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Synthesis and evaluation of new heterocyclic compounds as potential antitrypanosomal agents

Grant number: 17/22001-0
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): June 01, 2018
Effective date (End): August 01, 2023
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Organic Chemistry
Principal Investigator:Flavio da Silva Emery
Grantee:Daniel Gedder Silva
Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:14/50265-3 - Distribution and metabolism of natural and synthetic xenobiotics: from the comprehension of reactional process to tissue imaging generation, AP.BTA.TEM
Associated scholarship(s):21/11899-0 - Development of novel series of potent and selective heterocyclic compounds as anti-infectives agents, BE.EP.PD


A serie of imidazopyridine-containing compounds have been synthesized and identified as having potent activity on parasite cultures, low cytotoxicity, excellent metabolic stability, and very good plasma exposure upon oral dosing in mice. Promising two new fused ring tested (imidazo[1,2-a]pyridine and imidazo[1,2-c]pyrimidine), have potential for the development of drugs for the treatment of infectious inflammatory diseases. The activity of the best compound (imidazo[1,2-c]pyrimidine derivative) leading to substantial suppression of parasite infection in mice warrants further development as drug. The low solubility of the most potent compound needs to be improved as well as to explore a greater chemical diversity in this series of compounds. In order to achieve these goals: i) we aim to design, synthesize and identify new heterocyclic compounds with antitrypanosomal/antileishmanial activities; ii) to employ and modify synthetic routes to obtain the proposed heterocyclic compounds; iii) to carry out the T. cruzi, T. brucei and Leishmania growth inhibition assays, to evaluate the stability of selected compounds to mouse microsomes, solubility, protein binding, pharmacokinetic studies and in vivo efficacy studies against T.cruzi, T. brucei and Leishmania infections. These studies will be through a partnership with the researchers working on thematic project (FAPESP: 2014/50265-3) and the researchers at the University of Washington; iv) use of the MALDI imaging mass spectrometry methodology to investigate the mechanism of action of the compounds in cell assays through the identification of metabolites. Based on all these results select the best compound that can be transitioned into clinical trials for these parasitic infections.

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Scientific publications (5)
(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)
WAGNER, STEFAN; GATTI, FERNANDO DE MOURA; SILVA, DANIEL G.; ZACARIAS, NATALIA V. ORTIZ; ZWEEMER, ANNELIEN J. M.; HERMANN, SVEN; DE MARIA, MONICA; KOCH, MICHAEL; WEISS, CHRISTINA; SCHEPMANN, DIRK; et al. Development of the First Potential Nonpeptidic Positron Emission Tomography Tracer for the Imaging of CCR2 Receptors. CHEMMEDCHEM, v. 16, n. 4, . (17/22001-0)
SILVA, DANIEL G.; JUNKER, ANNA; DE MELO, SHAIANI M. G.; FUMAGALLI, FERNANDO; GILLESPIE, J. ROBERT; MOLASKY, NORA; BUCKNER, FREDERICK S.; MATHEEUSSEN, AN; CALJON, GUY; MAES, LOUIS; et al. Synthesis and Structure-Activity Relationships of Imidazopyridine/Pyrimidine- and Furopyridine-Based Anti-infective Agents against Trypanosomiases. CHEMMEDCHEM, v. 16, n. 6, . (17/21146-4, 17/22001-0)
SILVA, DANIEL GEDDER; EMERY, FLAVIO DA SILVA. Strategies towards expansion of chemical space of natural product-based compounds to enable drug discovery. Brazilian Journal of Pharmaceutical Sciences, v. 54, n. SI, . (17/22001-0, 14/50265-3, 17/21146-4)
SILVA, DANIEL GEDDER; EMERY, FLAVIO DA SILVA. Strategies towards expansion of chemical space of natural product-based compounds to enable drug discovery. Brazilian Journal of Pharmaceutical Sciences, v. 54, p. 16-pg., . (14/50265-3, 17/21146-4, 17/22001-0)
SILVA, DANIEL G.; FEIJENS, PIM-BART; HENDRICKX, RIK; MATHEEUSSEN, AN; GREY, LUCIE; CALJON, GUY; MAES, LOUIS; EMERY, FLAVIO S.; JUNKER, ANNA. Development of Novel Isoindolone-Based Compounds against Trypanosoma brucei rhodesiense. CHEMISTRYOPEN, v. 10, n. 9, p. 922-927, . (17/22001-0, 17/21146-4)

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