Synthesis of novel anti-Trypanosoma cruzi agents

• Grant number: 19/06271-2
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: May 01, 2019
• End date: November 30, 2020
• Field of knowledge: Physical Sciences and Mathematics - Chemistry
• Principal Investigator: Carlos Alberto Montanari
• Grantee: Felipe Cardoso Prado Martins
• Host Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Associated research grant: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors, AP.TEM

Abstract

Chagas Disease is still considered a neglected disease, endemic to Latin America, and caused by the protozoan Trypanosoma cruzi. Even though it was characterized more than 100 years ago by Carlos Chagas, there are still only two methods of treatment that primarily act only in the acute phase of the disease. Benznidazole, which is the only drug used in Brazil, may have severe adverse effects, which does not contribute for the patients compliance to the treatment. Thus, considering the previous results obtained by the Medicinal Chemistry Research Group - NEQUIMED/IQSC/USP, this current work has two distinct objetives revolving around the synthesis of novel compounds potentially active against T. cruzi. Neq0831 inhibits cruzain with a pKi = 7 (100 nM). Its in vitro action against T. cruzi is equipotent to benznidazole (pEC50 = 5,7). However, when employed in therapeutical combination with benznidazole, its potency rises 0,7 log units and makes the pEC50 equals to 6,4. The in vitro and in vivo Proof of Concept (PoC) of Neq0720 was successfully performed. In vitro, its potency pEC50 is equal to 6,7. Its in vivo potency is the same as the one observed for benznidazole. In this project, analogs of both molecules will be synthesized and their chemical structures will be hybridized in order to optimize their pharmacodynamics and pharmacokinetics properties. (AU)