Microwave assisted synthesis of new quinolone and coumarin molecular hybrids: SAR, molecular modelling studies as dual antagonists and its antimicrobial evaluation targeting bacterial and fungal infections

Abstract

A highly efficient microwave assisted synthesis of new quinolone and coumarin molecular hybrids has been developed in the present work by direct approach. The synthesis is based on dehydrohalogenation and dehydration followed by the condensation of amine derivatives with oxygen atom of the chromone intermediate ring and CCl bonds. A series of 7-(2‑chloro ethoxy)-4-methyl-1H-quinolones 5(a-b), 6(a-c) and 7-(2-substituted ethoxy)-4-methyl-chromones 7(a-f) derivatives have been explored as dual antagonists using molecular modelling simulations targeting bacterial and fungal infections. The results clearly demonstrated the stronger binding affinity of compounds 6b (-8.5 kcal/mol, -9.4 kcal/mol) and 7d (-7.9 kcal/mol, -9.3 kcal/mol) towards peptide formylase and tubulin alpha beta heterodimer proteins which were comparatively higher as compared to standards ciprofloxacin (-7.1 kcal/mol) and griseofulvin (-7.6 kcal/mol) respectively. The in-vitro antimicrobial studies carried out using broth dilution method on various bacterial and fungal strains were found to be consistent with the docking results. Out of the synthesized derivatives compounds 5b, 6b and 7d revealed significant antibacterial activity against E.coli (MIC: 15.62, 15.62 and 15.62 μg/ml), P.aeruginosa (MIC: 31.25, 31.25 and 15.62 μg/ml), S.pyogenes (MIC: 31.25, 15.62 and 31.25 μg/ml) and antifungal activity against C.albicans (MIC: 31.25, 31.25 and 31.25 μg/ml) and A.niger (MIC: 31.25, 31.25 and 62.5 μg/ml) respectively. The results obtained from in-vitro antimicrobial studies clearly depicts the potential antimicrobial activity of outperformed compounds 5b, 6b and 7d in the management of bacterial and fungal infections.