%0 Journal Article
%9 ACL : Articles dans des revues avec comité de lecture répertoriées par l'AERES
%A Jacquet, I.
%A Paoli-Lombardo, R.
%A Castera-Ducros, C.
%A Pomares, H.
%A Bourgeade-Delmas, Sandra
%A Vanelle, P.
%A Primas, N.
%T Discovery of antileishmanial hits in the 3-nitroimidazo[1,2-a]pyridine series via newly optimized tetrakis(dimethylamino)ethylene (TDAE) methodology at position 2
%D 2026
%L fdi:010096002
%G ENG
%J European Journal of Medicinal Chemistry
%@ 0223-5234
%K TDAE ; N-Tosylbenzylimine ; Leishmania ; Nitroaromatic compounds ; Nucleophilic aromatic substitution ; Palladium-catalyzed cross-coupling ; 3-Nitroimidazo[1,2-a]pyridine
%M ISI:001653982000001
%P 118506 [14 ]
%R 10.1016/j.ejmech.2025.118506
%U https://www.documentation.ird.fr/hor/fdi:010096002
%> https://horizon.documentation.ird.fr/exl-doc/pleins_textes/2026-02/010096002.pdf
%V 304
%W Horizon (IRD)
%X 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.
%$ 020 ; 050 ; 052