title: Biological evaluation of potent triclosan-derived inhibitors of the enoyl-acyl carrier protein reductase InhA in drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis.
abstract: 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 positions 5 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 0.6 μg mL(-1) (1.5 μM) against wild-type Mtb. At a concentration equal to its MIC, this compound inhibited purified InhA by 98 %, and showed an IC50 value of 90 nM. 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.
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry & Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612 (USA); Department of Pharmaceutical Sciences, College of Pharmacy, Chicago State University, 9501 South King Drive, Chicago, IL 60628 (USA). jstec@csu.edu.
authors.forename: Jozef
authors.initials: J
authors.lastname: Stec
authors.forename: Catherine
authors.initials: C
authors.lastname: Vilchèze
authors.forename: Shichun
authors.initials: S
authors.lastname: Lun
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Perryman
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Joel S
authors.initials: JS
authors.lastname: Freundlich
authors.forename: William
authors.initials: W
authors.lastname: Bishai
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D009171:Mycolic Acids / Q000737:chemistry; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014260:Triclosan / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D009171:Mycolic Acids; D014260:Triclosan; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium
keywords: Mycobacterium tuberculosis; enoyl reductase; molecular docking; mycolic acid; triclosan scaffold