Synthesis and Characterization of Fexinidazole Derivatives Against Trypanosoma brucei.

• Grant number: 25/11713-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: September 01, 2025
• End date: August 31, 2026
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Cauê Benito Scarim
• Grantee: Yasmin Revejes Bovolenta
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Human African Trypanosomiasis (HAT), also known as Sleeping Sickness, is a neglected tropical disease caused by protozoan parasites of the Trypanosoma brucei complex, transmitted by the bite of the infected tsetse fly (Glossina spp.). Despite recent advances in diagnostics and treatment, HAT still presents significant therapeutic challenges, particularly in its meningoencephalic stage, when the infection reaches the central nervous system. Fexinidazole, the first oral drug approved for both stages of the gambiense form of the disease, represents a major therapeutic milestone; however, it has limitations, including reduced efficacy in advanced neurological stages, the need for food intake to ensure absorption, and adverse effects with prolonged use. These shortcomings underscore the need to develop new derivatives that retain selective bioactivation by type I nitroreductases - enzymes absent in the human host but essential in T. brucei - while overcoming the pharmacokinetic limitations of the parent drug. In this context, the present project proposes the synthesis and characterization of a new series of fexinidazole derivatives containing hydrazone moieties, with the potential for enhanced antiparasitic activity. Hydrazones are versatile chemical structures with tunable properties that can modulate lipophilicity, metabolic stability, and permeability across the blood-brain barrier - features that are essential to improving efficacy in the advanced stages of HAT. The synthetic route includes selective nitration of imidazole, benzyl functionalization, derivatization with hydrazones, followed by final coupling to obtain the target compounds (9a-p). The molecules will be purified and structurally characterized using chromatographic and spectroscopic techniques (TLC, IR, NMR, melting point, and mass spectrometry). Physicochemical properties such as the octanol-water partition coefficient (LogP) by HPLC and chemical stability under physiological conditions will also be evaluated. The most promising derivatives will undergo in vitro biological assays to assess their ability to inhibit T. brucei nitroreductase (in collaboration with Prof. Maria Cristina Nonato's laboratory, USP-Ribeirão Preto), and their antiparasitic activity against bloodstream trypomastigotes (in partnership with Prof. Conor Caffrey's laboratory, UCSD). This approach is expected to yield compounds with greater selectivity, improved pharmacological profiles, and better clinical potential. The project aims to contribute to innovative therapeutic solutions for Sleeping Sickness and establish a foundation for preclinical development of new drug candidates targeting neglected parasitic diseases.