Synthesis of PfCLK1 inhibitors

Eganda, Shaun (2025) Synthesis of PfCLK1 inhibitors. MSc(R) thesis, University of Glasgow.

Abstract

Despite international efforts to deal with malaria, it remains a serious health concern on a global scale, contributing to a considerable number of deaths worldwide, especially in LEDCs (less economically developed countries) on the African and Asian continents. Unfortunately, a lack of research has resulted in no new antimalarial drugs being introduced into the market since 1996. Current treatment strategies against malaria have been seen in the form of artemisinin; however, due to constant usage, this drug has become compromised, as the most virulent malaria parasite strain, Plasmodium falciparum, has developed resistance. As a result, significant efforts must be targeted towards the development of new antimalarial drugs that target not only the symptomatic blood stage of infection, but all stages of the parasite life cycle to prevent transmission and hopefully allow the eradication of malaria.

In recent times, a four-membered protein kinase family known as ‘Plasmodium falciparum cyclin-like kinase’ (PfCLK1-4) has been identified as an essential eukaryotic protein for the survival of the parasite during the ‘blood stage’ of its lifecycle. Studies have shown these kinases to be pivotal in regulating RNA expression throughout the asexual and sexual stages of the parasite lifecycle, which are important in parasite survival. As a result, efforts have been made to focus on this protein kinase family to see if targeting these protein kinases could offer a novel therapeutic strategy to treat malaria. Henceforth, this project aims to validate one of these family members ‘PfCLK1 as a new therapeutic target against malaria by synthesizing tool compounds that selectively inhibit PfCLK1.

As this project is still in the early ‘hit to lead’ stage of the drug discovery process, the focus so far has been on developing a synthetic route towards the ‘hit’ molecules identified from a HTS (high throughput screen) that showed biological activity against PfCLK1. As a result, the main discussion of this report will outline the synthetic route used to synthesize two of the four hit molecules, compounds A & B.

• Item Type: Thesis (MSc(R))
• Qualification Level: Masters
• Subjects: Q Science > QD Chemistry
• Colleges/Schools: College of Science and Engineering > School of Chemistry
• Supervisor's Name: Jamieson, Professor Andrew and Rouah, Dr. Maxime
• Date of Award: 2025
• Depositing User: Theses Team
• Unique ID: glathesis:2025-85577
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 12 Nov 2025 16:33
• Last Modified: 12 Nov 2025 16:37
• Thesis DOI: 10.5525/gla.thesis.85577
• URI: https://theses.gla.ac.uk/id/eprint/85577