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

Publication date: Available online 6 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Manikandan Alagumuthu, Sivakumar Arumugam
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), IC50 0.389 μg/mL; 2-(3-phenoxyphenyl)-4-phenylquinolin-6-ol (4e), IC50 0.328 μg/mL; and 5,7-dichloro-2-(3-phenoxyphenyl)-4-phenylquinolin-6-ol (4h), IC50 0.214 μg/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^-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 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^+ve bacteria rather than Gram^-ve. 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.

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