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 |
| |
| Authors: | Dr Jozef Stec Dr Catherine Vilchèze Dr Shichun Lun Dr Alexander L Perryman Xin Wang Prof Joel S Freundlich Prof William Bishai Prof William R Jacobs Jr Prof Alan P Kozikowski |
| |
| Affiliation: | 1. Drug Discovery Program, Department of Medicinal Chemistry & Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612 (USA);2. Department of Pharmaceutical Sciences, College of Pharmacy, Chicago State University, 9501 South King Drive, Chicago, IL 60628 (USA);3. Howard Hughes Medical Institute, Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY 10461 (USA);4. Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, Baltimore, MD 21231‐1044 (USA);5. Center for Emerging & Re‐emerging Pathogens, Division of Infectious Diseases, Department of Medicine, Rutgers University – New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 (USA);6. Department of Pharmacology & Physiology, Rutgers University – New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 (USA) |
| |
| 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, mc24914, 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. |
| |
| Keywords: | enoyl reductase molecular docking Mycobacterium tuberculosis mycolic acid triclosan scaffold |
|
|
