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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Structure-activity relationships of antitubercular nitroimidazoles. 1. structural features associated with aerobic and anaerobic activities of 4 - And 5-nitroimidazoles
Journal of Medicinal Chemistry, Volume 52, No. 5, Year 2009
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Description
The 4-nitroimidazole PA-824 is active against aerobic and anaerobic Mycobacterium tuberculosis(Mtb)while 5-nitroimidazoles like metronidazole are active against only anaerobic Mtb. We have synthesized analogues of both 4 - and 5-nitroimidazoles and explored their antitubercular activities. The nitro group is required for both activities in all compounds. The key determinants of aerobic activity in the 4-nitroimidazoles include the bicyclic oxazine, the lipophilic tail, and the 2-position oxygen. For the 5-nitroimidazoles, neither the corresponding bicyclic analogue nor addition of a lipophilic tail conveyed aerobic activity. Incorporation of a 2-position oxygen atom into a rigid 5-nitroimidazooxazine provided the first 5-nitroimidazole with aerobic activity. Across both series, anaerobic and aerobic activities were not correlated and Mtb mutants lacking the deazaflavin-dependent nitroreductase(Ddn)retained anaerobic sensitivity to some compounds. Aerobic activity appears to be correlated with efficiency as a substrate for Ddn, suggesting a means of structure-based optimization of improved nitroimidazoles. © 2009 American Chemical Society.
Authors & Co-Authors
Manjunatha, Ujjini H.
United States, Bethesda
National Institutes of Health Nih
Singapore, Singapore City
Novartis Institute for Tropical Diseases Pte. Ltd.
Keller, Thomas H.
Singapore, Singapore City
Novartis Institute for Tropical Diseases Pte. Ltd.
Boshoff, Helena Ingrid M.
United States, Bethesda
National Institutes of Health Nih
Barry, Clifton Earl
United States, Bethesda
National Institutes of Health Nih
Dowd, Cynthia S.
United States, Bethesda
National Institutes of Health Nih
United States, Washington, D.c.
The George Washington University
Statistics
Citations: 98
Authors: 5
Affiliations: 5
Identifiers
Doi:
10.1021/jm801246z
ISSN:
00222623