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Saleem, Tabrez Ali (2023) Synthesis of Potential Mycobacterium Tuberculosis InhA Inhibitors. MRes thesis, University of Nottingham.

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Abstract

Tuberculosis caused by Mycobacterium tuberculosis is an infectious disease that predominately affects the lungs. Mycobacterium tuberculosis can be prevented or treated by many anti-tuberculosis drugs. Isoniazid 1 is a prodrug that is used in the treatment against Mycobacterium tuberculosis and for isoniazid 1 to become potent it requires to be activated by KatG prior to forming the isoniazid-NAD+ adduct. However, mutations within the KatG peroxidase results in the resistance of the major antituberculosis drugs, isoniazid 1 and ethionamide 7.

2-Trans-enoyl-acyl carrier protein reductase, InhA, plays a key role in the synthesis of long fatty acid chains. The fatty acid chains are not found within other bacteria or mammals which makes it a key aspect for potential anti-tuberculosis drugs. Triclosan 11 has shown unique InhA inhibition as two molecules of triclosan bind to InhA without the need of activation by KatG. A library of new triclosan derivatives were synthesised and the in silico docking of the proposed products into InhA was completed with the GOLD docking program. The binding affinity of the proposed compounds and InhA was calculated using the GOLD fitness score. The score indicated that [5-(((2,4-dichlorobenzyl)oxy)methyl)-2-phenoxyphenol] 51 had the lowest binding affinity of 77.18 kcal/mol and [5-(((4-(cyclopropylmethoxy)benzyl)oxy)methyl)-2-phenoxyphenol] 52 having the greatest binding affinity of 86.79 kcal/mol, the binding affinity of the designed products correlate to the potential protein-ligand bond energies with 51 having the weakest bond energies and 52 having strong bond energies. GOLD docking also portrayed successful Inh docking potential with 4-(trifluoromethyl)benzyl 48 and 4-bromobenzyl 50 groups which resulted in the preparation and synthesis of the compounds.

Item Type:	Thesis (University of Nottingham only) (MRes)
Supervisors:	Thomas, Neil
Keywords:	tuberculosis, Mycobacterium tuberculosis, fatty acid chains, InhA inhibitors
Subjects:	Q Science > QD Chemistry > QD241 Organic chemistry
Faculties/Schools:	UK Campuses > Faculty of Science > School of Chemistry
Item ID:	73969
Depositing User:	Saleem, Tabrez
Date Deposited:	11 Aug 2025 10:55
Last Modified:	11 Aug 2025 10:55
URI:	https://eprints.nottingham.ac.uk/id/eprint/73969

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