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. Issue 11 (27th August 2014)

• Record Type: Journal Article
• Authors: Stec, Jozef; Vilchèze, Catherine; Lun, Shichun; Perryman, Alexander L.; Wang, Xin; Freundlich, Joel S.; Bishai, William; Jacobs, William R.; Kozikowski, Alan P.
• Is Part Of: ChemMedChem. Volume 9:Issue 11(2014:Nov.)
• Page Start: 2528
• Page End: 2537
• Publication Date: 2014-08-27
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201402255
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>New triclosan (TRC) analogues were evaluated for their activity against the enoyl–acyl carrier protein reductase InhA in <italic>Mycobacterium tuberculosis</italic> (<italic>Mtb</italic>). 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 <italic>Mtb</italic> strains. The most active compound in this series, 4‐(<italic>n</italic>‐butyl)‐1, 2, 3‐triazolyl TRC derivative <bold>3</bold>, had an MIC value of 0.6 μg mL⁻¹ (1.5 μ<sc>M</sc>) against wild‐type <italic>Mtb</italic>. At a concentration equal to its MIC, this compound inhibited purified InhA by 98 %, and showed an IC₅₀ value of 90 n<sc>M</sc>. Compound <bold>3</bold> and the 5‐methylisoxazole‐modified TRC <bold>14</bold> were able to inhibit the biosynthesis of mycolic acids. Furthermore, mc²4914, an <italic>Mtb</italic> strain overexpressing <italic>inhA</italic>, was found to be less susceptible to compounds <bold>3</bold> and <bold>14</bold>, supporting the notion that InhA is the likely molecular target of the TRC derivatives presented herein.</p> </abstract>