Journal
CHEMMEDCHEM
Volume 9, Issue 11, Pages 2528-2537Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201402255
Keywords
enoyl reductase; molecular docking; Mycobacterium tuberculosis; mycolic acid; triclosan scaffold
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Funding
- NIH Centers for AIDS Research Grant (CFAR) at the Albert Einstein College of Medicine [AI-051519]
- National Institutes of Health Grant [AI26170]
- Rutgers University-NJMS
- Chicago State University College of Pharmacy
- Chicago State University Center for Teaching and Research Excellence (Faculty Seed Grant)
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New triclosan (TRC) analogues were evaluated for their activity against the enoyl-acyl carrier protein reductase InhA in Mycobacterium tuberculosis (Mtb). TRC is a well-known inhibitor of InhA, and specific modifications to its positions5 and 4 afforded 27 derivatives; of these compounds, seven derivatives showed improved potency over that of TRC. These analogues were active against both drug-susceptible and drug-resistant Mtb strains. The most active compound in this series, 4-(n-butyl)-1,2,3-triazolyl TRC derivative 3, had an MIC value of 0.6gmL(-1) (1.5M) against wild-type Mtb. At a concentration equal to its MIC, this compound inhibited purified InhA by 98%, and showed an IC50 value of 90nM. Compound 3 and the 5-methylisoxazole-modified TRC 14 were able to inhibit the biosynthesis of mycolic acids. Furthermore, mc(2)4914, an Mtb strain overexpressing inhA, was found to be less susceptible to compounds 3 and 14, supporting the notion that InhA is the likely molecular target of the TRC derivatives presented herein.
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