NLCQ-1 and NLCQ-2, two new agents with activity against dormant Mycobacterium tuberculosis

4-[3-(2-Nitro-1-imidazolyl)-propylamino]-7-chloroquinoline hydrochloride (NLCQ-1; NSC 709257) and 4-[4-(2-nitro-1-imidazolyl)butylamino]-7-chloroquinoline hydrochloride (NLCQ-2), two weak DNA-intercalating nitroimidazole-based bioreductive prodrugs, have been tested against dormant Mycobacterium tuberculosis and demonstrated a significant activity comparable with that of the nitroimidazopyran PA-824. Minimum bactericidal concentrations (MBCs) of 3.1-18.4 and 4.9-9.8 mu g/mL were obtained for NLCQ-I and NLCQ-2, respectively. In the same test setting; the corresponding MBC range for PA-824 was 6.4-12.8 mu g/mL. For rifampicin, isoniazid, minocycline, streptomycin, clarithromycin and capreomycin, the corresponding MBC values were 2.5, > 100, > 156.25, > 12.5, > 312.5 and 37.5 mu g/mL, respectively. Toxicity against Vero cells provided 50% inhibitory concentrations (IC50) of 146.7, > 640 and > 640 mu g/mL for NLCQ-1, NLCQ-2 and PA-824, respectively. Therefore, the selectivity index (SI) was 8-47.3, > 65.3-130.6 and > 50-100 for NLCQ-1, NLCQ-2 and PA-824, respectively. These results suggest the potential usefulness of these compounds in the therapy of the latent form of tuberculosis. (c) 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.