Design, Synthesis, and Pharmacological Evaluation of Nitroimidazooxazole Derivatives with Dual Activity Against Cysteine Protease B (CPB) and Nitroreductase (NTR2) of Leishmania spp.

• Grant number: 24/20579-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: April 01, 2025
• End date: March 31, 2028
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Flavio da Silva Emery
• Grantee: Juliana Romano Lopes
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Leishmaniasis is a Neglected Tropical Disease (NTD) caused by protozoa of the genus Leishmania. It is transmitted to humans and animals through the bite of phlebotomine sandflies and is present in over 98 countries, affecting 12 million people and putting approximately 350 million people at risk. Currently, treatment is limited and presents several issues, including high toxicity of available drugs and elevated treatment costs, highlighting the urgent need for the development of new drugs. Proteases are important therapeutic targets, making this enzyme class widely studied for potential treatments of infectious diseases. In Leishmania spp., the main cysteine protease is CPB, which is associated with various functions, ranging from nutrition to infection of host cells. Recently, the compound delamanid (OPC-67683), from the nitroimidazooxazole class, demonstrated potent activity against the amastigote form of L. donovani. In vivo studies showed that this compound was able to suppress parasitic infection by 99.9% in murine models of visceral leishmaniasis (VL). The target of action of this compound is not fully understood, but recent studies suggest a new nitroreductase, different from the one targeted by benznidazole and nifurtimox drugs. This proposal aims to combine the nitroimidazooxazole core, present in delamanid, with the peptidic structure of CPB inhibitors containing different warheads. The new derivatives will be evaluated directly on the CPB protease and assessed for their ability to act via the nitroreductase (NRT2) mechanism. Additionally, the most promising compounds will be tested against the amastigote forms of L. donovani and L. amazonensis. Cytotoxicity and selectivity index will be determined using murine macrophages. The ADME properties of the most promising compounds with leishmanicidal activity will also be determined. Finally, with the identification of new "hits," structural optimization will be proposed to enhance the pharmacokinetic and pharmacodynamic profile of these candidates. Mechanism of action studies will be conducted at the end of the project with one or more optimized hits showing the best leishmanicidal activity and ADME properties.