title: Design, synthesis, biological evaluation and molecular modelling studies of novel quinoline derivatives against Mycobacterium tuberculosis.
abstract: We herein describe the synthesis and antimycobacterial activity of a series of 27 different derivatives of 3-benzyl-6-bromo-2-methoxy-quinolines and amides of 2-[(6-bromo-2-methoxy-quinolin-3-yl)-phenyl-methyl]-malonic acid monomethyl ester. The antimycobacterial activity of these compounds was evaluated in vitro against Mycobacterium tuberculosis H37Rv for nine consecutive days upon a fixed concentration (6.25 microg/mL) at day one in Bactec assay and compared to untreated TB cell culture as well as one with isoniazide treated counterpart, under identical experimental conditions. The compounds 3, 8, 17 and 18 have shown 92-100% growth inhibition of mycobacterial activity, with minimum inhibitory concentration (MIC) of 6.25 microg/mL. Based on our molecular modelling and docking studies on well-known diarylquinoline antitubercular drug R207910, the presence of phenyl, naphthyl and halogen moieties seem critical. Comparison of docking studies on different stereoisomers of R207910 as well as compounds from our data set, suggests importance of electrostatic interactions. Further structural analysis of docking studies on our compounds suggests attractive starting point to find new lead compounds with potential improvements.
authors.affiliation: Institute of Molecular Medicine, Pune 411 057, India.
authors.forename: Ram Shankar
authors.initials: RS
authors.lastname: Upadhayaya
authors.forename: Jaya Kishore
authors.initials: JK
authors.lastname: Vandavasi
authors.forename: Nageswara Rao
authors.initials: NR
authors.lastname: Vasireddy
authors.forename: Vivek
authors.initials: V
authors.lastname: Sharma
authors.forename: Shailesh S
authors.initials: SS
authors.lastname: Dixit
authors.forename: Jyoti
authors.initials: J
authors.lastname: Chattopadhyaya
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D064687:Diarylquinolines; D015195:Drug Design; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; D011804:Quinolines; C493870:bedaquiline