Inhibition of Mycobacterium tuberculosis InhA: Design, synthesis and evaluation of new di-triclosan derivatives. Issue 22 (15th November 2020)

• Record Type: Journal Article
• Authors: Armstrong, Tom; Lamont, Malcolm; Lanne, Alice; Alderwick, Luke J.; Thomas, Neil R.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 22(2020)
• Publication Date: 2020-11-15
• Subjects: InhA -- Triclosan -- Triazole -- Isoniazid -- Mycobacterium tuberculosis -- TB; ETH ethambutol -- GOLD Genetic Optimisation for Ligand Docking -- HIV human immunodeficiency virus -- HPLC high-performance liquid chromatography -- INH isoniazid -- MDR-TB multi-drug resistant tuberculosis -- NAD nicotinamide adenine dinucleotide (oxidised form) -- NADH nicotinamide adenine dinucleotide (reduced form) -- PZA pyrazinamide -- RIF rifampicin -- RuAAC ruthenium-catalysed azide alkyne cycloaddition, TB, tuberculosis -- TCS triclosan -- XDR-TB extensively drug-resistant tuberculosis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115744
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 .