Molecular docking, discovery, synthesis, and pharmacological properties of new 6-substituted-2-(3-phenoxyphenyl)-4-phenyl quinoline derivatives; an approach to developing potent DNA gyrase inhibitors/antibacterial agents.

Synthesis and molecular validation of 6-substituted-2-(3-phenoxyphenyl)-4-phenylquinoline derivatives (4a-h) as antibacterial/DNA gyrase inhibitors reported. Primarily, 6-substituted-2-(3-phenoxyphenyl)-4-phenylquinoline derivatives were docked into the active sites of DNA gyrase A&B, to ensure the binding mode of the compounds, and the results were superior on DNA gyrase A over DNA gyrase B. Based on this, S. aureus DNA gyrase A assay was proposed and executed. Most prominent DNA gyrase inhibition showed by 6-fluoro-2-(3-phenoxyphenyl)-4-phenylquinoline (4c), IC 0.389μg/mL; 2-(3-phenoxyphenyl)-4-phenylquinolin-6-ol (4e), IC 0.328μg/mL; and 5,7-dichloro-2-(3-phenoxyphenyl)-4-phenylquinolin-6-ol (4h), IC 0.214μg/mL which were substituted with fluorine (4F), nitrile (4CN), hydroxyl group (4OH) and dichloro-hydroxyl (3,5Cl, 4OH) groups in the quinoline scaffold. Antimicrobial activity on Gram bacteria Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 424), and Gram bacteria Staphylococcus aureus (MTCC 96) and Streptococcus pyogenes (MTCC 442) was evaluated. Excellent antibacterial activity showed by S. aureus and S. pyogenes which indicates the activity dominance of 6-substituted-2-(3-phenoxyphenyl)-4-phenylquinoline derivatives on Gram bacteria rather than Gram. Subsequently, the cytotoxicity of 6-substituted-2-(3-phenoxyphenyl)-4-phenylquinoline derivatives was evaluated. Cytotoxicity results of MCF-7 (human breast cancer) and G361 (skin melanoma cancer) cell lines reveals that the 6-substituted-2-(3-phenoxyphenyl)-4-phenylquinoline derivatives are highly toxic to cancer cells. Predicted SAR, Lipinski's filter, Pharmacokinetic, and ADMET properties were also ensured the druggability probabilities of most favorable compounds among 6-substituted-2-(3-phenoxyphenyl)-4-phenylquinoline derivatives.