Design, synthesis and evaluation of the trypanocidal activity of new nitroheterocyclic analogues via click chemistry

• Grant number: 24/14763-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2025
• End date: April 30, 2027
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Sérgio de Albuquerque
• Grantee: Bruno Ivo Pelizaro
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Chagas disease (Trypanosoma cruzi) is a neglected disease that affects approximately 6 million people worldwide, especially in underdeveloped countries such as Brazil and also in non-endemic regions such as Europe, Japan, and Australia. Current chemotherapy therapy includes only two nitroheterocyclic drugs, benznidazole (BZ) and nifurtimox (NFX), which are effective in the acute phase of the disease. However, BZ is the only drug approved by Anvisa for the treatment of this disease in Brazil. Given problems of resistance to benznidazole, toxicity, and low effectiveness in the chronic phase of the disease, new drug candidates need to be developed. In a study recently published by our research group, synthesized nitroheterocyclic analogues showed excellent inhibition capacity of intracellular amastigote forms of T. cruzi at nanomolar concentrations and a relevant selectivity index. Of these, the 15g analogue was considered a suitable substrate for type I nitroreductases (TcNTR I), contributing as a possible potential mechanism of action for antiChagasic activity, in addition to not presenting mutagenic potential in the Ames test. Partial results obtained from the in vivo assay showed that 15g controlled 100% of the acute phase infection at a dose 4 times lower than the dose used for Benznidazole (100 mg/kg/day) and maintained animal survival at the end of treatment. Thus, the objective of this work will be to (i) design, (ii) synthesize new nitrotriazole analogues using the click chemistry concept, (iii) evaluate the trypanocidal activity in vitro and in vivo and (iv) investigate the mechanism of action in an experimental model of acute and chronic phases of T. cruzi infection. The results obtained in this study may contribute to scientific advances in the search for new therapeutic options in the treatment of Chagas disease. (AU)