Design, synthesis and evaluation of novel antimalarials based on fendiline
Design, synthesis and evaluation of novel antimalarials based on fendiline
Dr Rachael Magwaza, Dr J Wilkinson, Dr Holly Matthews
Applications accepted all year round
Self-Funded PhD Students Only
About the Project
Malaria is a life-threatening, infectious disease caused by the Plasmodium parasite. In 2023 more than 263 million cases were reported globally, with an estimated 597 000 deaths (WHO, 2024). Global malaria cases and deaths, steadily declining from 2000 until 2015, have now come to a plateau, revealing the weakness of current control measures. One of the critical issues is the increasing prevalence of resistance that can counteract every antimalarial drug currently used. Therefore, innovative treatments and prevention measures are needed.
Fendiline is a clinically approved, but now obsolete inhibitor of voltage-gated L-type calcium channels, which was used as an antianginal agent for the treatment of coronary heart disease (Bayer & Mannhold, 1987). Fendiline belongs to the subclass of compounds known as lipophilic calcium antagonists along with other phenylalkylamines. However, fendiline is different from other phenylalkylamines as it blocks calcium channels in their open state, a characteristic that has been linked to the drug’s relatively low potency as a calcium channel blocker.
Our group at Salford have found that fendiline potently inhibited P. falciparum growth when repurposed as potential antimalarial candidate. It was also able to reverse resistance to the established antimalarial chloroquine. Furthermore, a range of analogues showed better activity when compared to fendiline (Rajab, 2018). Fendiline analogues synthesised by our group have also shown interesting biological activity in other important therapeutic areas, including cancer (Wilkinson et al., 2007a).
This project aims to design, synthesise and characterise new analogues of fendiline to optimise drug-like properties and elucidate key traits of the antimalarial activity of these compounds, presenting an in-depth analysis of their activity in vitro and in vivo.
Objectives:
i. Synthesise and fully characterise new fendiline analogues by NMR spectroscopy, infrared spectroscopy, and mass spectrometry.
ii. To investigate antimalarial efficacy and potency of the fendiline analogues, evaluate their toxicity and further investigate the interaction with currently used antimalarial drugs for potential combination therapies.
iii. In silico modelling to probe the mechanism of action of these compounds.
iv. Evaluate the antimalarial activity ofthe lead compound in vivo in P. falciparum models.
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