Design, synthesis, antimicrobial screening and molecular modeling of novel 6,7 dimethylquinoxalin-2(1H)-one and thiazole derivatives targeting DNA gyrase enzyme.

New 6,7-dimethylquinoxalin-2(1H)-one and hydrazineylidene thiazol-4-one derivatives were synthesized, and evaluated for their in vitro antimicrobial activity. The obtained results revealed marked antimicrobial potential against four bacterial, and two fungal strains. Both 6,7-dimethyl-3-(2-(4-nitrophenyl)-2-oxoethyl)quinoxalin-2(1H)-one (4d), and 2-(2-(9H-fluoren-9-ylidene)hydrazineyl)-5-(2-(p-tolyl)hydrazineylidene)thiazol-4(5H)-one (11b) displayed significant antibacterial and antifungal activities having MIC ranges (1.98-15.6 mg/mL) and (1.98-3.9 mg/mL) compared to Tetracycline and Amphotericin B as standard drugs. In addition, they showed noticeable inhibitory activity against DNA gyrase enzyme. Interestingly the thiazole derivative (11b) showed marked inhibitory activity against DNA gyrase with IC50  = 7.82 ± 0.45 μM better than that of ciprofloxacin. The time-kill kinetics profile of the most active compounds against S. aureus and E. coli microorganisms displayed both concentration dependent and time dependent reduction in the number of viable cells. Furthermore, molecular docking study of both compounds in the DNA gyrase binding site was performed, showing agreement with the in vitro inhibitory activities.