4-Quinolone derivatives as antimalarial drug candidates: Antiplasmodial activity characterization in vitro, in vivo and of the mode of action

• Grant number: 17/26679-0
• Support type: Scholarships in Brazil - Master
• Effective date (Start): April 01, 2018
• Effective date (End): November 30, 2019
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal researcher: Rafael Victorio Carvalho Guido
• Grantee: Juliana Oliveira de Souza
• Home 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, a tropical disease caused by protozoa of the Plasmodium genus remain a major cause of mortality, especially among children below five years of age, causing socioeconomic problems for population of endemic areas worldwide. Transmission of the disease happens in 91 countries, and it is endemic in tropical and sub-tropical regions of Africa, Southeast Asia and Latin America. Nearly half the world's population (3,2 billion people) are under risk of transmission of malaria. In 2016 there were 216 million cases and 445 thousand deaths, most in the sub-Saharian region of the African continent. In the last decades, global efforts for eradication of malaria have caused a marked reduction in the number of cases, however the emergence of parasites resistant to the available medicines makes it extremely important to search for new chemotherapeutic agents against the disease.The aim of this research project is the discovery and development of 4-quinolone compounds as candidates to lead compounds for the development of new antimalarial medicines. In this sense, studies of cellular biology and parasitology will be carried out, as well as medicinal chemistry. The derivatives studied will be evaluated in growth inhibition assays in vitro and in vivo against strains that are sensible and resistant to conventional antimalarials. In addition, cytotoxicity and hemolytic activity assays will be applied to determine the toxicologic profile of the series. A study of the structure-activity relationship of the series will also be conducted. Preliminary results indicated antiplasmodial activity of the 4-quinolone and acridone derivatives against Plasmodium falciparum in vitro. The work to be developed in this Master's project will complement the experience obtained in the candidate´s scientific initiation project, and will add knowledge of new techniques, in the context of the application of experimental methods for the discovery of new antimalarial medicine candidates.The Physics Institute of São Carlos - USP houses laboratories with vast experience in medicinal chemistry, which benefitted from the creation of the Center of Research and Innovation in Biodiversity and Pharmaceuticals (CIBFar-CEPID), and it provides adequate installations and equipment for the process of search for new candidates to medicines, reuniting all the fundamental factors for the execution of the proposed project. Furthermore, the group is part of the network of laboratories associates with the non-profit organization Medicines for Malaria Venture (MMV), acting as Center of Triage and Evaluation of Antimalarial Medicine Candidates. In consequence, the laboratories of the CIBFar-CEPID have the infrastructure for the execution of this research project in its entirety. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SILVEIRA, FLAVIA F.; DE SOUZA, JULIANA O.; HOELZ, LUCAS V. B.; CAMPOS, VINICIUS R.; JABOR, VALQUIRIA A. P.; AGUIAR, ANNA C. C.; NONATO, M. CRISTINA; ALBUQUERQUE, MAGALY G.; GUIDO, RAFAEL V. C.; BOECHAT, NUBIA; PINHEIRO, LUIZ C. S. Comparative study between the anti-P. falciparum activity of triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives and the identification of new PfDHODH inhibitors. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 209, JAN 1 2021. Web of Science Citations: 0.

MARTELLI, LORENA S. R.; VIEIRA, LUCAS C. C.; PAIXAO, MARCIO W.; ZUKERMAN-SCHPECTOR, JULIO; DE SOUZA, JULIANA O.; AGUIAR, ANNA CAROLINE C.; OLIVA, GLAUCIUS; GUIDO, RAFAEL V. C.; CORREA, ARLENE G. Organocatalytic asymmetric vinylogous 1,4-addition of alpha,alpha-Dicyanoolefins to chalcones under a bio-based reaction media: Discovery of new Michael adducts with antiplasmodial activity. Tetrahedron, v. 75, n. 25, p. 3530-3542, JUN 21 2019. Web of Science Citations: 1.