5‑Nitrofuran-Semicarbazone Hybrids as Antitrypanosomal Agents: Structure-Activity Relationship and Nitroreductase Activation

  • ACS Med Chem Lett. 2026 May 26;17(6):1398-1406. doi: 10.1021/acsmedchemlett.6c00200.
Temitayo O Alegbejo Price  1 ,  Daniel G Silva  1  2 ,  Miguel M Vaidergorn  1 ,  Beatriz S Augusto  1 ,  An Matheeussen  3 ,  Natascha Van Pelt  3 ,  Guy Caljon  3 ,  Jennifer Riley  4 ,  Kevin D Read  4 ,  José L Medina-Franco  5 ,  M Cristina Nonato  1 ,  Flavio S Emery  1
Affiliations
  • 1. Center for the Research and Advancement in Fragments and Molecular Targets (CRAFT), School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto 14040-903, SP, Brazil.
  • 2. University of São Paulo (USP) School of Pharmaceutical Sciences (FCF) Department of Biochemical-Pharmaceutical Technology (FBT), Av. Prof. Lineu Prestes, 580 - Butantã, São Paulo, SP 05508-000, Brazil.
  • 3. Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Infla-Med Centre of Excellence, University of Antwerp, Universiteitsplein 1, Antwerp 2610, Wilrijk, Belgium.
  • 4. Drug Discovery Unit, University of Dundee, School of Life Sciences, Dow Street, Dundee, DD1 5EH, U.K.
  • 5. DIFACQUIM Research Group, Department of Pharmacy, School of Chemistry, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico.
PMID: 42305192 DOI: 10.1021/acsmedchemlett.6c00200
Abstract

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.

Keywords
Nitroreductase; compound fragmentation; drug discovery; neglected tropical diseases; nitrofuran; trypanosomatids.
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