Planning, synthesis and trypanosomicidal activity of enzyme cruzain reversible covalent inhibitors

• Grant number: 16/12047-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: August 01, 2016
• End date: July 31, 2017
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Carlos Alberto Montanari
• Grantee: Juliana Jarussi dos Santos
• 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 one of the 17 Neglected Tropical Diseases of the World, According to the OMS and it is caused by the parasite Trypanosoma cruzi, which is transmitted through mosquitoes called "barbeiro". Besides being an endemic problem in Latin America countries, reports have shown it is expanding to the US, Europe and Japan. Currently, in the Pharmaceutical Industry there are only two available drugs, nifurtimox and benznidazole, and both of them present low efficacy for the chronic phase of the illness, besides severe side effects. Therefore, research to discover compounds with the chemotherapeutics potential and less side effects is essential. Reviewing the literature looking for molecules with high potential trypanocidal, it was found great interest into nitro-triazol compounds, due to its potent inhibition of the TcCYP51 enzyme and for being excellent substrates for the Type 1 of nitroreductase (NTR). Therefore, this project has the proposal to synthesise nitro-triazol compounds that are derivatived from the previously dipeptidyl nitriles synthesized by the Nequimed group, since it has shown to be potential cruzain inhibitors. The new molecules are going to be structually characterized and, afterwards, will undergo through biological tests by Nequimed group, which involves testing the molecules at the cruzain enzyme and at the infectious form of the Tulahuen lacZ strain. (AU)