Parallel Microscale Synthesis of Pyrazolo[1,5-a]pyrimidine Derivatives as Potential T Anti-trypanosomal Agents

• Grant number: 24/22239-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: February 01, 2025
• End date: January 31, 2029
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Daniel Gedder Silva
• Grantee: Maurício Ferreira de Lima
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 23/11804-5 - Combining Microscale Parallel Synthesis (MPS) and Medium-Throughput Screening (MTS) for Accelerated Hit-to-lead Optimization of Anti-Infective Agents., AP.JP

Abstract

Trypanosomiasis, caused by the unicellular protozoan parasites Trypanosoma cruzi, poses significant economic obstacles to human well-being. Chagas disease is a devastating illness in the Americas. Existing drugs for the treatment of these diseases are insufficient, toxic, prone to parasite resistance, and require parenteral administration. DNDi has identified a series of 3,5-diarylpyrazoles with antiparasitic activity. A compound with good potency and metabolic stability is necessary to advance to in vivo efficacy studies. In this context, the synthesis of new pyrazolo[1,5-a]pyrimidine derivatives from aminopyrazole will be carried out using a parallel microscale synthesis platform, validated through traditional synthesis. Synthetic strategies involving electrophilic substitutions, halogenations, and cyclizations will result in libraries of compounds with varied modifications. In addition, other heterocycles that are pyrazole bioisosteres will be synthesized using click chemistry. Through biological assays against T. cruzi, structure-activity relationship (SAR) studies will be developed, and new compound series will be synthesized. In addition to a collaboration with DNDi, this project will involve the capabilities of the Universities of São Paulo, Dundee, Münster, and Antwerp. With the expertise of researchers involved in the FAPESP Young Investigator project (2023/11804-5), to which this direct PhD project is linked, the goal is to obtain drug candidates with the required potency and pharmacokinetic properties to combat Chagas disease.