Ionic Liquid-Promoted Synthesis of Novel Chromone-Pyrimidine Coupled Derivatives, Antimicrobial Analysis, Enzyme Assay, Docking Study and Toxicity Study.

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

doi:10.3390/molecules23020440

Abstract

Herein, we report an environmentally friendly, rapid, and convenient ionic liquid ([Et3NH][HSO4])-promoted facile synthesis of ethyl 4-(6-substituted-4-oxo-4H-chromen-3-yl)-6-methyl-2-thioxo/oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives 4(a–f) and 4-(6-substituted-4-oxo-4H-chromen-3-yl)-6-methyl-2-thioxo/oxo-1,2,3,4-tetrahydropyrimidine-5- carbohydrazide derivatives 6(a–f). All the synthesized derivatives 4(a–f) and 6(a–f) were evaluated for their in vitro antifungal and antibacterial activity, by method recommended by National Committee for Clinical Laboratory Standards (NCCLS). The compound 6c bearing a fluoro group on the chromone ring and oxygen and a hydrazino group (–NHNH2) on the pyrimidine ring, was found to be the most potent antibacterial compound amongst the synthesized derivatives. The compound 6f bearing a methoxy group (–OCH3) on the chromone ring and sulphur group on the pyrimidine ring, was found to exhibit equipotent antifungal activity when compared with the standard drug miconazole. A d-alanine-d-alanine ligase (DdlB) enzyme assay study and an ergosterol extraction and quantitation assay study were performed to predict the mode of action of the synthesized compounds. A molecular docking study was performed to predict the binding interactions with receptors and mode of action of the synthesized derivatives. Further, analysis of the ADMET parameters for the synthesized compounds has shown that these compounds have good oral drug-like properties and can be developed as oral drug candidates. To establish the antimicrobial selectivity and safety, the most active compounds 6c and 6f were further tested for cytotoxicity against the 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 6c and 6f and the results indicated that the compounds are non-toxic in nature.

Highlights

In the past few decades many drug-resistant human pathogenic microbes have been observed [1]and this is a serious public health dilemma in a wide range of infectious disease [2,3]
The compound 6f bearing a –OCH3 group on the chromone ring and a sulphur group on the pyrimidine ring, was found to exhibit equipotent antifungal activity when compared with the standard drug miconazole
There is almost a flat peak of compound 6f at its MIC100 value, which is almost similar to that of standard drug miconazole at its MIC100 value. These results suggest that the compound 6f might inhibit the important enzyme in fungus, i.e., lanosterol 14α-demethylase, in a similar manner to that accepted mechanism of the standard drug miconazole

Summary

Introduction

In the past few decades many drug-resistant human pathogenic microbes have been observed [1]and this is a serious public health dilemma in a wide range of infectious disease [2,3]. Failure in the antimicrobial treatment is mostly observed due to the resistance developed in the microbes, which leads to increased risks to mortality and sometimes contributes to complications. Molecules 2018, 23, 440 the antimicrobial treatment is mostly observed due to the resistance developed in the microbes, which leads to increased risks to mortality and sometimes contributes to complications. In spite of the large number of antibiotics which will be effective against strains which have developed resistance. In spite of the large number and chemotherapeutics available for medical use, antimicrobial resistance has created a substantial of antibiotics and chemotherapeutics available for medical use, antimicrobial resistance has created medical need for new classes of antimicrobial agents. The design and synthesis of novel antimicrobials a substantial medical need for new classes of antimicrobial agents. The design and synthesis of agents will forever remain an area gigantic connotation

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Discussion

Conclusion