Co-authors Anie Thomas and Hadiqa Hyder, 26 March 2025
For third-year chemistry projects, the focus has been on showcasing the inspiring and dedicated work of the Medicinal Chemistry Research group at the University of Liverpool’s Department of Chemistry. The use of ChemTube3D has allowed us to model pages and molecules on topics the group has published from their publications page. This research group has explored various aspects of malaria, contributing to a deeper understanding of the disease. In these pages, we highlight two distinct antimalarial treatments, examining their effectiveness and binding interactions to provide greater insight into their mechanisms of action.
The group’s research on malaria and antimalarial drugs is innovative as tetraoxanes such as RKA 182, N205 and E209 have emerged as candidates for antimalarial drugs as resistance against Artemisinin and other antimalarials arises globally. Currently, Artemisinin-based combined therapy is the treatment for malaria, but as semi-synthetic analogues of Artemisinin become impotent, new drugs need to be evaluated and synthesised.
Furthermore, pages have focused on the development of molecular probes incorporating a photoreactive moiety, such as diazirine or benzophenone, to facilitate covalent attachment to target proteins. A key area of this research is the synthesis of hydroxyethylamine photoaffinity labelling (PAL) probes, which are specifically designed to study the interactions between drugs, PMIX and PMX proteins in Plasmodium parasites. Additionally, these probes feature a terminal alkyne handle, enabling bio-orthogonal ligation to further study the binding interactions.
Additionally, detailed sections have been developed on the synthesis of the anti-Wolbachia drug AWZ1066S, which is designed to target lymphatic filariasis, a neglected tropical disease. This research highlights the importance of chirality in AWZ1066S, demonstrating that the S-enantiomer exhibits superior potency compared to the R-enantiomer, with a three-fold increase in efficacy and enhanced pharmacological properties.
Nitazoxanide and RM5038 are anti-infective agents known for their potency against a wide range of RNA and DNA viruses. However, the active metabolite of nitazoxanide, tizoxanide has poor solubility, limiting its effectiveness. To address this issue, amino acid ester prodrugs of Nitazoxanide and RM5038 were synthesized. These salts were found to be unstable at a pH of 5. Despite this, the degradation products of these prodrugs exhibited high antiviral potency and were structurally similar to the original prodrugs.
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