Paoli-Lombardo R. auteur aut IRD Primas N. auteur aut IRD Bourgeade-Delmas Sandra auteur aut IRD Hutter S. auteur aut IRD Sournia-Saquet A. auteur aut IRD Boudot C. auteur aut IRD Brenot E. auteur aut IRD Castera-Ducros C. auteur aut IRD Corvaisier S. auteur aut IRD Since M. auteur aut IRD Malzert-Freon A. auteur aut IRD Courtioux B. auteur aut IRD Valentin A. auteur aut IRD Verhaeghe P. auteur aut IRD Azas N. auteur aut IRD Rathelot P. auteur aut IRD Vanelle P. auteur aut IRD text journalArticle eng text/pdf reformatted digital access An antileishmanial structure-activity relationship (SAR) study focused on positions 2 and 8 of the imidazo[1,2-a]pyridine ring was conducted through the synthesis of 22 new derivatives. After being screened on the promatigote and axenic amastigote stages of Leishmania donovani and L. infantum, the best compounds were tested against the intracellular amastigote stage of L. infantum and evaluated regarding their in vitro physicochemical and pharmacokinetic properties, leading to the discovery of a new antileishmanial6-chloro-3-nitro-8-(pyridin-4-yl)-2-[(3,3,3-trifluoropropylsulfonyl)methyl]imidazo[1,2-a]pyridine hit. It displayed low cytotoxicities on both HepG2 and THP1 cell lines (CC50 > 100 mu M) associated with a good activity against the intracellular amastigote stage of L. infantum (EC50 = 3.7 mu M versus 0.4 and 15.9 mu M for miltefosine and fexinidazole, used as antileishmanial drug references). Moreover, in comparison with previously reported derivatives in the studied series, this compound displayed greatly improved aqueous solubility, good mouse microsomal stability (T-1/2 > 40 min) and high gastrointestinal permeability in a PAMPA model, making it an ideal candidate for further in vivo studies on an infectious mouse model. specialized Imidazo[1,2-a]pyridine nitroaromatic nitroreductases Leishmania spp. structure-activity relationships thermodynamic solubility microsomal stability gastrointestinal permeability 050 020 052 15 8 998 [24 p.] 2022 https://www.documentation.ird.fr/hor/fdi:010086035 10.3390/ph15080998 [F B010086035] https://www.documentation.ird.fr/hor/fdi:010086035 https://horizon.documentation.ird.fr/exl-doc/pleins_textes/2022-10/010086035.pdf IRD - Base Horizon / Pleins textes 2022-10-07 2025-02-24 fdi:010086035 fre