The design of donecopride, a dual 5-HT4R agonist/AChE inhibitor with potential interest for AD treatment

Cédric Lecoutey (1) , Damien Hedou (1) , Thomas Freret (2) , Patrizia Giannoni (3) , Florence Gaven (4) , Marc Since (1) , Valentine Bouet (2) , Céline Ballandonne (1) , Sophie Corvaisier (5) , Aurélie Malzert-Fréon (1) , Serge Mignani (1) , Thierry Cresteil (6) , Michel Boulouard (2) , Sylvie Claeysen (3) , Christophe Rochais (1) , Patrick Dallemagne (1)

1 CERMN - Centre d'Etudes et de Recherche sur le Médicament de Normandie
2 GMPc - Groupe Mémoire et Plasticité comportementale
3 IGF - Institut de Génomique Fonctionnelle
4 Institut du Fer à Moulin
5 COMETE - Mobilités : Vieillissement, Pathologie, Santé
6 ICSN - Institut de Chimie des Substances Naturelles

A series of nitrated 2-substituted-quinolines was synthesized and evaluated in vitro toward Leishmania donovani promastigotes. In parallel, the in vitro cytotoxicity of these molecules was assessed on the murine J774 and human HepG2 cell lines. Thus, a very promising antileishmanial hit molecule was identified (compound 21), displaying an IC50 value of 6.6 μM and CC50 values ≥ 100 μM, conferring quite good selectivity index to this molecule, in comparison with 3 drug-compounds of reference (amphotericin B, miltefosine and pentamidine). Compound 21 also appears as an efficient in vitro antileishmanial molecule against both Leishmania infantum promastigotes and the intracellular L. donovani amastigotes (respective IC50 = 7.6 and 6.5 μM). Moreover, hit quinoline 21 does not show neither significant antiplasmodial nor antitoxoplasmic in vitro activity and though, presents a selective antileishmanial activity. Finally, a structure–activity relationships study enabled to define precisely the antileishmanial pharmacophore based on this nitroquinoline scaffold: 2-hydroxy-8-nitroquinoline.

Mots clés: Selectivity index; 8-Nitroquinoline; Visceral leishmaniasis; Leishmania donovani; Leishmania infantum; Promastigotes; Amastigotes hepG2 cytotoxicity

Domaines: Sciences cognitives; Neurobiologie; Biologie moléculaire; Neurosciences; Chimie thérapeutique

Cédric Lecoutey, Damien Hedou, Thomas Freret, Patrizia Giannoni, Florence Gaven, et al.. The design of donecopride, a dual 5-HT4R agonist/AChE inhibitor with potential interest for AD treatment. Proceedings of the National Academy of Sciences of the United States of America, 2014, 54, pp.75-86. ⟨10.1016/j.ejmech.2012.04.029⟩. ⟨hal-01800439v1⟩