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Neglected tropical diseases such as Chagas disease remain poorly served by current chemotherapies due to toxicity and the emergence of drug resistance. Nitroaromatic compounds represent an established antitrypanosomal strategy, relying on bioactivation by Trypanosoma type I nitroreductases. In this study, a fragment-based design approach was applied to the nitroaromatic drugs nifurtimox and benznidazole to generate a novel hybrid scaffold, (E)-N-benzyl-2-((5-nitrofuran-2-yl)methylene)hydrazine-1-carboxamide (1). A series of twenty-two analogues was synthesized by modifying the benzylamine substituent and evaluated for antitrypanosomal activity and susceptibility to nitroreductase I-mediated activation and early ADME properties. Among the series, (E)-N-(4-methylbenzyl)-2-((5-nitrofuran-2-yl)methylene)hydrazine-1-carboxamide (3) and (1) exhibited potent anti-T. cruzi activity (0.14 μM and 0.23 μM), anti-T. b. brucei activity (0.59 ± 0.03 μM and 29.3 ± 15.6 μM), and anti-T. b. rhodesiense (0.87 ± 0.8 μM and 7.44 ± 1.00 μM) in parasite cultures. These findings identify this chemotype as a promising starting point for the further development of nitroreductase-activated therapeutics for Trypanosomiasis disease.
Price et al. (Tue,) studied this question.