Synthesis and antileprosy activity of some dialkyldithiocarbamates.
OBJECTIVE
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.
Makarov
Vadim
V
Department of Medicinal Chemistry, Research Center for Antibiotics, 117105 Moscow, Russia.
Riabova
Olga B
OB
Yuschenko
Anatoly
A
Urlyapova
Nailya
N
Daudova
Adilya
A
Zipfel
Peter F
PF
Möllmann
Ute
U
D000818:Animals; D015169:Colony Count, Microbial; D003622:Dapsone / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006801:Humans; D007917:Leprostatic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D007918:Leprosy / Q000188:drug therapy* / Q000382:microbiology; D051379:Mice; D008808:Mice, Inbred CBA; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009161:Mycobacterium / Q000187:drug effects*; D009166:Mycobacterium leprae / Q000187:drug effects*; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use
D007917:Leprostatic Agents; D013859:Thiocarbamates; D003622:Dapsone