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

Dionissia Pepe (1) , Dimitra Toumpa (1) , Christiane André-Barrès (2) , Christophe Menendez (2) , Elisabeth Mouray (3) , Michel Baltas (2) , Philippe Grellier (3) , Dionissios Papaioannou (1) , Constantinos Athanassopoulos (1)

1 University of Patras
2 SPCMIB - Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique
3 MCAM - Molécules de Communication et Adaptation des Micro-organismes

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 antimalarial activity were 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.

Keywords: artemisinin; phytormones G-factors; chloroquine; hybrids; conjugates; polyamines; antimalarials

Domains: Chemical Sciences; Medicinal Chemistry; Life Sciences [q-bio]; Microbiology and Parasitology

Dionissia Pepe, Dimitra Toumpa, Christiane André-Barrès, Christophe Menendez, Elisabeth Mouray, et al.. Synthesis of Novel G Factor or Chloroquine-Artemisinin Hybrids and Conjugates with Potent Antiplasmodial Activity. ACS Medicinal Chemistry Letters, 2020, 11 (5), pp.921-927. ⟨10.1021/acsmedchemlett.9b00669⟩. ⟨mnhn-02867374⟩