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
  • The electronic version of this thesis is currently under moratorium due to copyright restrictions. If you are the author of this thesis, please contact the Library to resolve this issue.

Relations

Items