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Evaluation of the activity of new 4-quinolones compounds against hepatic and sexual forms of Plasmodium spp.

Grant number: 23/02543-3
Support Opportunities:Scholarships abroad - Research Internship - Master's degree
Effective date (Start): October 01, 2023
Effective date (End): March 31, 2024
Field of knowledge:Biological Sciences - Parasitology
Principal Investigator:Anna Caroline Campos Aguiar
Grantee:Yasmin Annunciato
Supervisor: João Pedro Soares da Silva Pinto
Host Institution: Instituto de Saúde e Sociedade (ISS). Universidade Federal de São Paulo (UNIFESP). Campus Baixada Santista. Santos , SP, Brazil
Research place: Universidade Nova de Lisboa, Portugal  
Associated to the scholarship:22/05873-1 - Activity evaluation of new 4-quinolone compounds against sexual forms of Plasmodium spp., BP.MS

Abstract

Malaria has a prominent position among tropical diseases, causing a serious worldwide impact due to its high mortality and morbidity, with consequences for the socioeconomic development of communities and the health and productivity of populations living in endemic regions of the disease. Currently, cases of resistance to treatment in combination with artemisinin derivatives (ACTs) have already been reported in 5 countries in the Southeast Asian region. Furthermore, in Africa, parasites with a mutation in the Kelch 13 gene have already been detected, which is directly related to resistance to artemisinin. The emergence of multidrug-resistant strains is a worrying scenario, in which the search for new candidates for antimalarials with innovative action is essential to achieve the goals of controlling and eliminating the disease. Furthermore, the development of effective transmission blocking therapies and prophylaxis in order to achieve the goal of malaria eradication is of great importance. In this sense, the class of 4-quinolone compounds (Synthesized by Prof. Dr. Arlene Correa from the Federal University of São Carlos-UFSCar) was recently evaluated and had its activity against asexual forms of P. falciparum (3d7-sensitive) previously determined and characterized (with IC50 against P. falciparum in vitro below 1 µM). The action of this class of compounds was characterized by our group (Oliveira et al, 2021), targeting the BC1 complex of P. falciparum, which is an important target for the search for transmission blockers. From the development of this project (FAPESP-2022/05873-1 master's scholarship) it was possible to demonstrate the activity of the compounds in an ex vivo model of P. vivax, where compound 182 showed a reduction of oocysts and sporozoites by ~95%. and ookinetes at ~97%. In this sense, the continuation of studies evaluating the effect of this new class of compounds against the sexual stage of P. berghei, using an in vivo transmission model, is of great importance. Furthermore, evaluating the prophylactic effect of these compounds against hepatic asexual stages will provide valuable information about the studied compounds. To carry out this part of the project, collaboration with the group from Universidade Nova de Lisboa will be crucial and will allow us to have access to models not yet available in Brazil. (AU)

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