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

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 (S_NAr) 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.