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 microg/mL were obtained for NLCQ-1 and NLCQ-2, respectively. In the same test setting; the corresponding MBC range for PA-824 was 6.4-12.8 microg/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 microg/mL, respectively. Toxicity against Vero cells provided 50% inhibitory concentrations (IC(50)) of 146.7, >640 and >640 microg/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.
Papadopoulou
Maria V
MV
Department of Radiation Medicine, Evanston Northwestern Healthcare, Evanston, 2650 Ridge Ave., IL 60201, USA. m-papadopoulou@northwestern.edu
Bloomer
William D
WD
McNeil
Michael R
MR
D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D007093:Imidazoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000502:physiology*; D009593:Nitroimidazoles / Q000494:pharmacology; D011355:Prodrugs / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D013997:Time Factors; D014709:Vero Cells
C434187:4-(3-(2-nitro-1-imidazolyl)-propylamino)-7-chloroquinoline hydrochloride; D000995:Antitubercular Agents; D007093:Imidazoles; D009593:Nitroimidazoles; D011355:Prodrugs; D011804:Quinolines; C410767:pretomanid