Makarov Vadim, Riabova Olga B, Yuschenko Anatoly, Urlyapova Nailya, Daudova Adilya, Zipfel Peter F, Möllmann Ute
Department of Medicinal Chemistry, Research Center for Antibiotics, 117105 Moscow, Russia.
J Antimicrob Chemother. 2006 Jun;57(6):1134-8. doi: 10.1093/jac/dkl095. Epub 2006 Apr 4.
To investigate the antileprosy potential of a set of original compounds with antimycobacterial activity.
We developed a facile synthesis of 2-chloro-3-cyano-5-nitropyridine and synthesized a series of 3-cyano-2-dialkyldithiocarbamoyl-5-nitropyridine derivatives. In vivo therapeutic efficacy against Mycobacterium leprae was assessed in the infected mouse footpad model.
The compounds were active in vitro against Mycobacterium smegmatis, Mycobacterium aurum, Mycobacterium vaccae and Mycobacterium fortuitum, with MICs generally in the range of 0.4-6.25 mg/L. Reduction of the bacterial load in vivo in the mouse footpad and toxic side effects were dependent on the individual structure of the compounds and on the doses applied. Compounds 2a, 3a and 3b reduced the number of M. leprae by two orders of magnitude, comparable to the effect of dapsone. Co-administration of compounds 2a and 3a with dapsone synergistically enhanced the activity. In addition, these compounds were well tolerated over the treatment period of 7.5 months.
Individual synthetic dithiocarbamate derivatives have promising antileprosy activity.
