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Triclosan Derivatives: Towards Potent Inhibitors of Drug‐Sensitive and Drug‐Resistant Mycobacterium tuberculosis
Author(s) -
Freundlich Joel S.,
Wang Feng,
Vilchèze Catherine,
Gulten Gulcin,
Langley Robert,
Schiehser Guy A.,
Jacobus David P.,
Jacobs William R.,
Sacchettini James C.
Publication year - 2009
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200800261
Subject(s) - triclosan , inha , isoniazid , mycobacterium tuberculosis , chemistry , microbiology and biotechnology , pharmacology , drug , stereochemistry , tuberculosis , medicine , biology , pathology
Overcoming resistance : Isoniazid (INH) is a frontline antitubercular drug that inhibits the enoyl acyl carrier protein reductase InhA. Novel inhibitors of InhA that are not cross‐resistant to INH represent a significant goal in antitubercular chemotherapy. The design, synthesis, and biological activity of a series of triclosan‐based inhibitors is reported, including their promising efficacy against INH‐resistant strains of M. tuberculosis.Triclosan has been previously shown to inhibit InhA, an essential enoyl acyl carrier protein reductase involved in mycolic acid biosynthesis, the inhibition of which leads to the lysis of Mycobacterium tuberculosis . Using a structure‐based drug design approach, a series of 5‐substituted triclosan derivatives was developed. Two groups of derivatives with alkyl and aryl substituents, respectively, were identified with dramatically enhanced potency against purified InhA. The most efficacious inhibitor displayed an IC 50 value of 21 n M , which was 50‐fold more potent than triclosan. X‐ray crystal structures of InhA in complex with four triclosan derivatives revealed the structural basis for the inhibitory activity. Six selected triclosan derivatives were tested against isoniazid‐sensitive and resistant strains of M. tuberculosis . Among those, the best inhibitor had an MIC value of 4.7 μg mL −1 (13 μ M ), which represents a tenfold improvement over the bacteriocidal activity of triclosan. A subset of these triclosan analogues was more potent than isoniazid against two isoniazid‐resistant M. tuberculosis strains, demonstrating the significant potential for structure‐based design in the development of next generation antitubercular drugs.