Inhibition of Mycobacterium tuberculosis InhA: Design, synthesis and evaluation of new di-triclosan derivatives

Armstrong, Tom; Lamont, Malcolm; Lanne, Alice; Alderwick, Luke J.; Thomas, Neil R.

Abstract

Multi-drug resistant tuberculosis (MDR-TB) represents a growing problem for global healthcare systems. In addition to 1.3 million deaths in 2018, the World Health Organisation reported 484,000 new cases of MDR-TB. Isoniazid is a key anti-TB drug that inhibits InhA, a crucial enzyme in the cell wall biosynthesis pathway and identical in Mycobacterium tuberculosis and M. bovis. Isoniazid is a pro-drug which requires activation by the enzyme KatG, mutations in KatG prevent activation and confer INH-resistance. ‘Direct inhibitors’ of InhA are attractive as they would circumvent the main clinically observed resistance mechanisms. A library of new 1,5-triazoles, designed to mimic the structures of both triclosan molecules uniquely bound to InhA have been synthesised. The inhibitory activity of these compounds was evaluated using isolated enzyme assays with 2 (5-chloro-2-(4-(5-(((4-(4-chloro-2-hydroxyphenoxy)benzyl)oxy)methyl)-1H-1,2,3-triazol-1-yl)phenoxy)phenol) exhibiting an IC50 of 5.6 µM. Whole-cell evaluation was also performed, with 11 (5-chloro-2-(4-(5-(((4-(cyclopropylmethoxy)benzyl)oxy)methyl)-1H-1,2,3-triazol-1-yl)phenoxy)phenol) showing the greatest potency, with an MIC99 of 12.9 µM against M. bovis.

• Journal Article Type: Article
• Acceptance Date: Aug 27, 2020
• Online Publication Date: Sep 8, 2020
• Publication Date: Nov 15, 2020
• Deposit Date: Oct 14, 2020
• Publicly Available Date: Sep 9, 2021
• Journal: Bioorganic & Medicinal Chemistry
• Print ISSN: 0968-0896
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 28
• Issue: 22
• Article Number: 115744
• DOI: https://doi.org/10.1016/j.bmc.2020.115744
• Keywords: Organic Chemistry; Clinical Biochemistry; Molecular Medicine; Biochemistry; Molecular Biology; Drug Discovery; Pharmaceutical Science
• Public URL: https://nottingham-repository.worktribe.com/output/4963509
• Publisher URL: https://www.sciencedirect.com/science/article/abs/pii/S0968089620305745