Triclosan Derivatives: Towards Potent Inhibitors of Drug‐Sensitive and Drug‐Resistant Mycobacterium tuberculosis

Abstract

Triclosan has been previously shown to inhibit InhA, an essential enoyl acyl carrier protein reductase of mycolic acid biosynthesis, whose inhibition leads to the lysis of Mycobacterium tuberculosis. Using a structure-based drug design approach, a series of 5-substituted derivatives of triclosan was developed. Two groups of triclosan derivatives with alkyl and aryl substituents, respectively, were identified with dramatically enhanced potency against purified InhA. The most efficacious inhibitor displayed an IC50 value of 21 nM, 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 (13 µM), which represents a tenfold improvement over the bacteriocidal activity of triclosan. A subset of these triclosan analogs 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.

Novel Inhibitors of InhA Efficiently Kill Mycobacterium tuberculosis under Aerobic and Anaerobic Conditions

“…GlaxoSmithKline and the TB Alliance have conducted an InhA target-based screen of a million compounds and are in the lead optimization phase (http://www.tballiance.org/new /portfolio/html-portfolio-item.php?idϭ5). Series of analogs of triclosan, another InhA inhibitor (25), that showed good activities against the enoyl reductase InhA of M. tuberculosis (7), as well as the enoyl reductase PfENR of Plasmodium falciparum (15), have also been synthesized. Our goal was to identify new InhA inhibitors that, unlike INH, do not require activation by KatG and could therefore be active against katG-deficient INH R M. tuberculosis strains.…”

X‐ray crystallographic analysis of the complexes of enoyl acyl carrier protein reductase of Plasmodium falciparum with triclosan variants to elucidate the importance of different functional groups in enzyme inhibition

“…Our study also revealed the structural basis for the enhanced affinity of triclosan in the presence of a cofactor and the better binding of the cofactor in the ternary complex (20). Different triclosan analogues were generated and tested against different organisms such as E. coli ENR (EcENR) (28) and M. tuberculosis InhA (MtENR) (29,30). Freundlich et al have also synthesized and tested 2 0 , 4 0 , and 4 substituted triclosan derivatives for their biological activity against PfENR (31)(32)(33).…”

Insight into the Key Structural Features of Potent Enoyl Acyl Carrier Protein Reductase Inhibitors Based on Computer Aided Molecular Design

“…Chemical structures and experimental biological activities expressed as IC 50 (the half maximal inhibitory concentration) of 17 compounds of 5-substituted triclosan derivatives (Freundlich et al, 2009) and 12 alkyl diphenyl ether derivatives (am Ende et al, 2008; were selected for the present study. All chemical structures of these compounds were constructed using standard tools available in GaussView 3.07 program (Gaussian, Inc., 2006) and were then fully optimized using an ab initio quantum chemical method (HF/3-21G) implemented in the Gaussian 03 program (Gaussian, Inc., 2004).…”

“…The mutations in KatG have been linked to the major mechanism of INH resistance ( de la Iglesia et al, 2006;Banerjee et al, 1994). To overcome the INH resistance associated with mutations in KatG, compounds that directly inhibit the InhA enzyme without requiring activation of KatG have been developed as new promising agents against tuberculosis (Freundlich et al, 2009;am Ende et al, 2008;Boyne et al, 2007;He et al, 2006;He et al, 2007;Kuo et al, 2003). Triclosan, 5-chloro-2-(2,4-dichlorophenoxy)phenol as shown in Fig.1, has been shown to inhibit InhA without the requirement for KatG-mediated activation (Parikh et al, 2000;Kuo et al, 2003).…”

“…Triclosan, 5-chloro-2-(2,4-dichlorophenoxy)phenol as shown in Fig.1, has been shown to inhibit InhA without the requirement for KatG-mediated activation (Parikh et al, 2000;Kuo et al, 2003). Because of the remarkable properties of triclosan, a series of triclosan derivatives with modifications at the 5-chloro of triclosan, 5-substituted triclosan derivatives shown in Fig.1, was synthesized in order to optimize the potency of triclosan against InhA (Freundlich et al, 2009). Furthermore, using structure-based drug design, three lipophilic chlorine atoms of triclosan were removed, and one chlorine atom of ring A was replaced by an alkyl chain of varying length resulting in the alkyl diphenyl ethers shown in Fig.…”