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Lead Identification and Optimization of Plasmodium falciparum Inhibitors as Drug Candidates for Malaria

Grant number: 22/15947-2
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): April 01, 2023
Effective date (End): May 31, 2024
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Organic Chemistry
Principal Investigator:Glaucius Oliva
Grantee:Sarah El Chamy Maluf
Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Associated research grant:13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery, AP.CEPID

Abstract

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 because of high mortality rates (Figure 1A). In 2020, 241 million cases of malaria with estimated 600,000 deaths were reported by World Health Organization (WHO).1 Nearly 90% of malaria deaths occurred in the African continent, with children aged less than 5 years and pregnant women being the most severely affected.The overall goal of this project is to deliver a clinical candidate, as defined by the criteria for an MMV Preclinical candidate. Such a compound should have the potential to be developed, in combination, to deliver a Single Exposure Radical Cure and Prophylaxis (SERCaP) or Single Exposure Chemoprotection (SEC) drug. MMV will provide the project with quality lead molecules, aligned to a particular target product profile (TPP) of interest. The team will investigate structure-activity relationships in these series to further optimize them and deliver drug candidates, as well as to aim to elucidate novel mechanisms of action.The project will seek to optimize the selected leads utilizing iterative design-synthesis-test cycles focused on achieving high potency against 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 hot spots and hence sites for further optimization. Additional screening will be carried out where appropriate to determine the overall strengths and weaknesses of each series and guide the optimization process. The specific objectives for the Post-Doc position is the antimalarial profiling of new chemical targets to achieve the goals described above.

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