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Article

New InhA Inhibitors Based on Expanded Triclosan and Di-Triclosan Analogues to Develop a New Treatment for Tuberculosis

1
Biodiscovery Institute, School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
2
School of Pharmacy, University of Nottingham, University Park, Nottingham NG7 2RD, UK
3
Department of Biological Sciences, Birkbeck, Institute of Structural and Molecular Biology, University of London, London WC1E 7HX, UK
*
Author to whom correspondence should be addressed.
Current Addresses: S.C. Pharmacology Division, Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 1864, South Africa; D.E. Department of Microbial Diseases, UCL Eastman Dental Institute, University College London, London NW3 2PF, UK; S.S.K. Agenus, Lexington, MA 02421, USA.
Academic Editor: Paweł Kafarski
Pharmaceuticals 2021, 14(4), 361; https://doi.org/10.3390/ph14040361
Received: 11 March 2021 / Revised: 7 April 2021 / Accepted: 10 April 2021 / Published: 14 April 2021
(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2020)
The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) has reinforced the need for the development of new anti-TB drugs. The first line drug isoniazid inhibits InhA. This is a prodrug requiring activation by the enzyme KatG. Mutations in KatG have largely contributed to clinical isoniazid resistance. We aimed to design new ‘direct’ InhA inhibitors that obviate the need for activation by KatG, circumventing pre-existing resistance. In silico molecular modelling was used as part of a rational structure-based drug-design approach involving inspection of protein crystal structures of InhA:inhibitor complexes, including the broad spectrum antibiotic triclosan (TCS). One crystal structure exhibited the unusual presence of two triclosan molecules within the Mycobacterium tuberculosis InhA binding site. This became the basis of a strategy for the synthesis of novel inhibitors. A series of new, flexible ligands were designed and synthesised, expanding on the triclosan structure. Low Minimum Inhibitory Concentrations (MICs) were obtained for benzylphenyl compounds (12, 43 and 44) and di-triclosan derivative (39), against Mycobacterium bovis BCG although these may also be inhibiting other enzymes. The ether linked di-triclosan derivative (38) displayed excellent in vitro isolated enzyme inhibition results comparable with triclosan, but at a higher MIC (125 µg mL−1). These compounds offer good opportunities as leads for further optimisation. View Full-Text
Keywords: tuberculosis; structure-based drug-design; molecular modelling; InhA; triazole; triclosan; isoniazid; Mycobacterium tuberculosis; Mycobacterium bovis BCG tuberculosis; structure-based drug-design; molecular modelling; InhA; triazole; triclosan; isoniazid; Mycobacterium tuberculosis; Mycobacterium bovis BCG
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MDPI and ACS Style

Chetty, S.; Armstrong, T.; Sharma Kharkwal, S.; Drewe, W.C.; De Matteis, C.I.; Evangelopoulos, D.; Bhakta, S.; Thomas, N.R. New InhA Inhibitors Based on Expanded Triclosan and Di-Triclosan Analogues to Develop a New Treatment for Tuberculosis. Pharmaceuticals 2021, 14, 361. https://doi.org/10.3390/ph14040361

AMA Style

Chetty S, Armstrong T, Sharma Kharkwal S, Drewe WC, De Matteis CI, Evangelopoulos D, Bhakta S, Thomas NR. New InhA Inhibitors Based on Expanded Triclosan and Di-Triclosan Analogues to Develop a New Treatment for Tuberculosis. Pharmaceuticals. 2021; 14(4):361. https://doi.org/10.3390/ph14040361

Chicago/Turabian Style

Chetty, Sarentha, Tom Armstrong, Shalu Sharma Kharkwal, William C. Drewe, Cristina I. De Matteis, Dimitrios Evangelopoulos, Sanjib Bhakta, and Neil R. Thomas 2021. "New InhA Inhibitors Based on Expanded Triclosan and Di-Triclosan Analogues to Develop a New Treatment for Tuberculosis" Pharmaceuticals 14, no. 4: 361. https://doi.org/10.3390/ph14040361

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