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

TY - JOUR

T1 - 5-Nitrofuran-Semicarbazone Hybrids as Antitrypanosomal Agents

T2 - Structure–Activity Relationship and Nitroreductase Activation

AU - Alegbejo Price, Temitayo O.

AU - Silva, Daniel G.

AU - Vaidergorn, Miguel M.

AU - Augusto, Beatriz S.

AU - Matheeussen, An

AU - Van Pelt, Natascha

AU - Caljon, Guy

AU - Riley, Jennifer

AU - Read, Kevin D

AU - Medina-Franco, José L

AU - Nonato, M Cristina

AU - Emery, Flavio S

N1 - Publisher Copyright: © 2026 The Authors. Published by American Chemical Society.

PY - 2026/6/11

Y1 - 2026/6/11

N2 - 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.

AB - 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.

KW - compound fragmentation

KW - drug discovery

KW - neglected tropical diseases

KW - nitrofuran

KW - Nitroreductase

KW - trypanosomatids

UR - https://www.scopus.com/pages/publications/105041506847

U2 - 10.1021/acsmedchemlett.6c00200

DO - 10.1021/acsmedchemlett.6c00200

M3 - Letter

C2 - 42305192

AN - SCOPUS:105041506847

SN - 1948-5875

VL - 17

SP - 1398

EP - 1406

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 6

ER -