Development of covalent inhibitors of the enzyme dihydroorotate dehydrogenase for the discovery of therapeutic candidates for Chagas disease

• Grant number: 21/10084-3
• Support Opportunities: Scholarships in Brazil - Master
• Effective date (Start): March 01, 2022
• Effective date (End): July 31, 2023
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Flavio da Silva Emery
• Grantee: Bruna Fleck Godoi
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 22/06007-6 - Development of covalent inhibitors of the enzyme dihydroorotate dehydrogenase for the discovery of therapeutic candidates for Chagas Disease, BE.EP.MS

Abstract

Chagas disease is characterized as a neglected tropical disease, caused by the parasite Trypanosoma cruzi, which affects about 8 million people worldwide. However, despite alarming rates, the treatment consists of only 2 drugs, benznidazole and nifurtimox, which have numerous adverse reactions, high toxicity, and limited efficacy in the chronic phase. Furthermore, given the limited interest of industries in the search for new therapeutic candidates, it is urgent to research drugs for this disease. In this context, the search for specific targets in the parasite offers the possibility of reducing adverse events and toxicity, and for this reason it has been widely used in the rational planning of new compounds. Thus, the enzyme dihydroorotate dehydrogenase (DHODH), essential in the synthesis of pyrimidine nucleotides via de novo pathway, becomes a target to be investigated in this project, since, as it is a specific protein of T. cruzi, the development of inhibitors for the enzyme tends to be promising. Based on the structure of DHODH, which contains cysteine residues in its active binding site, and on the structure of its orotate substrate, with acidic groups that carry out hydrogen bonds, the proposal is to develop compounds that mimic the interactions that occur between the orotate and the enzyme, in order to inhibit it. Thus, in an attempt to explore hererocyclic fragments with future application capacity in medicinal chemistry, combined with functional groups that are known to have a covalent bond to cysteine, such as arylamides and sulfones, the objective is to synthesize analogues derived from the pyrazolo-pyridine group with several substituents and evaluate its biological activity against the enzyme dihydroorotate dehydrogenase from T. cruzi.