Antiplasmodial activity characterization of synthetic derivatives as lead candidates for malaria: In vitro and in vivo studies

• Grant number: 25/02800-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: January 01, 2026
• End date: July 31, 2029
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Rafael Victorio Carvalho Guido
• Grantee: Sara Franchin Duarte de Souza
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Associated research grant: 24/04805-8 - Integrated investigation of inhibitors active on infectious diseases: insights into molecular and cellular mechanisms of function, AP.TEM

Abstract

Malaria, a tropical disease caused by protozoa of the genus Plasmodium, remains a leading cause of mortality, particularly among children under five and pregnant women. It also poses significant socioeconomic challenges in endemic regions. The disease is transmitted in 87 countries and is prevalent in tropical and subtropical areas of Africa, Southeast Asia, and Latin America. In 2023, there were 263 million reported cases and over 597,000 deaths, with Africa being the most affected region. Although global efforts over recent decades have significantly reduced malaria cases, the emergence and spread of drug-resistant parasites underscore the urgent need for new chemotherapeutic agents.This project aims to discover promising lead compounds for malaria treatment through structure-activity relationship (SAR) studies of two molecular series with favorable activity and safety profiles. The series under investigation include indole-based peptidomimetic derivatives and marine-quinoline derivatives. The new analogs to be designed are expected to exhibit high potency, selectivity, and suitable physicochemical and pharmacokinetic properties. To achieve these objectives, the project will employ an integrated approach encompassing molecular design, organic synthesis, SAR studies, and biological assays. The design and synthesis of these derivatives will be conducted in collaboration with renowned organic synthesis groups led by Prof. Arlene G. Corrêa (DQ/UFSCar) and Prof. Carlos Roque Duarte Correia (IQ/UNICAMP).The derivatives will be evaluated through a range of in vitro assays against strains sensitive and resistant to conventional antimalarials to determine their biological activity. Additional assays, including cytotoxicity, speed of action, combination studies, and duration of action, will be performed to comprehensively assess the antiparasitic profiles of the compounds. For derivatives demonstrating significant inhibition of parasite growth (IC50 < 100 nM) and an appropriate selectivity index (SI > 10), proof-of-concept studies will be carried out using a Plasmodium berghei model to evaluate in vivo activity.The laboratories at IFSC/USP, DQ/UFSCar, and IQ/UNICAMP bring extensive expertise in medicinal chemistry and bioactive compound synthesis. This collaboration is consolidated under the Center for Research and Innovation in Biodiversity and Drugs (CIBFar-CEPID) and has been further strengthened by the approval of the thematic project (FAPESP 2024/04805-8). Our Center is equipped with state-of-the-art facilities and infrastructure essential for the drug discovery process. Additionally, the group is part of the associated laboratories of the nonprofit organization Medicines for Malaria Venture (MMV), serving as an MMV Center of Excellence for determining the inhibitory activity of new antimalarial drug candidates. (AU)