Computational design and drug synthesis of novel anti-tuberculosis agents

Abdali, Jabril Mohammed M 2025. Computational design and drug synthesis of novel anti-tuberculosis agents. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Tuberculosis (TB) remains a major global health challenge, driven by the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains and the limitations of existing treatment regimens. The urgent need for new antimycobacterial agents with novel mechanisms of action has driven investigation into alternative biological targets essential for Mtb survival. Cytochrome P450 (CYP) enzymes are haem-containing monooxygenases involved in a wide range of oxidative metabolic processes. 20 CYP enzymes unique to Mtb represent an underexploited class of targets, offering opportunities for selective inhibition. Among these, CYP121A1 enzyme has been identified as a promising target due to its essentiality for bacterial viability and absence in humans. The aim of this project was to design and develop novel CYP121A1 inhibitors for the treatment of TB, with a focus on achieving both effective target binding and antimycobacterial activity. This thesis investigates the design and development of novel small-molecule inhibitors of CYP121A1 through classical medicinal chemistry using the well-known heterocyclic scaffold chroman-4-one, which has reported antimycobacterial activity, as the starting design. The scaffold was furnished with haem-binding groups and aryl substituents, and structural modifications were applied, including variation of the haem-binding group, linker, and aryl substituents, with the aim of achieving effective CYP121A1 binding and antimycobacterial activity. Computational methods were used to evaluate ligand fit and potential binding interactions within the CYP121A1 active site and to support the interpretation of experimental data. Computational methods were used to evaluate ligand fit and potential binding interactions within the CYP121A1 active site and to support the interpretation of experimental data. Computational modelling, including molecular docking and molecular dynamics simulations, was used to predict binding behaviour within the CYP121A1 active site. Different heterocyclic framework was used in the design: chroman- 4-one (Chapter 2), chromen-4-one (Chapter 3), coumarin, benzofuran, indole and benzisoxazole (Chapter 4), and different haem binding groups were incorporated including pyridine, imidazole and triazole. Computational studies indicated that the designed ligands occupied a region of the CYP121A1 active site situated between the haem centre and the substrate access channel formed by the F and G helices, consistent with the binding position of cYY. Synthetic routes were developed and optimised for each compound series, yielding the final compounds in variable yields, with structural confirmation by NMR spectroscopy and purity assessment using HPLC-MS or elemental analysis. XIX Binding affinities (KD) of the final compounds were determined by UV-Vis spectroscopy and compared with the natural substrate cYY, while antimycobacterial activity was evaluated against both drug sensitive and resistant Mtb strains, with reference to isoniazid, rifampicin, ethambutol, and ethionamide. Several compounds exhibited strong binding affinity alongside antimycobacterial activity, whereas others demonstrated effective target binding without corresponding antimycobacterial activity. This work enabled the rational design and synthesis of CYP121A1 inhibitors exhibiting favourable CYP121A1 binding and antimycobacterial activity.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Pharmacy
Subjects:	Q Science > Q Science (General)
Funders:	Saudi Government
Date of First Compliant Deposit:	19 May 2026
Last Modified:	19 May 2026 14:48
URI:	https://orca.cardiff.ac.uk/id/eprint/187115

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