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 Leadcompounds and the investigation of further new entities focused on aminoindoles aspotential new antimalarials.This thesis communicates endeavours to identify molecules with enhanced propertiesover the Lead compound GSK3539992A (3.23) using three different strategies, in orderto improve solubility, lipophilicity, and safety liabilities.At the end of the first round of the Lead Optimisation program, four compounds withvarious improved properties were identified. Having this knowledge, a secondgeneration of compounds was designed and synthesised in order to ameliorate the initialfour molecules. From this effort, a tetrahydroindole core was identified in order toreplace the initial indole core, reducing the number of aromatic rings and the planarityof the overall structure, and therefore improving the physicochemical properties.From the study of the different substitutions in the 2-position of the molecule from invitro activity and metabolic stability points of view, one of the linkers was found to befavoured: Amides type II. Based on this finding, a library of amides wascomputationally designed, and the most promising target molecules were synthesised.From this library of amides, one compound bearing a quinuclidine stood out due to itsbalanced profile. This was then introduced in the scaffold of the precandidateGSK3531659A (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 thepredicted human dose were carried out. This work has allowed the identification of 5,5’-difluorotetrahydroindole as a possible replacement for the original indole core. Thisunit, which has one aromatic ring less and is more flexible than the indole core gives apromising opportunity to work within optimised chemical space.
- Advisor / supervisor
- Kerr, William
- 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
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