Facile Synthesis of Novel Coumarin Derivatives, Antimicrobial Analysis, Enzyme Assay, Docking Study, ADMET Prediction and Toxicity Study

• Published in: Molecules (Basel, Switzerland) Switzerland), 2017-07, Vol.22 (7), p.1172
• Main Authors: Tiwari, Shailee V, Seijas, Julio A, Vazquez-Tato, Maria Pilar, Sarkate, Aniket P, Karnik, Kshipra S, Nikalje, Anna Pratima G
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - therapeutic use; Anti-Infective Agents - chemical synthesis; Anti-Infective Agents - chemistry; Anti-Infective Agents - therapeutic use; Antibacterial activity; Antibacterial materials; antifungal activity; Antimicrobial agents; Assaying; Biocompatibility; Biosynthesis; Cancer; Candida albicans - drug effects; Candida albicans - pathogenicity; Coumarin; Coumarins - chemical synthesis; Coumarins - chemistry; Coumarins - therapeutic use; Cytotoxicity; Enzymes; Ergosterol; Fungicides; Humans; in vivo acute oral toxicity; In vivo methods and tests; ionic liquid; Ionic liquids; Lanosterol; Microbial Sensitivity Tests; Mode of action; Molecular docking; Molecular Docking Simulation; Molecular Structure; Quantitation; Structure-Activity Relationship; Toxicity testing
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules22071172

The work reports the synthesis under solvent-free condition using the ionic liquid [Et₃NH][HSO₄] as a catalyst of fifteen novel 3-((dicyclohexylamino)(substituted phenyl/heteryl)-methyl)-4-hydroxy-2 -chromen-2-onederivatives - as potential antimicrobial agents. The structures of the synthesized compounds were confirmed by IR, ¹H-NMR, C-NMR, mass spectral studies and elemental analyses. All the synthesized compounds were evaluated for their antifungal and antibacterial activity. The compound bearing 4-hydroxy-3-ethoxy group on the phenyl ring was found to be the most active antifungal agent. The compound bearing a 2,4-difluoro group on the phenyl ring was found to be the most active antibacterial agent. The mode of action of the most promising antifungal compound was established by an ergosterol extraction and quantitation assay. From the assay it was found that acts by inhibition of ergosterol biosynthesis in . Molecular docking studies revealed a highly spontaneous binding ability of the tested compounds to the active site of lanosterol 14α-demethylase, which suggests that the tested compounds inhibit the synthesis of this enzyme. The synthesized compounds were analyzed for ADMET properties to establish oral drug like behavior and showed satisfactory results. To establish the antimicrobial selectivity and safety, the most active compounds and were further tested for cytotoxicity against human cancer cell line HeLa and were found to be non-cytotoxic in nature. An acute oral toxicity study was also performed for the most active compounds and and results indicated that the compounds are non-toxic.