DMPK Optimisation of B-hydroxyethylamine Antimalarials

Malaria is a severe, worldwide public health problem spread by Plasmodium parasites which caused an estimated 627,000 deaths in 2020 alone, and resistance to current treatment highlights the need for newer therapeutics with novel mechanisms of action. Successful drug candidates would ideally show multistage activity on the three life cycle stages (liver, blood, and mosquito) of malaria. Plasmepsins (PMs) are aspartic acid proteases used by malaria parasites for various functions, and PMIX and PMX make excellent drug targets as they together are involved in all three life cycle stages. They are essential for parasite egress and invasion, and PMIX/X inhibitors have a unique mechanism of action, therefore the barrier to resistance development is high. An early lead series of B-hydroxyethylamines have reported exceptional antimalarial potency in vitro and in vivo, as they mimic the transition state formed by PMIX/PMX and their protein substrate. They are however limited by a poor DMPK profile, so a key aim of this project is to optimise the DMPK properties - particularly the metabolic stability but also devising approaches to increase cell membrane permeability. Analogues will be screened for in vitro target enzyme inhibition, phenotypic antimalarial assessment, and PK testing. In addition, this project will also examine the synthesis of photoaffinity probes to enable chemical proteomic target engagement studies to be initiated post biological activity assessment.