Design, synthesis, and characterization of novel aminoalcohol quinolines with strong in vitro antimalarial activity

Alexandra Dassonville-Klimpt (1) , J. Schneider (1) , Céline Damiani (1) , Camille Tisnerat (1) , Anita Cohen (2) , Nadine Azas (2) , Mathieu Marchivie (3) , J Guillon (4) , Catherine Mullié (1) , P. Agnamey (1) , Anne Totet (1) , Jérôme Dormoi (2, 5, 6) , Nicolas Taudon (5) , Bruno Pradines (2, 5, 6, 7) , Pascal Sonnet (1)

1 AGIR - Agents infectieux, résistance et chimiothérapie - UR UPJV 4294
2 VITROME - Vecteurs - Infections tropicales et méditerranéennes
3 ICMCB - Institut de Chimie de la Matière Condensée de Bordeaux
4 ARNA - Acides Nucléiques : Régulations Naturelle et Artificielle
5 IRBA - Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge]
6 IHU Marseille - Institut Hospitalier Universitaire Méditerranée Infection
7 CNRP - Centre National de Référence du Paludisme [IRBA, Marseille]

Malaria is the fifth most lethal parasitic infections in the world. Herein, five new series of aminoalcohol quinolines including fifty-two compounds were designed, synthesized and evaluated in vitro against Pf3D7 and PfW2 strains. Among them, fourteen displayed IC50 values below or near of 50.0 nM whatever the strain with selectivity index often superior to 100. 17b was found as a promising antimalarial candidate with IC50 values of 14.9 nM and 11.0 nM against respectively Pf3D7 and PfW2 and a selectivity index higher than 770 whatever the cell line is. Further experiments were achieved to confirm the safety and to establish the preliminary ADMET profile of compound 17b before the in vivo study performed on a mouse model of P. berghei ANKA infection. The overall data of this study allowed to establish new structure-activity relationships and the development of novel agents with improved pharmacokinetic properties

Mots clés: Malaria; P. falciparum; antimalarial drug resistance; mefloquine analogs; aminoalcohol quinolines; Malaria

Domaines: Matériaux

Alexandra Dassonville-Klimpt, J. Schneider, Céline Damiani, Camille Tisnerat, Anita Cohen, et al.. Design, synthesis, and characterization of novel aminoalcohol quinolines with strong in vitro antimalarial activity. European Journal of Medicinal Chemistry, 2022, 228, 113981 (26 p.). ⟨10.1016/j.ejmech.2021.113981⟩. ⟨hal-03464917⟩