Microscale Parallel Synthesis and Evaluation of Pyrazolyl Urea Derivatives as Potential Antitrypanosomal Agents

• Grant number: 24/22131-4
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: March 01, 2025
• End date: February 28, 2029
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Daniel Gedder Silva
• Grantee: Claudia Verônica da Silva Crispim
• 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

Neglected diseases impact over 1 billion people worldwide, causing significant physical, mental, and socioeconomic harm. Current treatments for these diseases often lead to adverse side effects due to pharmacokinetic limitations, which can potentially be addressed. The discovery of safer, more effective drugs can be accelerated and optimized through in silico tools, as well as biological and physicochemical assays to evaluate predictive properties. A Virtual Screening was conducted to identify promising candidates, and the selected compounds were tested against a panel of parasitic pathogens. Notably, one derivative exhibited an IC50 of 8 µM against Trypanosoma brucei rhodesiense. These preliminary results provided a solid foundation for the design of a new series of pyrazolyl urea derivatives with enhanced inhibitory activity. The objective of this project is to develop a library of compounds using a Microscale Parallel Synthesis (MPS) platform and to conduct Structure-Activity Relationship (SAR) studies to optimize the biological activity of the designed compounds. Biological evaluation will be carried out against a comprehensive parasitic panel. This Direct PhD project is part of the Young Investigator Project (2023/11804-5), led by Dr. Daniel Gedder Silva. The project is carried out in collaboration with Dr. Guy Caljon from the University of Antwerp and Dr. Kevin Read from the University of Dundee. Throughout the project, in vivo studies, as well as DMPK (Drug Metabolism and Pharmacokinetics) and mode-of-action investigations, will be performed to identify the most promising lead compound. The ultimate goal is to advance toward the development of urgently needed therapies for infectious diseases.