Design, Synthesis and Biological Evaluation of Novel Inhibitors of InhA from Mycobacterium tuberculosis

Armstrong, Tom (2021) Design, Synthesis and Biological Evaluation of Novel Inhibitors of InhA from Mycobacterium tuberculosis. PhD thesis, University of Nottingham.

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Multi-drug resistant tuberculosis (MDR-TB) represents a growing problem for global healthcare systems. The World Health Organisation reported 1.3 million deaths from tuberculosis in 2019, making the disease a leading cause of global mortality. In addition to this, there is an increasing spread of drug-resistant tuberculosis infections, with 390,000 new cases of MDR-TB recorded in 2019, these are infections resistant to Rifampicin and Isoniazid. Isoniazid is a key anti-TB drug and an inhibitor of InhA, a crucial enzyme in the cell wall biosynthesis pathway and identical in Mycobacterium tuberculosis and Mycobacterium bovis. Isoniazid is a prodrug which requires activation by the enzyme KatG, this active species then forms an adduct with the NAD+ cofactor which then binds to InhA and prevents substrate recognition. Mutations in KatG prevent this activation and confer INH-resistance. ‘Direct inhibitors’ of InhA are attractive as they would circumvent the main clinically observed resistance mechanisms.

A total of 50 new compounds have been designed and synthesised as potential direct InhA inhibitors. These compounds were based on the triclosan (TCL) scaffold, which has been shown to act as a moderate, direct inhibitor of InhA. These compounds were evaluated using the GOLD molecular docking platform to interrogate their ability to bind to InhA.

The inhibitory activity of these compounds was evaluated via isolated enzyme assays using octenoyl CoA as the substrate. The most potent novel design strategy derivative inhibitor was di-TCL triazole compound 55 exhibiting an IC50 value 5.6 μM, compared to 10 μM for TCL. TCL derivatives bearing modifications to the phenolic ring have previously been shown to be effective InhA inhibitors, the most potent derivative synthesised in this work was ether-linked 97, exhibiting an IC50 of 340 nM. Whole-cell evaluation of these compounds was performed against M. bovis. This testing revealed a number of compounds which were potent against the whole-cell bacteria despite being only weakly active against InhA. The most potent of these compounds were triazole 64 and amines 88 and 94, which all displayed MIC99 values of 13 μM against M. bovis, respectively. There is scope for the structure of these compounds to be optimised to further improve their potency.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Thomas, Neil R.
Keywords: Tuberculosis, Drug Design, Enzyme Inhibitors, TB, Triazoles, Triclosan, Spider Silk
Subjects: Q Science > QD Chemistry > QD241 Organic chemistry
R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Faculties/Schools: UK Campuses > Faculty of Science > School of Chemistry
Item ID: 65723
Depositing User: Armstrong, Tom
Date Deposited: 18 Jan 2024 09:29
Last Modified: 18 Jan 2024 09:29

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