Work

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

Year: 2025

Type: article

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 (S N Ar) 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 (IC 50 ) = 0.35 μM) without displaying any cytotoxicity on THP1 cell line (50% cytotoxic concentration (CC 50 ) > 100 μM). The reduction of its nitro group afforded an amino analogue, which retained antileishmanial activity (IC 50 = 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. • TDAE methodology applied to N -tosylbenzylimines for 3-nitroimidazo[1,2- a ]pyridine derivatives • Simple and reproducible access to modulation at position 2 • 25 new derivatives synthesized via S N Ar and Suzuki-Miyaura cross-coupling at position 8 • Several new compounds display submicromolar antileishmanial activity • Nitro-independent antileishmanial activity was observed

Source: European Journal of Medicinal Chemistry

DOI: 10.1016/j.ejmech.2025.118506