Martin, Liam Thomas;
(2021)
The Synthesis and Evaluation of N-Heterocycles as Antitubercular Agents.
Doctoral thesis (Ph.D), UCL (University College London).
Abstract
Tuberculosis, the disease caused by the microbial pathogen Mycobacterium tuberculosis, is one of the world’s leading infectious causes of death. In 2019, the World Health Organisation estimated that 10 million new cases of tuberculosis were contracted, and 1.4 million people died from the disease. Among these new cases, it is estimated that 465,000 displayed resistance to at least one first line antitubercular drug. Consequently, there is an urgent need for novel antitubercular drug candidates to combat the growing number and variety of drug-resistant strains of M. tuberculosis. It has previously been established that several C-1-substituted tetrahydroisoquinolines have antitubercular properties. To probe the antimycobacterial potential of this scaffold, two chemical series were synthesised for structure-activity relationship analysis. The influence of key structural features on the antimycobacterial potency and mammalian cell cytotoxicity of this compound class was determined. However, it was found that structural features which lead to an increase in the former also lead to an increase in the latter. This resulted in limited selectivity for toxicity to mycobacterial cells over mammalian cells. It has previously been demonstrated that the carbazole-based non-steroidal anti-inflammatory drug carprofen has antitubercular activity. In order to build an understanding of the antitubercular potential of carprofen-like compounds, three chemical series were synthesised for structure-activity relationship analysis. A convenient synthetic route to a range of carprofen analogues was established, while key structural features responsible for the antimycobacterial potency of carprofen were identified. The exploration and elaboration of these features led to the identification of highly potent and selective carprofen analogues, while also providing information on the antimycobacterial structure-activity-relationships of these compounds, providing a clear direction for future research.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The Synthesis and Evaluation of N-Heterocycles as Antitubercular Agents |
| Event: | UCL (University College London) |
| Language: | English |
| Additional information: | Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10134163 |
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