title: Biological evaluation of novel substituted chloroquinolines targeting mycobacterial ATP synthase.
abstract: The ATP synthase of Mycobacterium tuberculosis is a validated drug target against which a diarylquinoline drug is under clinical trials. The enzyme is crucial for the viability both of actively replicating and non-replicating/dormant M. tuberculosis. Enzyme levels drop drastically as the bacilli enter dormancy and hence an inhibitor would make the dormant bacilli even more vulnerable. In this study, a set of 18 novel substituted chloroquinolines were screened against Mycobacterium smegmatis ATP synthase; 6 compounds with the lowest 50% inhibitory concentration (IC(50)) values (0.36-1.83 μM) were selected for further in vitro studies. All six compounds inhibited the growth of M. tuberculosis H37Rv in vitro, with minimum inhibitory concentrations (MICs) of 3.12 μg/mL (two compounds) or 6.25 μg/mL (four compounds). All of them were bactericidal to non-replicating M. tuberculosis H37Rv in hypoxic culture; three compounds caused a >2 log(10) reduction in CFU counts in 4 days at concentrations of 16× or 32× their MICs, compared with a 0.2 log(10) reduction by isoniazid and a >4 log(10) reduction by rifampicin at 100× their MICs. The compounds also contributed to a greater reduction in total cellular ATP of the bacilli compared with isoniazid and rifampicin during an exposure time of 18 h. The compounds at 100 μM caused only 5-35% inhibition of mouse liver mitochondrial ATP synthase, leading to selectivity indices ranging from >55-fold to >278-fold. In vitro cytotoxicity to the Vero cell line measured as the 50% cytotoxic concentration (CC(50)) of the compounds ranged between 55 μg/mL and >300 μg/mL.
authors.affiliation: Division of Microbiology, Council of Scientific and Industrial Research (CSIR)-Central Drug Research Institute, Lucknow, India.
authors.forename: Shaheb Raj
authors.initials: SR
authors.lastname: Khan
authors.forename: Supriya
authors.initials: S
authors.lastname: Singh
authors.forename: Kuldeep K
authors.initials: KK
authors.lastname: Roy
authors.forename: Md Sohail
authors.initials: MS
authors.lastname: Akhtar
authors.forename: Anil K
authors.initials: AK
authors.lastname: Saxena
authors.forename: Manju Yasoda
authors.initials: MY
authors.lastname: Krishnan
mesh_terms: D025181:ATP Synthetase Complexes / Q000037:antagonists & inhibitors*; D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D002739:Chloroquinolinols / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D015169:Colony Count, Microbial; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008826:Microbial Sensitivity Tests; D020102:Mycobacterium smegmatis / Q000201:enzymology; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D002739:Chloroquinolinols; D004791:Enzyme Inhibitors; D025181:ATP Synthetase Complexes