Abstract
Pulmonary tuberculosis, caused by the pathogen Mycobacterium tuberculosis, was declared a world health emergency by the World Health Organisation (WHO) in 1993 and is among the top ten killing infectious diseases. A significant challenge in its treatment is the rise of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains to the antitubercular drug treatments currently used. The rise has been an increasing issue partially attributed to treatment noncompliance, inadequate treatment regimens, and the emergence of TB strains resistant to existing antitubercular drugs. Through the adoption of the strategy of molecular hybridisation, a series of N-aryl-2,5-dimethylpyrrole derivatives, designed as hybrids of the MmpL3 inhibitor antitubercular agents BM212 and SQ109, have been synthesised and evaluated against susceptible and drug-resistant mycobacteria strains. Several derivatives displayed submicromolar activity against M. tuberculosis strains while reporting low eukaryotic toxicity. Additionally, multiple derivatives were active against MDR and XDR strains and intramacrophagic M. tuberculosis. The MmpL3 protein is a therapeutic target for antimycobacterial drug discovery, whose 3D structure, at the time of this work, was not yet elucidated. Through a series of computational techniques, an appropriate 3D model for MmpL3 was generated and evaluated and used to analyse and optimise the binding of the hybrid derivatives previously synthesised. Computational studies suggest that the mycolic acid transporter MmpL3 is a plausible target for the N-aryl-2,5-dimethylpyrrole derivatives, which display similar conformation binding within the active pocket as BM212 and SQ109.A Virtual High-throughput Screening cascade utilising the designed homology model of M. tuberculosis MmpL3 was also performed, leading to the identification of two compounds highly active against the H37Rv strain as well as MDR and XDR strains at submicromolar concentrations. Additionally, these compounds displayed minimal eukaryotic toxicity and therefore present as attractive candidates for preclinical trials.
Lastly, a series of indole derivatives was designed, synthesised, and biologically evaluated through a computer-aided structural rigidification approach of N-aryl-2,5-dimethylpyrroles. One indole derivative was identified as a hit compound, and it exhibited submicromolar activity against M. tuberculosis H37Rv strain, possessed putative intramacrophagic activity, and was highly active against MDR strains while maintaining low eukaryotic toxicity.
| Date of Award | 1 Sept 2022 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Daniele Castagnolo (Supervisor) & James Mason (Supervisor) |