Jacquet I. auteur aut IRD Paoli-Lombardo R. auteur aut IRD Castera-Ducros C. auteur aut IRD Pomares H. auteur aut IRD Bourgeade-Delmas Sandra auteur aut IRD Vanelle P. auteur aut IRD Primas N. auteur aut IRD text journalArticle eng text/pdf reformatted digital access 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 mu M) without displaying any cytotoxicity on THP1 cell line (50 % cytotoxic concentration (CC50) > 100 mu M). The reduction of its nitro group afforded an amino analogue, which retained antileishmanial activity (IC50 = 2.77 mu M), indicating potential alternative mechanisms of action beyond nitro bioactivation. Despite its low solubility (<1 mu M), this scaffold represents a novel and versatile entry point for antileishmanial drug discovery. specialized TDAE N-Tosylbenzylimine Leishmania Nitroaromatic compounds Nucleophilic aromatic substitution Palladium-catalyzed cross-coupling 3-Nitroimidazo[1,2-a]pyridine 020 050 052 304 118506 [14 ] 2026 0223-5234 https://www.documentation.ird.fr/hor/fdi:010096002 10.1016/j.ejmech.2025.118506 0223-5234 [F B010096002] https://www.documentation.ird.fr/hor/fdi:010096002 https://horizon.documentation.ird.fr/exl-doc/pleins_textes/2026-02/010096002.pdf IRD - Base Horizon / Pleins textes 2026-02-04 2026-02-05 fdi:010096002 fre