Biological evaluation of novel substituted chloroquinolines targeting mycobacterial ATP synthase

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 (IC50) values (0.36-1.83 mu M) 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 mu g/mL (two compounds) or 6.25 mu g/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 16x or 32x their MICs, compared with a 0.2 log(10) reduction by isoniazid and a > 4 log(10) reduction by rifampicin at 100x 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 mu M 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 (CC50) of the compounds ranged between 55 mu g/mL and >300 mu g/mL. (C) 2012 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.