Recent progress in the identification and development of InhA direct inhibitors of Mycobacterium tuberculosis.
The InhA-related enoyl-ACP reductase, an enzyme involved in fatty acid synthesis, is one of the best validated targets for the development of anti-tubercular agents. However, the majority of isoniazid (INH)-resistant clinical strains are observed mainly due to the emergence of KatG mutants that do not form an INH-NAD adduct. Thus compounds that directly inhibit InhA avoiding activation by KatG would be promising candidates for combating MDR-TB. Herein, some predominant examples of InhA direct inhibitors recently developed are reviewed and special attention is paid to 3D-structures of InhA in drug design process.
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Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing210009, China.
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Chen
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D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D007538:Isoniazid / Q000031:analogs & derivatives / Q000494:pharmacology; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D009243:NAD / Q000031:analogs & derivatives / Q000494:pharmacology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D014260:Triclosan / Q000737:chemistry / Q000494:pharmacology
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D009243:NAD; D014260:Triclosan; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium; D007538:Isoniazid