Synthesis of new heterocyclic compounds as potential trypanosomicidal agents

• Grant number: 24/03910-2
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: October 01, 2024
• End date: January 31, 2028
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Flavio da Silva Emery
• Grantee: Yvnni Maria Sales de Medeiros e Silva
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

New imidazopyridine (imidazo[1,2-a]pyridine and imidazo[1,2-c]pyrimidines) derivatives were synthesized and showed potent biological activity against parasite cultures (T. cruzi and T. brucei), low cytotoxicity and high metabolic stability. It was observed that an imidazo[1,2-c]pyrimidine derivative exhibited excellent plasma exposure upon oral administration in rats, however, the low solubility is a property issue that should be improved. Therefore, this proposal aims to design and synthesize new imidazo-azines derivatives and synthesize new compounds with modifications with improved solubility. This strategy will allow the development of a small library to build a structure-activity relationship study (SAR) for the phenotypic studies against T. cruzi and T. brucei. We also aim to select the best modifications for the synthesis of new optimized compounds and analyze their mode of action and pharmacokinetic profile in vitro and in vivo, which will be performed in collaboration with partners at the University of Dundee. Finally, this project aims to select the most promising compounds for in vivo efficacy studies through acute and chronic models of infections with T. cruzi and T. brucei. Thus, guided by our previous SAR studies, we proposed new imidazopyridine/imidazopyrimidine for preclinical studies.