A series of new quinoline derivatives has been designed, synthesized and evaluated as antibacterial and antifungal agents functioning as peptide deformylase enzyme (PDF) inhibitors and fungal cell wall disruptors on the basis of computational and experimental methods. The molecular docking and ADMET assessment aided in the synthesis of quinoline derivatives starting from 6-amino-4-methyl-1H-quinoline-2-one substituted with different types of sulfonyl/benzoyl/propargyl moieties. These newly synthesized compounds were evaluated for their in vitro antibacterial and antifungal activity. Antibacterial screening of all compounds showed excellent MIC value (MIC, 50 - 3.12 µg/mL) against bacterial strains, viz. Bacillus cerus, Staphylococcus, Pseudomonas and Escherichia coli. Compounds 2 and 6 showed better activity. Fractional inhibitory concentration (FIC) values of compounds were lowered by 1/2 to 1/128 of the original MIC values when a combinatorial screening with reference drugs was performed. Further, antifungal screening against fungal strains, viz. A. flavus, A. niger, F. oxysporum and C. albicans also showed that all compounds were potentially active and compound 6 being the most potent. Further, the cytotoxicity experiments revealed that compound 6 was the least toxic molecule. The molecular dynamics (MD) simulation investigations elucidated the conformational stability of compound 6-PDF complex with flexible binding pocket residues. The highest number of stable hydrogen bonds with the PDF residues during the entire simulation time illustrated strong binding affinity of compound 6 with PDF.Communicated by Ramaswamy H. Sarma.
Keywords: DFT; FIC; MD simulations; MIC; Quinolines; antimicrobial assay; docking.