Synthesis of Novel G Factor or Chloroquine-Artemisinin Hybrids and Conjugates with Potent Antiplasmodial Activity

Dionissia A Pepe; Dimitra Toumpa; Christiane André-Barrès; Christophe Menendez; Elisabeth Mouray; Michel Baltas; Philippe Grellier; Dionissios Papaioannou; Constantinos M Athanassopoulos

doi:10.1021/acsmedchemlett.9b00669

Synthesis of Novel G Factor or Chloroquine-Artemisinin Hybrids and Conjugates with Potent Antiplasmodial Activity

ACS Med Chem Lett. 2020 Mar 24;11(5):921-927. doi: 10.1021/acsmedchemlett.9b00669. eCollection 2020 May 14.

Authors

Dionissia A Pepe¹, Dimitra Toumpa¹, Christiane André-Barrès², Christophe Menendez², Elisabeth Mouray³, Michel Baltas², Philippe Grellier³, Dionissios Papaioannou¹, Constantinos M Athanassopoulos¹

Affiliations

¹ Synthetic Organic Chemistry Laboratory, Department of Chemistry, University of Patras, Patras GR-26504, Greece.
² LSPCMIB, UMR-CNRS 5068, Université Paul Sabatier-Toulouse III, 118 route de Narbonne, Toulouse CEDEX 9 31062, France.
³ MCAM, UMR 7245 CNRS, Muséum National d'Histoire Naturelle, CNRS, CP52, 57 rue Cuvier, Paris 75005, France.

Abstract

A series of novel hybrids of artemisinin (ART) with either a phytormone endoperoxide G factor analogue (GMeP) or chloroquine (CQ) and conjugates of the same compounds with the polyamines (PAs), spermidine (Spd), and homospermidine (Hsd) were synthesized and their antiplasmodial activity was evaluated using the CQ-resistant P. falciparum FcB1/Colombia strain. The ART-GMeP hybrid 5 and compounds 9 and 10 which are conjugates of Spd and Hsd with two molecules of ART and one molecule of GMeP, were the most potent with IC₅₀ values of 2.6, 8.4, and 10.6 nM, respectively. The same compounds also presented the highest selectivity indexes against the primary human fibroblast cell line AB943 ranging from 16 372 for the hybrid 5 to 983 for the conjugate 10 of Hsd.