Identification and optimization of Plasmodium falciparum inhibitors as drug candidates for malaria

Malaria is a parasitic disease caused by Plasmodium species (P. falciparum, P. vivax, P. ovale, P. malariae and P. knowlesi). The disease is widespread in tropical and subtropical regions of the world and represents a global public health problem due to high mortality rates (Figure 1A). In 2020, 241 million cases of malaria with an estimated 600,000 deaths were reported by the World Health Organization (WHO). Almost 90% of deaths from malaria occurred on the African continent, with children under 5 years of age and pregnant women being the most severely affected. The candidate compound should have the potential to be developed, in combination, to provide a single exposure radical cure and prophylaxis (SERCaP) or single exposure chemoprotectant (SEC) drug. MMV will supply the project with quality lead compounds, aligned with a certain target product profile (TPP) of interest. The team will investigate the structure-activity relationships in these series to further optimize them and provide drug candidates, in addition to trying to elucidate new mechanisms of action. The project will seek to optimize selected lead compounds using iterative design-synthesis-test cycles focused on achieve high potency against the malaria parasite, excellent pharmacokinetic properties, good physical properties and acceptable in vitro safety parameters using well-established principles of Medicinal Chemistry. Structural changes will be explored to further increase malaria potency, while metabolite studies will identify metabolic transformation points and therefore sites for further optimization. Additional screening will be performed where appropriate to determine the overall strengths and weaknesses of each series and guide the optimization process. Specific goals for the Post-Doc position is to establish the antimalarial profile of new chemical targets to achieve the goals described above.

Project details

Drug-based Strategies
Product Development

Apr 2023 — May 2024

Brazil