Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-a]pyridine Antileishmanial Pharmacophore

Romain Paoli-Lombardo (1) , Nicolas Primas (1, 2) , Sandra Bourgeade-Delmas (3) , Sébastien Hutter (4) , Alix Sournia-Saquet (5) , Clotilde Boudot (6) , Emilie Brenot (6) , Caroline Castera-Ducros (1, 2) , Sophie Corvaisier (7) , Marc Since (7) , Aurélie Malzert-Fréon (7) , Bertrand Courtioux (6) , Alexis Valentin (3) , Pierre Verhaeghe (5, 8) , Nadine Azas (4) , Pascal Rathelot (1, 2) , Patrice Vanelle (1, 2)

1 ICR - Institut de Chimie Radicalaire
2 LA CONCEPTION - Hôpital de la Conception [CHU - APHM]
3 PHARMA-DEV - Pharmacochimie et Biologie pour le Développement
4 VITROME - Vecteurs - Infections tropicales et méditerranéennes
5 LCC - Laboratoire de chimie de coordination
6 EpiMaCT - Epidémiologie des Maladies Chroniques en zone tropicale
7 CERMN - Centre d'Etudes et de Recherche sur le Médicament de Normandie
8 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes

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 µM) associated with a good activity against the intracellular amastigote stage of L. infantum (EC50 = 3.7 µM versus 0.4 and 15.9 µM 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 (T1/2 > 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.

Mots clés: Nitroaromatic; Nitroreductases; Leishmania spp.; Structure-activity relationships; Thermodynamic solubility; Microsomal stability; Gastrointestinal permeability; Imidazo[1 2-a]pyridine

Domaines: Médicaments

Romain Paoli-Lombardo, Nicolas Primas, Sandra Bourgeade-Delmas, Sébastien Hutter, Alix Sournia-Saquet, et al.. Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-a]pyridine Antileishmanial Pharmacophore. Pharmaceuticals, 2022, 15 (8), pp.998. ⟨10.3390/ph15080998⟩. ⟨hal-03755519⟩