title: 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.
abstract: 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), IC500.389μg/mL; 2-(3-phenoxyphenyl)-4-phenylquinolin-6-ol (4e), IC500.328μg/mL; and 5,7-dichloro-2-(3-phenoxyphenyl)-4-phenylquinolin-6-ol (4h), IC500.214μg/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-vebacteria Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 424), and Gram+vebacteria 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+vebacteria 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.
authors.affiliation: Dept. of Biotechnology, School of Bio-Sciences and Technology, VIT University, Vellore 632014, India.
authors.forename: Manikandan
authors.initials: M
authors.lastname: Alagumuthu
authors.affiliation: Dept. of Biotechnology, School of Bio-Sciences and Technology, VIT University, Vellore 632014, India. Electronic address: mailtomicromani@gmail.com.
authors.forename: Sivakumar
authors.initials: S
authors.lastname: Arumugam
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D027081:DNA Gyrase / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004926:Escherichia coli / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects; D013297:Streptococcus pyogenes / Q000187:drug effects; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D011804:Quinolines; D059005:Topoisomerase II Inhibitors; D027081:DNA Gyrase
keywords: Antibacterial; DNA gyrase A; Drug discovery; Molecular docking; Phenoxyphenyl quinolines