Novel hybrid 1,4-naphthoquinone-endoperoxide antimalarial hits: Synthesis, stereoisomeric separation, and biological evaluation.

Hybrid molecules, chemical entities with two or more pharmacophore domains, are widely investigated for their antiparasitic potential. First-in-class antimalarial hybrids were designed and tested against Plasmodium falciparum. Our multistep synthesis, initiated by a Mn(III)-mediated radical reaction, led to new hybrids containing both the pharmacophores of atovaquone (naphthoquinone) and artemisinin (endoperoxide) separated by a piperazine linker. With 2 or 3 asymmetric carbons, 4 to 8 theoretical configurational isomers were expected. For two of our 5 final products, chiral chromatography separated all isomers. 20 single isomers or stereoisomeric mixtures were obtained and tested against Plasmodium falciparum W2 and K1 chloroquine-resistant strains for their antiplasmodial activity and against HepG2 and CHO cells for their cytotoxicity. Antiplasmodial activity was better than those obtained for reference compound chloroquine for 15 compounds on PfW2 strain and 8 compounds on PfK1 strain. Hit compounds were identified among stereoisomer mixtures (12, IC50PfW2 = 0.489 μM, IC50PfK1 = 1.061 μM, CC50 HepG2 = 11.99 μM, CC50 CHO >125 μM) but also among several stereoisomers. These results suggest that hybrid compounds naphthoquinone/endoperoxide synthesized by adding two pharmacophores can lead to a synergistic effect.