study is important for the discovery of new drugs since they should possess appropriate ADME properties at an appropriate dose. Lipinski's rule of five (ROF) analysis can be employed to separate drug-like molecules from other molecules. For this rule, H-bond acceptors ≤ 10, H-bond donors ≤ 5, molecular weight ≤ 500 Daltons, and log P ≤ 5, is to be noted for orally active drugs in humans, and a violation of a maximum of one is permissible (Table 7 ). The best docked substances and standards' pharmacokinetic properties and bioavailability features are briefly summarized by the bioavailability radar. (Fig. 1 .). Table 7 Drug-likeness screening of compounds 4a–4j. Compound Descriptors for Lipinski’s rule of five No. of violation M.W. Log P No. of H-donor No. of H-bond acceptor 4a 262.31 2.54 1 2 0 4b 296.75 2.74 1 2 0 4c 296.75 2.79 1 2 0 4d 296.75 2.73 1 2 0 4e 273.31 2.22 2 3 0 4f 273.31 2.25 2 3 0 4g 273.31 2.19 2 3 0 4h 307.30 2.25 2 4 0 4i 252.27 2.41 1 3 0 4j 301.34 2.28 1 3 0 Analytical discussion: 2-amino-7-methyl-4-phenyl-4-chromene-3-carbonitrile (4a) 2-amino-7-methyl-4-phenyl-4 H -chromene-3-carbonitrile (4a) Yield 88%, mp 110℃. IR spectrum, ν, cm − 1 : 3325, 2190, 1648, 1575. 1H NMR spectrum, δ, ppm: 2.34 s (3H, CH 3 ), 4.74 s (1H, CH), 6.50 s (2H, NH 2 ), 6.62–7.37 m (8H, Ar-H). 13C NMR spectrum, δC, ppm: 21.0 (CH 3 ), 29.5 (*CH), 59.2 (C-CN), 117.3 (CN), 118.7 (Ar-C), 123.4 (Ar-C), 128.2 (Ar-C), 128.4(Ar-C), 128.6 (Ar-C), 129.7 (Ar-C), 140.0 (C-CH3), 153.2 (C-O), 177.2 (C-NH 2 ). Mass spectrum, m/z: 263.0 [M + H] + . 2-amino-4-(4-chlorophenyl)-7-methyl-4H-chromene-3-carbonitrile (4b) Yield 93%, mp 90℃. IR spectrum, ν, cm − 1 : 3252, 2150, 1687, 1520. 1H NMR spectrum, δ, ppm: 2.32 s (3H, CH 3 ), 4.54 s (1H, CH), 6.20 s (2H, NH 2 ), 6.51–7.30 m (7H, Ar-H). 13C NMR spectrum, δC, ppm: 22.2 (CH 3 ), 28.4 (*CH), 60.1 (C-CN), 116.4 (CN), 117.5 (Ar-C), 124.7 (Ar-C), 127.4 (Ar-C), 128.3 (Ar-C), 128.8 (Ar-C), 131.3 (C-Cl), 141.1 (C-CH3), 152.1 (C-O), 178.3 (C-NH 2 ). Mass spectrum, m/z: 297.0 [M + H] + . 2-amino-4-(3-chlorophenyl)-7-methyl-4H-chromene-3-carbonitrile (4c) Yield 90%, mp 95℃. IR spectrum, ν, cm − 1 : 3250, 2148, 1678, 1525. 1H NMR spectrum, δ, ppm: 2.12 s (3H, CH 3 ), 4.62 s (1H, CH), 6.25 s (2H, NH 2 ), 6.19–7.27 m (7H, Ar-H). 13C NMR spectrum, δC, ppm: 21.3(CH 3 ), 27.5(*CH), 68.0 (C-CN), 115.2 (CN), 117.3 (Ar-C), 124.0 (Ar-C), 127.6 (Ar-C), 128.4 (Ar-C), 128.9 (Ar-C), 134.8 (C-Cl), 142.1 (C-CH 3 ), 154.3 (C-O), 179.3 (C-NH 2 ). Mass spectrum, m/z: 297.0 [M + H] + . 2-amino-4-(2-chlorophenyl)-7-methyl-4H-chromene-3-carbonitrile (4d) Yield 84%, mp 97℃. IR spectrum, ν, cm − 1 : 3236, 2123, 1648, 1598. 1H NMR spectrum, δ, ppm: 2.25 s (3H, CH 3 ), 4.25 s (1H, CH), 6.36 s (2H, NH 2 ), 6.59–7.48 m (7H, Ar-H). 13C NMR spectrum, δC, ppm: 22.9 (CH 3 ), 28.6 (*CH), 67.0 (C-CN), 116.1 (CN), 117.0 (Ar-C), 125.9 (Ar-C), 127.7 (Ar-C), 128.5 (Ar-C), 128.8 (Ar-C), 131.2 (C-Cl), 143.1 (C-CH 3 ), 155.6 (C-O), 179.3 (C-NH 2 ). Mass spectrum, m/z: 297.0 [M + H] + . 2-amino-4-(2-hydroxyphenyl)-7-methyl-4-chromene-3-carbonitrile (4e) 2-amino-4-(2-hydroxyphenyl)-7-methyl-4 H -chromene-3-carbonitrile (4e) Yield 83%, mp 120℃. IR spectrum, ν, cm − 1 : 3500, 3248, 2150, 1647, 1569. 1H NMR spectrum, δ, ppm: 2.28 s (3H, CH 3 ), 4.65 s (1H, CH), 6.45 s (2H, NH 2 ), 6.28–7.50 m (7H, Ar-H), 9.58 s (1H, OH). 13C NMR spectrum, δC, ppm: 21.9 (CH 3 ), 27.6 (*CH), 66.0 (C-CN), 117.1 (CN), 118.2(Ar-C), 126.9 (Ar-C), 127.7 (Ar-C), 128.5 (Ar-C), 128.9 (Ar-C), 129.5 (Ar-C), 144.1(C-CH 3 ), 155.3 (C-O), 155.6 (C-OH), 180.1 (C-NH 2 ). Mass spectrum, m/z: 274.0 [M + H] + . 2-amino-4-(3-hydroxyphenyl)-7-methyl-4-chromene-3-carbonitrile (4f) 2-amino-4-(3-hydroxyphenyl)-7-methyl-4 H -chromene-3-carbonitrile (4f) Yield 84%, mp 108℃. IR spectrum, ν, cm − 1 : 3545, 3220, 2145, 1648, 1578. 1H NMR spectrum, δ, ppm: 2.36 s (3H, CH 3 ), 4.78 s (1H, CH), 6.78 s (2H, NH 2 ), 6.59–7.47 m (7H, Ar-H), 10.21 s (1H, OH). 13C NMR spectrum, δC, ppm: 24.6 (CH 3 ), 28.5 (*CH), 68.0 (C-CN), 117.1 (CN), 118.7 (Ar-C), 127.7 (Ar-C), 128.6 (Ar-C), 128.9 (Ar-C), 129.6 (Ar-C), 129.9 (Ar-C), 145.5 (C-CH 3 ), 155.1 (C-O), 155.9 (C-OH), 182.5 (C-NH 2 ). Mass spectrum, m/z: 274.0 [M + H] + . 2-amino-4-(4-hydroxyphenyl)-7-methyl-4-chromene-3-carbonitrile (4g) 2-amino-4-(4-hydroxyphenyl)-7-methyl-4 H -chromene-3-carbonitrile (4g) Yield 85%, mp 115℃. IR spectrum, ν, cm − 1 : 3525, 3248, 2169, 1652, 1560. 1H NMR spectrum, δ, ppm: 2.34 s (3H, CH 3 ), 4.54 s (1H, CH), 6.69 s (2H, NH 2 ), 6.36–7.69 m (7H, Ar-H), 10.12 s (1H, OH). 13C NMR spectrum, δC, ppm: 21.5 (CH 3 ), 27.3 (*CH), 67.0 (C-CN), 117.1 (CN), 119.2 (Ar-C), 127.6 (Ar-C), 128.2 (Ar-C), 129.7 (Ar-C), 129.9 (Ar-C), 130.1 (Ar-C), 145.5 (C-CH 3 ), 155.1 (C-O), 155.9 (C-OH), 182.5 (C-NH 2 ). Mass spectrum, m/z: 274.0 [M + H] + . 2-amino-4-(4-nitrophenyl)-7-methyl-4-chromene-3-carbonitrile (4h) 2-amino-4-(4-nitrophenyl)-7-methyl-4 H -chromene-3-carbonitrile (4h) Yield 81%, mp 100℃. IR spectrum, ν, cm − 1 : 3250, 2154, 1663, 1525. 1H NMR spectrum, δ, ppm: 2.23 s (3H, CH 3 ), 4.48 s (1H, CH), 6.57 s (2H, NH 2 ), 6.23–7.54 m (7H, Ar-H). 13C NMR spectrum, δC, ppm: 22.5 (CH 3 ), 27.5 (*CH), 68.2 (C-CN), 117.4 (CN), 119.3 (Ar-C), 127.7 (Ar-C), 128.3 (Ar-C), 129.9 (Ar-C), 130.6 (Ar-C), 132.1 (Ar-C), 146.8 (C-NO 2 ), 156.7 (C-O), 183.4 (C-NH 2 ). Mass spectrum, m/z: 308.0 [M + H] + . 2-amino-4-(furan-2-yl)-7-methyl-4-chromene-3-carbonitrile (4i) 2-amino-4-(furan-2-yl)-7-methyl-4 H -chromene-3-carbonitrile (4i) Yield 80%, mp 126℃. IR spectrum, ν, cm − 1 : 3225, 2121, 1645, 1554. 1H NMR spectrum, δ, ppm: 2.20 s (3H, CH 3 ), 4.59 s (1H, CH), 6.23 s (2H, NH 2 ), 6.11–7.47 m (6H, Ar-H). 13C NMR spectrum, δC, ppm: 21.7 (CH 3 ), 28.3 (*CH), 67.1 (C-CN), 117.3 (CN), 127.1 (Ar-C), 128.1(Ar-C), 129.7 (Ar-C), 130.5 (Ar-C), 132.3 (Ar-C), 156.5 (C-O), 183.7 (C-NH 2 ). Mass spectrum, m/z: 253.0 [M + H] + . 2-amino-4-(3-indol-3-yl)-7-methyl-4-chromene-3-carbonitrile (4j) 2-amino-4-(3 H -indol-3-yl)-7-methyl-4 H -chromene-3-carbonitrile (4j) Yield 82%, mp 120℃. IR spectrum, ν, cm − 1 : 3214, 2154, 1665, 1587. 1H NMR spectrum, δ, ppm: 2.34 s (3H, CH 3 ), 3.64 d (1H, CH), 3.9 d (1H, CH), 6.58 s (2H, NH 2 ), 6.68–8.47 m (7H, Ar-H). 13C NMR spectrum, δC, ppm: 21.7 (CH3), 26.5 (*CH), 28.3(CH), 39.4 (CH), 62.1 (CH), 67.1 (C-CN), 110.2 (Ar-C), 115.4 (Ar-C), 127.2 (Ar-C), 128.5 (Ar-C), 129.8 (Ar-C), 130.4 (Ar-C), 132.1 (C-CH 3 ), 146.7 (Ar-C), 152.5 (Ar-C), 165.4 (C-NH), 183.7 (C-NH 2 ). Mass spectrum, m/z: 302.0 [M + H] + . Conclusion The present study successfully demonstrates the efficient green synthesis of 4H-chromene-3-carbonitrile derivatives through a multicomponent reaction method, enabling a sustainable and high-yielding technique. Optimization experiments proved the dependability and reproducibility of the established methodology. The synthesized compounds displayed remarkable antibacterial potential, backed by ADME predictions that highlight their attractive drug-likeness and pharmacokinetic features. Overall, these findings show that 4 H -chromene-based scaffolds hold substantial promise as physiologically active compounds and can be further studied for enhanced therapeutic applications. Declarations Conflict of Interest: There were no commercial or financial links that may be deemed a potential conflict of interest during the research. Consent to Publish declaration : not applicable. Ethics and Consent to Participate declarations not applicable. Funding Sources : The authors received no financial support for the research. Author Contribution Dr. Shweta Patel solely conceptualized the study, carried out the synthesis and characterization, performed biological analyses, interpreted the data, and prepared the manuscript. References John SE, Gulati S, Shankaraiah N. Recent advances in multi-component reactions and their mechanistic insights: a triennium review. Org Chem Front. 2021;8(15):4237–87. https://doi.org/10.1039/D0QO01480J Kar S, Sanderson H, Roy K, Benfenati E, Leszczynski J. Green chemistry in the synthesis of pharmaceuticals. Chem Rev. 2022;122(3):3637–710. https://doi.org/10.1021/acs.chemrev.1c00631 Patel S, Patel S, Vaghani H, Kumbhani J. Chemistry for sustainable development. Chemistry. 2023;31(3):309–16. https://doi.org/10.15372/CSD2023471 Raj V, Lee J. 2H/4H-chromenes: a versatile biologically attractive scaffold. Front Chem. 2020;8:623. https://doi.org/10.3389/fchem.2020.00623 Patel SA. ADME-based drug development of 2H-pyran derivatives with enhanced antimicrobial efficacy. Synlett. 2026;37(2):275–80. https://doi.org/10.1055/a-2726-4310 Song J, Wang SY, Wang X, Jia MQ, Tian XY, Fu XJ, et al. Discovery of a novel coumarin–dihydroquinoxalone derivative MY-673 as a tubulin polymerization inhibitor capable of inhibiting the ERK pathway with potent anti-gastric cancer activity. Bioorg Chem. 2023;137:106580. https://doi.org/10.1016/j.bioorg.2023.106580 Sahoo DK, Mishra NP, Shekh S, Etim EE. Unveiling the molecular interplay between a novel chromene derivative and DNA: a multifaceted investigation. Chem Pap. 2024;78(14):8045–57. https://doi.org/10.1007/s11696-024-03654-5 Jeong GH, Cho JH, Park KI, Kim K, Kim TH. Enzymatic transformation of esculetin as a potent class of α-glucosidase inhibitors. Bioorg Med Chem Lett. 2023;88:129302. https://doi.org/10.1016/j.bmcl.2023.129302 Al Jahdaly BA. Electrochemical and DFT insights into 2-amino-4-(4-hydroxy-3-methoxyphenyl)-7-methyl-4H-chromene-3-carbonitrile for antibacterial activity and corrosion protection of carbon steel. RSC Adv. 2024;14(33):24039–54. https://doi.org/10.1039/D4RA03785E Wu J, Yang X, Pan Y, Zuo T, Ning Z, Li C, et al. Recent developments of automated flow chemistry in pharmaceutical compound synthesis. J Flow Chem. 2023;13(4):385–404. https://doi.org/10.1007/s41981-023-00285-x Patel SP, Patel SA, Vaghani HV, Kumbhani JH. Ultrasound-promoted green synthesis of modified 2-oxochromane derivatives and their antimicrobial profile. Russ J Org Chem. 2023;59(9):1548–54. https://doi.org/10.1134/S1070428023090129 Ghani S, Khan N, Sable H, Yao F, Shafiq M. Computational techniques for enhancing PK/PD modeling, simulation and ADMET prediction. In: Computational Methods in Medicinal Chemistry, Pharmacology, and Toxicology . Academic Press; 2025. p.153–74. https://doi.org/10.1016/B978-0-443-33024-7.00001-1 Ramadan Q, Fardous RS, Hazaymeh R, Alshmmari S, Zourob M. Pharmacokinetics-on-a-chip: in vitro microphysiological models for emulating drug ADME. Adv Biol. 2021;5(9):2100775. https://doi.org/10.1002/adbi.202100775 Daoud NEH, Borah P, Deb PK, Venugopala KN, Hourani W, Alzweiri M, et al. ADMET profiling in drug discovery and development: perspectives of in silico, in vitro and integrated approaches. Curr Drug Metab. 2021;22(7):503–22. https://doi.org/10.2174/1389200222666210705122913 Ancuceanu R, Lascu BE, Drăgănescu D, Dinu M. In silico ADME methods used in the evaluation of natural products. Pharmaceutics. 2025;17(8):1002. https://doi.org/10.3390/pharmaceutics17081002 Patel V, Bambharoliya T, Shah D, Patel D, Patel M, Shah U, et al. Eco-friendly approaches to chromene derivatives: a comprehensive review of green synthesis strategies. Curr Top Med Chem. 2025;25(5):437–60. https://doi.org/10.2174/0115680266305231240712104736 Hojamberdiev M, Vargas R, Madriz L, Kadirova ZC, Yubuta K, Zhang F, et al. Effect of carbonaceous materials on the photoelectrochemical performance of BaTaO₂N. ACS Omega. 2024;9(6):7022–33. https://doi.org/10.1021/acsomega.3c08894 Chen S, Wang X, Cheng Y, Gao H, Chen X. Classification, biosynthesis, biological activities and potential applications of flavonoids. Molecules. 2023;28(13):4982. https://doi.org/10.3390/molecules28134982 Masmoudi N, Chtourou M. Ultrasound-assisted multicomponent synthesis of 4H-pyran derivatives catalyzed by LiOH·H₂O. Curr Org Synth. 2025;22(5):649–61. https://doi.org/10.2174/0115701794351667241112071850 Bendi A, Vashisth C, Devi P, Bhathiwal AS, Pundeer R, Mittal C, et al. From lab to life: the journey of imidazoles through advanced synthesis and biological applications. ChemistrySelect. 2025;10(15):e202500631.https://doi.org/10.1002/slct.202500631 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 11 Mar, 2026 Reviews received at journal 06 Mar, 2026 Reviewers agreed at journal 24 Feb, 2026 Reviews received at journal 21 Feb, 2026 Reviewers agreed at journal 20 Feb, 2026 Reviewers invited by journal 20 Feb, 2026 Editor assigned by journal 06 Feb, 2026 Submission checks completed at journal 05 Feb, 2026 First submitted to journal 28 Jan, 2026 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8718836","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":596122324,"identity":"e7b85446-29cf-4c2c-8e40-f4571add2161","order_by":0,"name":"Dr. Shweta Patel","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8klEQVRIiWNgGAWjYDCCAwxsYJqNvfnggw9gBnFaDBj4eI4lG84AaWEmVoucRI6ZMA9IhJAWvtvHnz3mqfgjz8ZzxozZ5tc2eT5mBsYPH3Nwa5E8l2NuzHPGwLCNva3scW7fbcM2ZgZmyZnbcGsxOMPDJp3bZsDYxnN4u3Fuz21GoBY2Zl68WtifSef+M7Bvk0gwk7bsuW1PhBYGM+ncBoPENokUM2mGH7cTCWqRPMNjJv3nmHFyGyiQextuJ7cxMzbj9Qsf0GGSM2rkbOe3A6Pyx5/bYMaHj3i0oALGNjDZQKx6EPhDiuJRMApGwSgYKQAABuRPlGkdEtgAAAAASUVORK5CYII=","orcid":"","institution":"Department of Chemistry, Faculty of science, Gokul Global University, Sidhpur-384151","correspondingAuthor":true,"prefix":"Dr.","firstName":"Shweta","middleName":"","lastName":"Patel","suffix":""}],"badges":[],"createdAt":"2026-01-28 09:55:53","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8718836/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8718836/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103398515,"identity":"5e1df5a6-1861-473a-8b64-7e955792849e","added_by":"auto","created_at":"2026-02-25 09:05:37","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":191049,"visible":true,"origin":"","legend":"\u003cp\u003eBioavailability radar of compounds 4a-4j where SIZE = molecular weight, POLAR = polarity, FLEX = flexibility, LIPO = lipophilicity and INSATU = unsaturation. The specified region (in red) represents adequate area for given bioavailability characteristics.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8718836/v1/7b2d40daddfd699f125a046a.jpg"},{"id":103507480,"identity":"f90b6c1b-11f6-46fe-b53b-767866e4c2b5","added_by":"auto","created_at":"2026-02-26 13:41:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1691692,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8718836/v1/7f9dac5b-328e-4568-951d-2768f62ae30b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eStructure–Activity Relationship and ADME-Guided Optimization of 4H-Chromene-3-Carbonitrile Derivatives as Promising Antimicrobial Agents\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMulticomponent reactions (MCRs) have emerged as powerful synthetic strategies in modern organic chemistry due to their ability to construct structurally complex and diverse molecules in a single operational step [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. These reactions offer remarkable advantages such as atom economy, operational simplicity, reduced reaction time, and minimal waste generation, making them highly compatible with the principles of green chemistry [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In recent years, the emphasis on sustainable and eco-friendly synthesis has accelerated the use of MCRs for generating biologically active heterocycles with improved efficiency and reduced environmental impact [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAmong the wide variety of heterocyclic scaffolds obtained through green multicomponent methodologies, 4H-chromene derivatives represent an exceptionally important class of compounds. They are widely recognized for their diverse pharmacological activities including antimicrobial, antioxidant, anticancer, anti-inflammatory, and enzyme inhibitory properties [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The presence of the chromene core, in combination with suitable electron-withdrawing or electron-donating substituents, allows for extensive structural modification, which can significantly enhance biological potency and drug-likeness [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In particular, 4H-chromene-3-carbonitrile derivatives have gained significant attention due to their broad-spectrum antimicrobial activity and potential utility as lead molecules in medicinal chemistry [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo develop efficient therapeutic candidates, optimization of reaction conditions is essential for maximizing yield, selectivity, and purity in synthetic pathways. Optimization studies not only refine the synthetic process but also enhance reproducibility and scalability, which are crucial for drug development [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Additionally, modern drug discovery relies heavily on computational approaches, particularly ADME (Absorption, Distribution, Metabolism, and Excretion) analyses, to predict pharmacokinetic behavior and identify compounds with favorable biological profiles prior to in-vivo studies [\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. ADME screening serves as a powerful filter to eliminate compounds with poor pharmacokinetic characteristics at an early stage, thereby accelerating identification of promising drug-like molecules [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eConsidering the biological importance of chromene scaffolds and the growing demand for sustainable synthetic methodologies, the development of green, multicomponent approaches for synthesizing 4H-chromene derivatives, followed by comprehensive optimization and ADME evaluation, holds significant potential. Moreover, the chromene nucleus has demonstrated a broad spectrum of biological applications\u0026mdash;such as anticancer, antioxidant, anti-inflammatory, antimicrobial, and enzyme inhibitory activities\u0026mdash;making it a highly valuable pharmacophore in medicinal chemistry [\u003cspan additionalcitationids=\"CR17 CR18 CR19\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The present work focuses on the eco-friendly synthesis of novel 4H-chromene-3-carbonitrile derivatives, optimization of reaction parameters, and assessment of their pharmacokinetic and antimicrobial properties. This integrated approach aims to identify potent, multifunctional, and drug-like chromene-based candidates that may contribute to future therapeutic and antimicrobial drug discovery efforts.\u003c/p\u003e"},{"header":"Materials and Method","content":"\u003cp\u003eSdfine Chemicals, LOBA Chemie, and Merk Ltd. provided all of the chemicals and solvents needed for the synthesis. The melting points shown here are uncorrected and were determined using the open-end capillary method. Merk supplied the TLC plates (TLC silica gel 60 F254) that were utilized to track the reaction's completion. Bruker FT-IR alpha-t (ATR) was used to measure the infrared spectrum data. The Bruker spectrophotometer-400 MHz was utilized to get the \u003csup\u003e1\u003c/sup\u003eH and \u003csup\u003e13\u003c/sup\u003eC NMR, with TMS serving as the reference and DMSO-d6 serving as the solvent. A Shimadzu mass spectrophotometer was used to perform the mass spectral analysis. The Perkin-Elmer 2400 CHN Analyzer was used to do the elemental analysis.\u003c/p\u003e"},{"header":"Result and discussion","content":"\u003cp\u003eUltrasound irradiation for the synthesis of 1,8- naphthyridine-3-carbonitrile\u003c/p\u003e \u003cp\u003eA mixture of 3-methylphenol (10 mmol, 1.08 g), malononitrile (10 mmol, 0.66 g), and benzaldehyde (10 mmol, 1.06 g, 1.01 mL) was suspended in water (10 mL). Morpholine (5 mmol, 0.44 g, ca. 0.43 mL) was added, and the reaction mixture was subjected to ultrasonic irradiation (33 kHz) at 40\u0026deg;C. Reaction progress was monitored by TLC using ethyl acetate/n-hexane (20:80, v/v) as eluent. After completion, the solid product was filtered, washed with water (5 mL), dried, and purified by recrystallization from ethanol to afford the desired 4H-chromene-3-carbonitrile derivative. \u003c/p\u003e \u003cp\u003e\u003cimg src=\"data:image/png;base64,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\" width=\"724\" height=\"214\"\u003e\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\u003eSynthesis of 4\u003cem\u003eH\u003c/em\u003e-chromene\u0026thinsp;\u0026minus;\u0026thinsp;3-carbonitrile derivatives in both sonication and non-sonication conditions.\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=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNo.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCompound\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e- R\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eUltrasonic irradiation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eConventional method\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTime\u003c/p\u003e \u003cp\u003e(min)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYield (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTime\u003c/p\u003e \u003cp\u003e(min)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eYield (%)\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\u003e4a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-H\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e50\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\u003e4b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4-Cl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e180\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e59\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\u003e4c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3-Cl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e54\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\u003e4d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2-Cl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e41\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\u003e4e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2-OH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e110\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4f\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3-OH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e180\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4-OH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4-NO2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e180\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4i\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFurfural\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4j\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIndole-3-carbaldehyde\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e160\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e59\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\u003eComparison of solvents\u003c/p\u003e \u003cp\u003e4\u003cem\u003eH\u003c/em\u003e-chromene-3-carbonitrile and its derivatives were produced utilizing 3-Methyl phenol, Malononitrile and various substituted aldehyde in 1:1:1 stoichiometric ratio. Water is employed as a green solvent and morpholine (5 mmol) as a catalyst. The reaction is taking place due of the ultrasonic irradiation method. A reaction was constructed as a model in order to figure out the ideal solvent which is illustrate in Table no.1\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\u003eThe use of different solvents for the reaction of 3-Methyl phenol 1, Malononitrile 2, and 4-chlorobenzaldehyde 3 to afford 2-amino-4-(4-chlorophenyl)-7-methyl-4\u003cem\u003eH\u003c/em\u003e-chromene-3-carbonitrile(4c)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolvent\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTime(min)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYield%\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\u003eSolvent free\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNone\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\u003eWater\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e93\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\u003eEthanol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e86\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\u003eMethanol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e76\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\u003eAcetone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en-Hexane\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eToluene\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\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\u003eComparison of ultrasonic irradiation and conventional methods:\u003c/p\u003e\u003cp\u003eEnhanced sound is used in ultrasonic irradiation to observe how ultrasound influences a certain reaction. When the reaction was conducted in the usual fashion, it produced low product yields and took longer to complete, but when it was executed under the presence of ultrasonic irradiation, it yielded good product yields in a short reaction time. Ultrasonic irradiation was proven to be superior to the standard approach in terms of yield, reagents, and yield of 4H-chromene-3-carbonitrile derivatives.\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\u003eEffect of amount of catalyst in the synthesis of the product 4b\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAmount of morpholine\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTime(min)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYield\u003c/p\u003e \u003cp\u003e%\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\u003eTrace\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTrace\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\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e93\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\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e87\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\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e82\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\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e72\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 \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\u003eIn the synthesis of product 4b, the effect of time is considerable.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolvent\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTime(min)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYield%\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\u003eWater\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e93\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\u003eWater\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\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\u003eWater\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e80\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\u003eWater\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e77\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\u003eWater\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e73\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 \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTemperature Effect on product 4b synthesis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolvent\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTemperature(˚C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTime(min)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYield%\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\u003eWater\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e93\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\u003eWater\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e87\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\u003eWater\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e83\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\u003eWater\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e79\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\u003ewater\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003ePharmacology\u003c/h3\u003e\n\u003cp\u003e \u003cb\u003eAntibacterial activity\u003c/b\u003e \u003c/p\u003e \u003cp\u003eGram-positive bacteria \u003cem\u003eBacillus subtilis\u003c/em\u003e and gram-negative bacteria \u003cem\u003eEscherichia coli\u003c/em\u003e were used for antimicrobial activity testing of the newly synthesized compounds 4a-j at different concentrations, with chloramphenicol used as a standard drug for comparison of antibacterial activity of the synthesised novel compounds. In comparison to the standard drug chloramphenicol, only four derivatives (4b (4-Cl), 4h (4-NO\u003csub\u003e2\u003c/sub\u003e), 4i (Furfural) and 4j (Indole-3-carbaldehyde) demonstrated very good activity against gram positive bacteria \u003cem\u003eBacillus subtilis\u003c/em\u003e at concentrations of 1000, 500, and 250 \u0026micro;g/ml. In comparison to the standard drugs, the compounds 4a (H), and 4e (2-OH) had poor activity against the gram-positive bacteria \u003cem\u003eBacillus subtilis\u003c/em\u003e. Other derivatives performed good against gram-positive bacteria when compared to the standard, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eThe novel synthesised compounds were tested against gram-negative bacteria \u003cem\u003eEscherichia coli\u003c/em\u003e at different concentrations of 1000, 500, 250 \u0026micro;g/ml, and only four compounds (4b (4-Cl), 4h (4-NO\u003csub\u003e2\u003c/sub\u003e), 4i (Furfural) and 4j (Indole-3-carbaldehyde) were found to have good activity against gram-negative bacteria \u003cem\u003eEscherichia coli\u003c/em\u003e when compared to standard drug. When compared to standard drug chloramphenicol, the compounds 4a (H), and 4e (2-OH) had poor activity against gram-negative bacteria \u003cem\u003eEscherichia coli\u003c/em\u003e. Other derivatives performed good against gram negative bacteria when compared to the standard, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e\n\u003ch3\u003eAntifungal activity\u003c/h3\u003e\n\u003cp\u003eThe newly synthesized compounds were tested for antifungal activity against \u003cem\u003eAspergillus niger\u003c/em\u003e at concentrations of 1000, 500, 250 \u0026micro;g/ml. Fluconazole was used as a control drug to compare and assess the antifungal activity of the synthesized compounds. At different concentrations, compounds compounds (4b (4-Cl), 4h (4-NO\u003csub\u003e2\u003c/sub\u003e), 4i (Furfural) and 4j (Indole-3-carbaldehyde) demonstrated excellent activity when compared to the standard drug. Only two derivatives, 4a (H), and 4e (2-OH) demonstrated significant activity against the standard. Othe derivatives performed good against the standard drug fluconazole reported in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e\n\u003ch3\u003eSAR study-Structure Activity Relationship\u003c/h3\u003e\n\u003cp\u003eThe synthetic 4H-chromene-3-carbonitrile derivatives' antibacterial assessment demonstrated a distinct structure\u0026ndash;activity connection determined by the structural and electronic characteristics of the aldehyde substituents. The strongest antibacterial and antifungal activity was consistently shown by compounds with strong electron-withdrawing groups, such as 4b (4-Cl) and 4h (4-NO₂). This suggests that electron-deficient aromatic rings improve membrane penetration and reinforce binding contacts with microbial targets. Similar to this, the heterocyclic aldehyde derivatives 4i (furfural) and 4j (indole-3-carbaldehyde) showed exceptional broad-spectrum activity, perhaps as a result of increased structural flexibility, hydrogen bonding, and π\u0026ndash;π stacking within the enzyme active sites. Conversely, compounds with electron-donating groups like 2-OH (4e) or those without substituents (4a) showed little activity, indicating that higher electron density reduces antimicrobial interactions. Overall, the SAR analysis demonstrates that heterocyclic moieties and para-EWG substitution are essential for boosting antibacterial activity in this series.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eZone of Inhibition (ZOI) Values of Newly Synthesized Compounds 4\u003csub\u003ea-j\u003c/sub\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e-R (Derivatives)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"9\" nameend=\"c10\" namest=\"c2\"\u003e \u003cp\u003eZone of Inhibition (mm)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e\u003cem\u003eB. subtilis\u003c/em\u003e\u003c/p\u003e \u003cp\u003e(Gram-positive bacteria)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e\u003cem\u003eE. coli\u003c/em\u003e\u003c/p\u003e \u003cp\u003e(Gram-negative bacteria)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e \u003cp\u003e\u003cem\u003eA.niger\u003c/em\u003e\u003c/p\u003e \u003cp\u003e(Fungi)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1000 \u003cem\u003e\u0026micro;g/ml\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e500 \u003cem\u003e\u0026micro;g/ml\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e250 \u003cem\u003e\u0026micro;g/ml\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1000 \u003cem\u003e\u0026micro;g/ml\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e500 \u003cem\u003e\u0026micro;g/ml\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e250 \u003cem\u003e\u0026micro;g/ml\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1000 \u003cem\u003e\u0026micro;g/ml\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e500 \u003cem\u003e\u0026micro;g/ml\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003e250 \u003cem\u003e\u0026micro;g/ml\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e4b\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e22\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e18\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e14\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e19\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e17\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e14\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e18\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e15\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e12\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\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\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10\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\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4f\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e4h\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e22\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e15\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e13\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e16\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e14\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e11\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e15\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e12\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e4i\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e23\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e16\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e14\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e16\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e14\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e11\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e15\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e12\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e4j\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e22\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e15\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e13\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e16\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e14\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e11\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e15\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e12\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFluconazole\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e22\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e22\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e21\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChloramphenicol\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e30\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e28\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e27\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e30\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e28\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e27\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eADME and drug-likeness study.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe ADME study is important for the discovery of new drugs since they should possess appropriate ADME properties at an appropriate dose. Lipinski's rule of five (ROF) analysis can be employed to separate drug-like molecules from other molecules. For this rule, H-bond acceptors\u0026thinsp;\u0026le;\u0026thinsp;10, H-bond donors\u0026thinsp;\u0026le;\u0026thinsp;5, molecular weight\u0026thinsp;\u0026le;\u0026thinsp;500 Daltons, and log P\u0026thinsp;\u0026le;\u0026thinsp;5, is to be noted for orally active drugs in humans, and a violation of a maximum of one is permissible (Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). The best docked substances and standards' pharmacokinetic properties and bioavailability features are briefly summarized by the bioavailability radar. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab7\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDrug-likeness screening of compounds 4a\u0026ndash;4j.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCompound\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eDescriptors for Lipinski\u0026rsquo;s rule of five\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNo. of violation\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM.W.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLog P\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo. of H-donor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo. of H-bond acceptor\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e262.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e296.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e296.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e296.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e273.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4f\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e273.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e273.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e307.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4i\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e252.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4j\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e301.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\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\n\u003ch3\u003eAnalytical discussion:\u003c/h3\u003e\n\n\u003ch3\u003e2-amino-7-methyl-4-phenyl-4-chromene-3-carbonitrile (4a)\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003e2-amino-7-methyl-4-phenyl-4\u003cem\u003eH\u003c/em\u003e-chromene-3-carbonitrile (4a)\u003c/div\u003e \u003cp\u003eYield 88%, mp 110℃. IR spectrum, ν, cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3325, 2190, 1648, 1575. 1H NMR spectrum, δ, ppm: 2.34 s (3H, CH\u003csub\u003e3\u003c/sub\u003e), 4.74 s (1H, CH), 6.50 s (2H, NH\u003csub\u003e2\u003c/sub\u003e), 6.62\u0026ndash;7.37 m (8H, Ar-H). 13C NMR spectrum, δC, ppm: 21.0 (CH\u003csub\u003e3\u003c/sub\u003e), 29.5 (*CH), 59.2 (C-CN), 117.3 (CN), 118.7 (Ar-C), 123.4 (Ar-C), 128.2 (Ar-C), 128.4(Ar-C), 128.6 (Ar-C), 129.7 (Ar-C), 140.0 (C-CH3), 153.2 (C-O), 177.2 (C-NH\u003csub\u003e2\u003c/sub\u003e). Mass spectrum, m/z: 263.0 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003e2-amino-4-(4-chlorophenyl)-7-methyl-4H-chromene-3-carbonitrile (4b)\u003c/h3\u003e\n\u003cp\u003eYield 93%, mp 90℃. IR spectrum, ν, cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3252, 2150, 1687, 1520. 1H NMR spectrum, δ, ppm: 2.32 s (3H, CH\u003csub\u003e3\u003c/sub\u003e), 4.54 s (1H, CH), 6.20 s (2H, NH\u003csub\u003e2\u003c/sub\u003e), 6.51\u0026ndash;7.30 m (7H, Ar-H). 13C NMR spectrum, δC, ppm: 22.2 (CH\u003csub\u003e3\u003c/sub\u003e), 28.4 (*CH), 60.1 (C-CN), 116.4 (CN), 117.5 (Ar-C), 124.7 (Ar-C), 127.4 (Ar-C), 128.3 (Ar-C), 128.8 (Ar-C), 131.3 (C-Cl), 141.1 (C-CH3), 152.1 (C-O), 178.3 (C-NH\u003csub\u003e2\u003c/sub\u003e). Mass spectrum, m/z: 297.0 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003e2-amino-4-(3-chlorophenyl)-7-methyl-4H-chromene-3-carbonitrile (4c)\u003c/h3\u003e\n\u003cp\u003eYield 90%, mp 95℃. IR spectrum, ν, cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3250, 2148, 1678, 1525. 1H NMR spectrum, δ, ppm: 2.12 s (3H, CH\u003csub\u003e3\u003c/sub\u003e), 4.62 s (1H, CH), 6.25 s (2H, NH\u003csub\u003e2\u003c/sub\u003e), 6.19\u0026ndash;7.27 m (7H, Ar-H). 13C NMR spectrum, δC, ppm: 21.3(CH\u003csub\u003e3\u003c/sub\u003e), 27.5(*CH), 68.0 (C-CN), 115.2 (CN), 117.3 (Ar-C), 124.0 (Ar-C), 127.6 (Ar-C), 128.4 (Ar-C), 128.9 (Ar-C), 134.8 (C-Cl), 142.1 (C-CH\u003csub\u003e3\u003c/sub\u003e), 154.3 (C-O), 179.3 (C-NH\u003csub\u003e2\u003c/sub\u003e). Mass spectrum, m/z: 297.0 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003e2-amino-4-(2-chlorophenyl)-7-methyl-4H-chromene-3-carbonitrile (4d)\u003c/h3\u003e\n\u003cp\u003eYield 84%, mp 97℃. IR spectrum, ν, cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3236, 2123, 1648, 1598. 1H NMR spectrum, δ, ppm: 2.25 s (3H, CH\u003csub\u003e3\u003c/sub\u003e), 4.25 s (1H, CH), 6.36 s (2H, NH\u003csub\u003e2\u003c/sub\u003e), 6.59\u0026ndash;7.48 m (7H, Ar-H). 13C NMR spectrum, δC, ppm: 22.9 (CH\u003csub\u003e3\u003c/sub\u003e), 28.6 (*CH), 67.0 (C-CN), 116.1 (CN), 117.0 (Ar-C), 125.9 (Ar-C), 127.7 (Ar-C), 128.5 (Ar-C), 128.8 (Ar-C), 131.2 (C-Cl), 143.1 (C-CH\u003csub\u003e3\u003c/sub\u003e), 155.6 (C-O), 179.3 (C-NH\u003csub\u003e2\u003c/sub\u003e). Mass spectrum, m/z: 297.0 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003e2-amino-4-(2-hydroxyphenyl)-7-methyl-4-chromene-3-carbonitrile (4e)\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003e2-amino-4-(2-hydroxyphenyl)-7-methyl-4\u003cem\u003eH\u003c/em\u003e-chromene-3-carbonitrile (4e)\u003c/div\u003e \u003cp\u003eYield 83%, mp 120℃. IR spectrum, ν, cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3500, 3248, 2150, 1647, 1569. 1H NMR spectrum, δ, ppm: 2.28 s (3H, CH\u003csub\u003e3\u003c/sub\u003e), 4.65 s (1H, CH), 6.45 s (2H, NH\u003csub\u003e2\u003c/sub\u003e), 6.28\u0026ndash;7.50 m (7H, Ar-H), 9.58 s (1H, OH). 13C NMR spectrum, δC, ppm: 21.9 (CH\u003csub\u003e3\u003c/sub\u003e), 27.6 (*CH), 66.0 (C-CN), 117.1 (CN), 118.2(Ar-C), 126.9 (Ar-C), 127.7 (Ar-C), 128.5 (Ar-C), 128.9 (Ar-C), 129.5 (Ar-C), 144.1(C-CH\u003csub\u003e3\u003c/sub\u003e), 155.3 (C-O), 155.6 (C-OH), 180.1 (C-NH\u003csub\u003e2\u003c/sub\u003e). Mass spectrum, m/z: 274.0 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003e2-amino-4-(3-hydroxyphenyl)-7-methyl-4-chromene-3-carbonitrile (4f)\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003e2-amino-4-(3-hydroxyphenyl)-7-methyl-4\u003cem\u003eH\u003c/em\u003e-chromene-3-carbonitrile (4f)\u003c/div\u003e \u003cp\u003eYield 84%, mp 108℃. IR spectrum, ν, cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3545, 3220, 2145, 1648, 1578. 1H NMR spectrum, δ, ppm: 2.36 s (3H, CH\u003csub\u003e3\u003c/sub\u003e), 4.78 s (1H, CH), 6.78 s (2H, NH\u003csub\u003e2\u003c/sub\u003e), 6.59\u0026ndash;7.47 m (7H, Ar-H), 10.21 s (1H, OH). 13C NMR spectrum, δC, ppm: 24.6 (CH\u003csub\u003e3\u003c/sub\u003e), 28.5 (*CH), 68.0 (C-CN), 117.1 (CN), 118.7 (Ar-C), 127.7 (Ar-C), 128.6 (Ar-C), 128.9 (Ar-C), 129.6 (Ar-C), 129.9 (Ar-C), 145.5 (C-CH\u003csub\u003e3\u003c/sub\u003e), 155.1 (C-O), 155.9 (C-OH), 182.5 (C-NH\u003csub\u003e2\u003c/sub\u003e). Mass spectrum, m/z: 274.0 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003e2-amino-4-(4-hydroxyphenyl)-7-methyl-4-chromene-3-carbonitrile (4g)\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003e2-amino-4-(4-hydroxyphenyl)-7-methyl-4\u003cem\u003eH\u003c/em\u003e-chromene-3-carbonitrile (4g)\u003c/div\u003e \u003cp\u003eYield 85%, mp 115℃. IR spectrum, ν, cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3525, 3248, 2169, 1652, 1560. 1H NMR spectrum, δ, ppm: 2.34 s (3H, CH\u003csub\u003e3\u003c/sub\u003e), 4.54 s (1H, CH), 6.69 s (2H, NH\u003csub\u003e2\u003c/sub\u003e), 6.36\u0026ndash;7.69 m (7H, Ar-H), 10.12 s (1H, OH). 13C NMR spectrum, δC, ppm: 21.5 (CH\u003csub\u003e3\u003c/sub\u003e), 27.3 (*CH), 67.0 (C-CN), 117.1 (CN), 119.2 (Ar-C), 127.6 (Ar-C), 128.2 (Ar-C), 129.7 (Ar-C), 129.9 (Ar-C), 130.1 (Ar-C), 145.5 (C-CH\u003csub\u003e3\u003c/sub\u003e), 155.1 (C-O), 155.9 (C-OH), 182.5 (C-NH\u003csub\u003e2\u003c/sub\u003e). Mass spectrum, m/z: 274.0 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003e2-amino-4-(4-nitrophenyl)-7-methyl-4-chromene-3-carbonitrile (4h)\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003e2-amino-4-(4-nitrophenyl)-7-methyl-4\u003cem\u003eH\u003c/em\u003e-chromene-3-carbonitrile (4h)\u003c/div\u003e \u003cp\u003eYield 81%, mp 100℃. IR spectrum, ν, cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3250, 2154, 1663, 1525. 1H NMR spectrum, δ, ppm: 2.23 s (3H, CH\u003csub\u003e3\u003c/sub\u003e), 4.48 s (1H, CH), 6.57 s (2H, NH\u003csub\u003e2\u003c/sub\u003e), 6.23\u0026ndash;7.54 m (7H, Ar-H). 13C NMR spectrum, δC, ppm: 22.5 (CH\u003csub\u003e3\u003c/sub\u003e), 27.5 (*CH), 68.2 (C-CN), 117.4 (CN), 119.3 (Ar-C), 127.7 (Ar-C), 128.3 (Ar-C), 129.9 (Ar-C), 130.6 (Ar-C), 132.1 (Ar-C), 146.8 (C-NO\u003csub\u003e2\u003c/sub\u003e), 156.7 (C-O), 183.4 (C-NH\u003csub\u003e2\u003c/sub\u003e). Mass spectrum, m/z: 308.0 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003e2-amino-4-(furan-2-yl)-7-methyl-4-chromene-3-carbonitrile (4i)\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003e2-amino-4-(furan-2-yl)-7-methyl-4\u003cem\u003eH\u003c/em\u003e-chromene-3-carbonitrile (4i)\u003c/div\u003e \u003cp\u003eYield 80%, mp 126℃. IR spectrum, ν, cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3225, 2121, 1645, 1554. 1H NMR spectrum, δ, ppm: 2.20 s (3H, CH\u003csub\u003e3\u003c/sub\u003e), 4.59 s (1H, CH), 6.23 s (2H, NH\u003csub\u003e2\u003c/sub\u003e), 6.11\u0026ndash;7.47 m (6H, Ar-H). 13C NMR spectrum, δC, ppm: 21.7 (CH\u003csub\u003e3\u003c/sub\u003e), 28.3 (*CH), 67.1 (C-CN), 117.3 (CN), 127.1 (Ar-C), 128.1(Ar-C), 129.7 (Ar-C), 130.5 (Ar-C), 132.3 (Ar-C), 156.5 (C-O), 183.7 (C-NH\u003csub\u003e2\u003c/sub\u003e). Mass spectrum, m/z: 253.0 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003e2-amino-4-(3-indol-3-yl)-7-methyl-4-chromene-3-carbonitrile (4j)\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003e2-amino-4-(3\u003cem\u003eH\u003c/em\u003e-indol-3-yl)-7-methyl-4\u003cem\u003eH\u003c/em\u003e-chromene-3-carbonitrile (4j)\u003c/div\u003e \u003cp\u003eYield 82%, mp 120℃. IR spectrum, ν, cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e: 3214, 2154, 1665, 1587. 1H NMR spectrum, δ, ppm: 2.34 s (3H, CH\u003csub\u003e3\u003c/sub\u003e), 3.64 d (1H, CH), 3.9 d (1H, CH), 6.58 s (2H, NH\u003csub\u003e2\u003c/sub\u003e), 6.68\u0026ndash;8.47 m (7H, Ar-H). 13C NMR spectrum, δC, ppm: 21.7 (CH3), 26.5 (*CH), 28.3(CH), 39.4 (CH), 62.1 (CH), 67.1 (C-CN), 110.2 (Ar-C), 115.4 (Ar-C), 127.2 (Ar-C), 128.5 (Ar-C), 129.8 (Ar-C), 130.4 (Ar-C), 132.1 (C-CH\u003csub\u003e3\u003c/sub\u003e), 146.7 (Ar-C), 152.5 (Ar-C), 165.4 (C-NH), 183.7 (C-NH\u003csub\u003e2\u003c/sub\u003e). Mass spectrum, m/z: 302.0 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe present study successfully demonstrates the efficient green synthesis of 4H-chromene-3-carbonitrile derivatives through a multicomponent reaction method, enabling a sustainable and high-yielding technique. Optimization experiments proved the dependability and reproducibility of the established methodology. The synthesized compounds displayed remarkable antibacterial potential, backed by ADME predictions that highlight their attractive drug-likeness and pharmacokinetic features. Overall, these findings show that 4\u003cem\u003eH\u003c/em\u003e-chromene-based scaffolds hold substantial promise as physiologically active compounds and can be further studied for enhanced therapeutic applications.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest:\u003c/h2\u003e \u003cp\u003eThere were no commercial or financial links that may be deemed a potential conflict of interest during the research.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eConsent to Publish\u003c/h2\u003e \u003cp\u003e \u003cb\u003edeclaration\u003c/b\u003e: not applicable.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEthics and Consent to Participate declarations\u003c/strong\u003e \u003cp\u003enot applicable.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003cb\u003eFunding Sources\u003c/b\u003e:\u003c/p\u003e \u003cp\u003eThe authors received no financial support for the research.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eDr. Shweta Patel solely conceptualized the study, carried out the synthesis and characterization, performed biological analyses, interpreted the data, and prepared the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003e\u003cstrong\u003eJohn SE, Gulati S, Shankaraiah N.\u003c/strong\u003e Recent advances in multi-component reactions and their mechanistic insights: a triennium review. \u003cem\u003eOrg Chem Front.\u003c/em\u003e 2021;8(15):4237\u0026ndash;87.\u003cstrong\u003ehttps://doi.org/10.1039/D0QO01480J\u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eKar S, Sanderson H, Roy K, Benfenati E, Leszczynski J.\u003c/strong\u003e Green chemistry in the synthesis of pharmaceuticals. \u003cem\u003eChem Rev.\u003c/em\u003e 2022;122(3):3637\u0026ndash;710. https://doi.org/10.1021/acs.chemrev.1c00631\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003ePatel S, Patel S, Vaghani H, Kumbhani J.\u003c/strong\u003e Chemistry for sustainable development. \u003cem\u003eChemistry.\u003c/em\u003e 2023;31(3):309\u0026ndash;16. https://doi.org/10.15372/CSD2023471\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eRaj V, Lee J.\u003c/strong\u003e 2H/4H-chromenes: a versatile biologically attractive scaffold. \u003cem\u003eFront Chem.\u003c/em\u003e 2020;8:623. https://doi.org/10.3389/fchem.2020.00623\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003ePatel SA.\u003c/strong\u003e ADME-based drug development of 2H-pyran derivatives with enhanced antimicrobial efficacy. \u003cem\u003eSynlett.\u003c/em\u003e 2026;37(2):275\u0026ndash;80. https://doi.org/10.1055/a-2726-4310\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eSong J, Wang SY, Wang X, Jia MQ, Tian XY, Fu XJ, et al.\u003c/strong\u003e Discovery of a novel coumarin\u0026ndash;dihydroquinoxalone derivative MY-673 as a tubulin polymerization inhibitor capable of inhibiting the ERK pathway with potent anti-gastric cancer activity. \u003cem\u003eBioorg Chem.\u003c/em\u003e 2023;137:106580. https://doi.org/10.1016/j.bioorg.2023.106580\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eSahoo DK, Mishra NP, Shekh S, Etim EE.\u003c/strong\u003e Unveiling the molecular interplay between a novel chromene derivative and DNA: a multifaceted investigation. \u003cem\u003eChem Pap.\u003c/em\u003e 2024;78(14):8045\u0026ndash;57. https://doi.org/10.1007/s11696-024-03654-5\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eJeong GH, Cho JH, Park KI, Kim K, Kim TH.\u003c/strong\u003e Enzymatic transformation of esculetin as a potent class of \u0026alpha;-glucosidase inhibitors. \u003cem\u003eBioorg Med Chem Lett.\u003c/em\u003e 2023;88:129302. https://doi.org/10.1016/j.bmcl.2023.129302\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eAl Jahdaly BA.\u003c/strong\u003e Electrochemical and DFT insights into 2-amino-4-(4-hydroxy-3-methoxyphenyl)-7-methyl-4H-chromene-3-carbonitrile for antibacterial activity and corrosion protection of carbon steel. \u003cem\u003eRSC Adv.\u003c/em\u003e 2024;14(33):24039\u0026ndash;54. https://doi.org/10.1039/D4RA03785E\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eWu J, Yang X, Pan Y, Zuo T, Ning Z, Li C, et al.\u003c/strong\u003e Recent developments of automated flow chemistry in pharmaceutical compound synthesis. \u003cem\u003eJ Flow Chem.\u003c/em\u003e 2023;13(4):385\u0026ndash;404. https://doi.org/10.1007/s41981-023-00285-x\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003ePatel SP, Patel SA, Vaghani HV, Kumbhani JH.\u003c/strong\u003e Ultrasound-promoted green synthesis of modified 2-oxochromane derivatives and their antimicrobial profile. \u003cem\u003eRuss J Org Chem.\u003c/em\u003e 2023;59(9):1548\u0026ndash;54. https://doi.org/10.1134/S1070428023090129\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eGhani S, Khan N, Sable H, Yao F, Shafiq M.\u003c/strong\u003e Computational techniques for enhancing PK/PD modeling, simulation and ADMET prediction. In: \u003cem\u003eComputational Methods in Medicinal Chemistry, Pharmacology, and Toxicology\u003c/em\u003e. Academic Press; 2025. p.153\u0026ndash;74. https://doi.org/10.1016/B978-0-443-33024-7.00001-1\u003c/li\u003e\n\u003cli\u003eRamadan Q, Fardous RS, Hazaymeh R, Alshmmari S, Zourob M. Pharmacokinetics-on-a-chip: in vitro microphysiological models for emulating drug ADME. \u003cem\u003eAdv Biol.\u003c/em\u003e 2021;5(9):2100775. \u003cstrong\u003ehttps://doi.org/10.1002/adbi.202100775 \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003eDaoud NEH, Borah P, Deb PK, Venugopala KN, Hourani W, Alzweiri M, et al. ADMET profiling in drug discovery and development: perspectives of in silico, in vitro and integrated approaches. \u003cem\u003eCurr Drug Metab.\u003c/em\u003e 2021;22(7):503\u0026ndash;22. https://doi.org/10.2174/1389200222666210705122913\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eAncuceanu R, Lascu BE, Drăgănescu D, Dinu M.\u003c/strong\u003e In silico ADME methods used in the evaluation of natural products. \u003cem\u003ePharmaceutics.\u003c/em\u003e 2025;17(8):1002. https://doi.org/10.3390/pharmaceutics17081002\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003ePatel V, Bambharoliya T, Shah D, Patel D, Patel M, Shah U, et al.\u003c/strong\u003e Eco-friendly approaches to chromene derivatives: a comprehensive review of green synthesis strategies. \u003cem\u003eCurr Top Med Chem.\u003c/em\u003e 2025;25(5):437\u0026ndash;60. https://doi.org/10.2174/0115680266305231240712104736\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eHojamberdiev M, Vargas R, Madriz L, Kadirova ZC, Yubuta K, Zhang F, et al.\u003c/strong\u003e Effect of carbonaceous materials on the photoelectrochemical performance of BaTaO₂N. \u003cem\u003eACS Omega.\u003c/em\u003e 2024;9(6):7022\u0026ndash;33. https://doi.org/10.1021/acsomega.3c08894\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eChen S, Wang X, Cheng Y, Gao H, Chen X.\u003c/strong\u003e Classification, biosynthesis, biological activities and potential applications of flavonoids. \u003cem\u003eMolecules.\u003c/em\u003e 2023;28(13):4982. \u003cbr\u003ehttps://doi.org/10.3390/molecules28134982\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eMasmoudi N, Chtourou M.\u003c/strong\u003e Ultrasound-assisted multicomponent synthesis of 4H-pyran derivatives catalyzed by LiOH\u0026middot;H₂O. \u003cem\u003eCurr Org Synth.\u003c/em\u003e 2025;22(5):649\u0026ndash;61. https://doi.org/10.2174/0115701794351667241112071850\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eBendi A, Vashisth C, Devi P, Bhathiwal AS, Pundeer R, Mittal C, et al.\u003c/strong\u003e From lab to life: the journey of imidazoles through advanced synthesis and biological applications. \u003cem\u003eChemistrySelect.\u003c/em\u003e 2025;10(15):e202500631.https://doi.org/10.1002/slct.202500631\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"chemistry-of-heterocyclic-compounds","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Chemistry of Heterocyclic Compounds](https://link.springer.com/journal/10593)","snPcode":"10593","submissionUrl":"https://submission.springernature.com/new-submission/10593/3","title":"Chemistry of Heterocyclic Compounds","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"4H-chromene-3-carbonitrile, Green synthesis, Multicomponent reaction, Optimization, Antimicrobial activity, ADME study, Bioactive heterocycles","lastPublishedDoi":"10.21203/rs.3.rs-8718836/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8718836/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe wide range of biological activities and advantageous pharmacological characteristics of 4H-chromene derivatives have drawn a lot of attention. In this work, a variety of 4\u003cem\u003eH\u003c/em\u003e-chromene-3-carbonitrile derivatives were synthesized under ideal conditions using an environmentally friendly and effective multicomponent process. High yields, quicker reaction times, and less environmental effect were provided by the synthetic protocol. Several derivatives with significant antibacterial and antifungal properties were found when the synthetic compounds' antimicrobial activity was assessed. ADME prediction experiments also showed appropriate pharmacokinetic behavior, excellent drug-likeness, and oral bioavailability. All things considered, the findings point to these 4H-chromene derivatives as viable options for more medicinal chemistry research.\u003c/p\u003e","manuscriptTitle":"Structure–Activity Relationship and ADME-Guided Optimization of 4H-Chromene-3-Carbonitrile Derivatives as Promising Antimicrobial Agents","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-25 09:05:32","doi":"10.21203/rs.3.rs-8718836/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-11T09:03:36+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-06T16:24:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"276085525057786467166464511294257543638","date":"2026-02-24T07:50:49+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-21T11:58:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"113062201737673789249006365341464289037","date":"2026-02-20T12:40:35+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-20T12:12:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-06T08:52:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-05T14:10:25+00:00","index":"","fulltext":""},{"type":"submitted","content":"Chemistry of Heterocyclic Compounds","date":"2026-01-28T08:23:20+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"chemistry-of-heterocyclic-compounds","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Chemistry of Heterocyclic Compounds](https://link.springer.com/journal/10593)","snPcode":"10593","submissionUrl":"https://submission.springernature.com/new-submission/10593/3","title":"Chemistry of Heterocyclic Compounds","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"fe5c1869-27db-459d-ba23-feed344ae722","owner":[],"postedDate":"February 25th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-23T12:23:05+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-25 09:05:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8718836","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8718836","identity":"rs-8718836","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}