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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. 2. determinants of aerobic activity and quantitative structure-activity relationships
Journal of Medicinal Chemistry, Volume 52, No. 5, Year 2009
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Description
The (S)-2-nitro-6-substituted 6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazines have been extensively explored for their potential use as new antituberculars based on their excellent bactericidal properties on aerobic whole cells of Mycobacterium tuberculosis. An oxygen atom at the 2-position of the imidazole ring is required for aerobic activity. Here, we show that substitution of this oxygen by either nitrogen or sulfur yielded equipotent analogues. Acylating the amino series, oxidizing the thioether, or replacing the ether oxygen with carbon significantly reduced the potency of the compounds. Replacement of the benzylic oxygen at the 6-position by nitrogen slightly improved potency and facilitated exploration of the SAR in the more soluble 6-amino series. Significant improvements in potency were realized by extending the linker region between the 6-(S) position and the terminal hydrophobic aromatic substituent. A simple four-feature QSAR model was derived to rationalize MIC results in this series of bicyclic nitroimidazoles. © 2009 American Chemical Society.
Authors & Co-Authors
Boshoff, Helena Ingrid M.
United States, Bethesda
National Institutes of Health Nih
Manjunatha, Ujjini H.
United States, Bethesda
National Institutes of Health Nih
Singapore, Singapore City
Novartis Institute for Tropical Diseases Pte. Ltd.
Goodwin, Michael B.
United States, Bethesda
National Institutes of Health Nih
Dick, Thomas
Singapore, Singapore City
Novartis Institute for Tropical Diseases Pte. Ltd.
Keller, Thomas H.
Singapore, Singapore City
Novartis Institute for Tropical Diseases Pte. Ltd.
Dowd, Cynthia S.
United States, Bethesda
National Institutes of Health Nih
United States, Washington, D.c.
The George Washington University
Barry, Clifton Earl
United States, Bethesda
National Institutes of Health Nih
Statistics
Citations: 83
Authors: 7
Affiliations: 6
Identifiers
Doi:
10.1021/jm801374t
ISSN:
00222623
Research Areas
Environmental
Study Approach
Quantitative