Optimization of covalent inhibitors of the enzyme dihydroorotate dehydrogenase (DHODH) from Leishmania braziliensis

• Grant number: 24/03911-9
• Support Opportunities: Scholarships in Brazil - Master
• Start date: February 01, 2025
• End date: January 31, 2026
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Flavio da Silva Emery
• Grantee: Aryane Maia de Castro
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Neglected diseases predominantly impact populations in developing countries, receiving scant attention and investment in research and treatment development compared to more prevalent diseases in developed nations. Leishmaniasis, one of these neglected diseases, is caused by parasites of the genus Leishmania sp. clinical forms, such as cutaneous leishmaniasis and visceral leishmaniasis. Annually, the disease affects millions of people, resulting in human suffering, disability and deaths, as well as contributing to social and economic stigmatization in vulnerable communities. Currently, only four therapeutic options are available to treat leishmaniasis, and antimonials are the initial choice, despite their limited efficacy and high toxicity. Given the limited interest of the industry in seeking new treatments, there is an urgency to research new drugs for this disease. In this context, the identification of specific targets in the parasite, such as the enzyme dihydroorostat dehydrogenase (DHODH), essential in the synthesis of pyrimidine nucleotides via novo, emerges as a promising area of investigation. DHODH, as an important protein for L. braziliensis, represents a potential target for inhibitors. Based on the structure of DHODH, which contains cysteine residues at its active binding site, and the structure of its orotate substrate, with acid groups that perform hydrogen bonds, it is proposed the development of compounds that mimic the interactions between the orotate and the enzyme, including electrophilic warheads for covalent enzyme inhibition. The approach includes the synthesis of analogues derived from barbituric acid and other heterocyclic rings, exploring fragments that may have future application in medicinal chemistry, allied to functional groups known to have covalent binding to cysteine, biological activity of these compounds against DHODH of L. braziliensis.