Structural optimization of 1,2,3-triazole benznidazole prototype with potent trypanocidal activity

• Grant number: 18/05549-4
• Support Opportunities: Scholarships in Brazil - Master
• Start date: July 01, 2018
• End date: August 31, 2020
• Field of knowledge: Health Sciences - Pharmacy
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Ivone Carvalho
• Grantee: Filipe Canto Oliveira
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Chagas disease is an infectious disease caused by the protozoan Trypanosoma cruzi. In Brazil alone, it is estimated that there are more than 4.5 million people infected. The main therapeutic option currently available is benznidazole. This drug exhibits significant activity in the acute phase of the disease, yet reduced efficacy in the chronic phase (the stage where most cases are diagnosed), and severe side effects. In the search for new drugs, the research group of the Laboratory of Pharmaceutical Chemistry (FCFRP-USP), coordinated by Profa. Dr. Ivone Carvalho, developed several analogs of benznidazole in a simple and efficient manner using "Click Chemistry" technique. The most remarkable analog was N-benzyl-2-[4-(4-nitrophenyl)-1H-1,2,3-triazol-1-yl] acetamide, which exhibit trypanocidal activity (IC50 7µM) nearly five times greater than benznidazole (IC50 34µM), good selectivity index (SI 114) and low cytotoxicity. However, in vivo assays of this prototype were not performed because of its high liposolubility. Thus, this project will address molecular modification strategies to optimize the physicochemical properties of this prototype in order to increase its hydrophilicity and activity. In addition to evaluate the trypanocidal activity of the synthesized compounds, it is planned to study the mechanism of action of the most active products. (AU)