2. Academic Validation
  3. Discovery of antileishmanial hits in the 3-nitroimidazo[1,2-a]pyridine series via newly optimized tetrakis(dimethylamino)ethylene (TDAE) methodology at position 2

Discovery of antileishmanial hits in the 3-nitroimidazo[1,2-a]pyridine series via newly optimized tetrakis(dimethylamino)ethylene (TDAE) methodology at position 2

  • Eur J Med Chem. 2025 Dec 19:304:118506. doi: 10.1016/j.ejmech.2025.118506.
Inès Jacquet 1,  Romain Paoli-Lombardo 2,  Caroline Castera-Ducros 3,  Hugo Pomares 4,  Sandra Bourgeade-Delmas 5,  Patrice Vanelle 6,  Nicolas Primas 7
Affiliations

Affiliations

  • 1 Aix Marseille Univ, CNRS, ICR UMR 7273, Team Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, Marseille, 13385, France. Electronic address: ines.jacquet@etu.univ-amu.fr.
  • 2 Aix Marseille Univ, CNRS, ICR UMR 7273, Team Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, Marseille, 13385, France; Service Central de la Qualité et de l'Information Pharmaceutiques, Hôpital de la Conception, AP-HM, Marseille, 13005, France. Electronic address: romain.paoli-lombardo@univ-amu.fr.
  • 3 Aix Marseille Univ, CNRS, ICR UMR 7273, Team Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, Marseille, 13385, France; Service Central de la Qualité et de l'Information Pharmaceutiques, Hôpital de la Conception, AP-HM, Marseille, 13005, France. Electronic address: caroline.ducros@univ-amu.fr.
  • 4 Aix Marseille Univ, CNRS, ICR UMR 7273, Team Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, Marseille, 13385, France. Electronic address: hugpomares@gmail.com.
  • 5 UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, 31062, France. Electronic address: sandra.bourgeade-delmas@ird.fr.
  • 6 Aix Marseille Univ, CNRS, ICR UMR 7273, Team Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, Marseille, 13385, France; Service Central de la Qualité et de l'Information Pharmaceutiques, Hôpital de la Conception, AP-HM, Marseille, 13005, France. Electronic address: patrice.vanelle@univ-amu.fr.
  • 7 Aix Marseille Univ, CNRS, ICR UMR 7273, Team Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, Marseille, 13385, France; Service Central de la Qualité et de l'Information Pharmaceutiques, Hôpital de la Conception, AP-HM, Marseille, 13005, France. Electronic address: nicolas.primas@univ-amu.fr.
PMID: 41448051 DOI: 10.1016/j.ejmech.2025.118506
Abstract

To explore the antileishmanial structure-activity relationships at position 2 of the 3-nitroimida-zo[1,2-a]pyridine scaffold, we developed a new synthetic method using Tetrakis(dimethylamino)ethylene (TDAE) and N-tosylbenzylimines. This original synthetic route was optimized to provide simple and reproducible access to diverse analogues functionalized at position 2. A library of 25 new derivatives was generated via efficient diversification at position 8 using nucleophilic aromatic substitution (SNAr) and Suzuki-Miyaura cross-coupling reactions. The 8-brominated analogues emerged as the most promising series, with six compounds exhibiting submicromolar activity against Leishmania infantum axenic amastigotes. Further substitution at position 8 with 4-pyridinyl or para-chlorothiophenol groups significantly decreased potency. The most active compound was also active on intramacrophagic amastigotes (half maximal inhibitory concentration (IC50) = 0.35 μM) without displaying any cytotoxicity on THP1 cell line (50 % cytotoxic concentration (CC50) > 100 μM). The reduction of its nitro group afforded an amino analogue, which retained antileishmanial activity (IC50 = 2.77 μM), indicating potential alternative mechanisms of action beyond nitro bioactivation. Despite its low solubility (<1 μM), this scaffold represents a novel and versatile entry point for antileishmanial drug discovery.

Keywords

3-Nitroimidazo[1,2-a]pyridine; Leishmania; N-Tosylbenzylimine; Nitroaromatic compounds; Nucleophilic aromatic substitution; Palladium-catalyzed cross-coupling; TDAE.

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