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

Shailee Tiwari,Aniket Sarkate,Maria Vazquez-Tato,Julio Seijas,Kshipra Karnik,Anna Nikalje

doi:10.3390/molecules22071172

Abstract

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-2H-chromen-2-onederivatives 4a–o as potential antimicrobial agents. The structures of the synthesized compounds were confirmed by IR, 1H-NMR, 13C-NMR, mass spectral studies and elemental analyses. All the synthesized compounds were evaluated for their in vitro antifungal and antibacterial activity. The compound 4k bearing 4-hydroxy-3-ethoxy group on the phenyl ring was found to be the most active antifungal agent. The compound 4e 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 4k was established by an ergosterol extraction and quantitation assay. From the assay it was found that 4k acts by inhibition of ergosterol biosynthesis in C. albicans. 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 in silico ADMET properties to establish oral drug like behavior and showed satisfactory results. To establish the antimicrobial selectivity and safety, the most active compounds 4e and 4k were further tested for cytotoxicity against human cancer cell line HeLa and were found to be non-cytotoxic in nature. An in vivo acute oral toxicity study was also performed for the most active compounds 4e and 4k and results indicated that the compounds are non-toxic.

Highlights

Many drug-resistant human pathogenic microbes have been observed in the past few decades [1]and this is becoming a serious public health problem in a wide range of infectious diseases [2,3].In spite of a large number of antibiotics and chemotherapeutics available for medical use, antimicrobial resistance has created a substantial medical need for new classes of antimicrobial agents as these resistant pathogenic microbe strains cause antimicrobial treatment failure and enhance the mortality risks and sometimes contribute to complications
One approach to the discovery of novel and potent antimicrobial agents is by Coumarin is a class of heterocyclic compounds containing a benzene ring structure and modifying the structure of a well- known antimicrobial agent while the second strategy is to combine an α-pyrone, a moiety found in Nature and withinto multiple biological activities [6]
Be biologically active, we of report our research program [18,19] studying the synthesis of the novel heterocyclic compound which may be the synthesis of some novel heterocyclic compounds incorporating a combination of coumarin, biologically active, we report the synthesis of some novel heterocyclic compounds incorporating dicyclohexylamine and β-amino carbonyl pharmacophores

Summary

Introduction

Many drug-resistant human pathogenic microbes have been observed in the past few decades [1]and this is becoming a serious public health problem in a wide range of infectious diseases [2,3].In spite of a large number of antibiotics and chemotherapeutics available for medical use, antimicrobial resistance has created a substantial medical need for new classes of antimicrobial agents as these resistant pathogenic microbe strains cause antimicrobial treatment failure and enhance the mortality risks and sometimes contribute to complications. One approach to the discovery of novel and potent antimicrobial agents is by Coumarin is a class of heterocyclic compounds containing a benzene ring structure and modifying the structure of a well- known antimicrobial agent while the second strategy is to combine an α-pyrone, a moiety found in Nature and withinto multiple biological activities [6]. It is together two or morecommonly different antimicrobial pharmacophores one molecule

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Discussion

Conclusion