Thesis
Structure activity studies of aminoindole anti-malarial agents to enhance physicochemical properties and safety profile
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2018
- Thesis identifier
- T16667
- Person Identifier (Local)
- 201463654
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- This thesis describes a programme of study relating to both the optimisation of Lead compounds and the investigation of further new entities focused on aminoindoles as potential new antimalarials. This thesis communicates endeavours to identify molecules with enhanced properties over the Lead compound GSK3539992A (3.23) using three different strategies, in order to improve solubility, lipophilicity, and safety liabilities. At the end of the first round of the Lead Optimisation program, four compounds with various improved properties were identified. Having this knowledge, a second generation of compounds was designed and synthesised in order to ameliorate the initial four molecules. From this effort, a tetrahydroindole core was identified in order to replace the initial indole core, reducing the number of aromatic rings and the planarity of the overall structure, and therefore improving the physicochemical properties. From the study of the different substitutions in the 2-position of the molecule from in vitro activity and metabolic stability points of view, one of the linkers was found to be favoured: Amides type II. Based on this finding, a library of amides was computationally designed, and the most promising target molecules were synthesised. From this library of amides, one compound bearing a quinuclidine stood out due to its balanced profile. This was then introduced in the scaffold of the precandidate GSK3531659A (5.53). Due to different issues, the progression of the precandidate was put on hold, and a backup strategy with two different approaches to improve solubility and decrease the predicted human dose were carried out. This work has allowed the identification of 5,5’-difluorotetrahydroindole as a possible replacement for the original indole core. This unit, which has one aromatic ring less and is more flexible than the indole core gives a promising opportunity to work within optimised chemical space.
- Advisor / supervisor
- Kerr, William J.
- Resource Type
- Note
- Previously held under moratorium in the Chemistry Department (GSK) from 22nd June 2018 until 21st July 2023.
- The confidentiality statement on each page of this thesis DOES NOT apply.
- DOI
- Managing organisation
- GlaxoSmithKline
- Embargo Note
Las relaciones
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File | 2023-08-02 | Privado |