Computational Approaches to Develop Isoquinoline Based Antibiotics through DNA Gyrase Inhibition Mechanisms Unveiled through Antibacterial Evaluation and Molecular Docking.

Developing a new antibacterial drug by using (Z/E)-4-(4-substituted-benzylidene)-2-isoquinoline-1,3(2H,4H)-diones (5a-h) via DNA gyrase inhibition mechanism is the main aim of this study. DNA gyrase inhibition assay was executed to confirm the DNA gyrase inhibition potentials of 5a-h. DNA gyrase inhibitory potentials were further validated through molecular docking. Docking study was also intended to get more insight into the binding mode of 5a-h into the active site of DNA gyrase A. Agar well diffusion method antimicrobial activity on Gram-ve bacteria Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 424), and Gram+ve bacteria (Staphylococcus aureus (MTCC 96) and Streptococcus pyogenes (MTCC 442) was evaluated. Excellent DNA gyrase inhibition was exhibited by the compound 5c, IC50 0.55±0.12 μM; 5d, IC50 0.65±0.075 μg/mL; 5e, IC50 0.45±0.035 μM; 5f, IC50 0.58±0.025 μM; 5h, IC50 0.25±0.015 μM while Clorobiocin (standard) showed IC50 0.5±0.05 μM. Apart from all the in vitro studies, a plausible mechanism of DNA gyrase inhibition was also proposed through the in silico validations that are including molecular docking, predicted SAR, functional group availability, pharmacokinetic, and ADMET properties. These predictions are well supported to confirm the druggability possibility of the most potent compounds among (Z/E)-4-(4-substituted-benzylidene)-2-isoquinoline-1,3(2H,4H) -diones (5a-h).