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JAC Advance Access published online on April 4, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl095
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received January 11, 2006
Revised February 24, 2006
Accepted March 1, 2006

Original article

Synthesis and antileprosy activity of some dialkyldithiocarbamates

Vadim Makarov 1, Olga B. Riabova 1, Anatoly Yuschenko 2, Nailya Urlyapova 2, Adilya Daudova 2, Peter F. Zipfel 3, and Ute Möllmann 3 *

1 Department of Medicinal Chemistry, Research Center for Antibiotics, 117105 Moscow, Russia
2 Leprosy Research Institute, 414000 Astrakhan, Russia
3 Leibniz Institute for Natural Product Research and Infection Biology--Hans-Knoell Institute, D-07745 Jena, Germany

* To whom correspondence should be addressed.
Ute Möllmann, E-mail: ute.moellmann{at}hki-jena.de


  Abstract

Objectives: To investigate the antileprosy potential of a set of original compounds with antimycobacterial activity.

Methods: 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.

Results: 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.

Conclusions: Individual synthetic dithiocarbamate derivatives have promising antileprosy activity.

Keywords: leprosy; mouse footpad model; antileprosy agents; dithiocarbamates; nitropyridines.
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