Emoquine‑1: A Hybrid Molecule Efficient against Multidrug-Resistant Plasmodium Parasites, Including the Artemisinin-Resistant Quiescent Stage, and Also Active In Vivo

To challenge the multidrug resistance of Plasmodium
falciparum malaria parasites, new hybrid compounds
were synthesized and evaluated against laboratory strains and multidrug-resistant
clinical isolates. Among these hybrids, emoquine-1 was the most active
on proliferative P. falciparum, with
IC50 values in the range of 20–55 nM and a high
selectivity index with respect to mammalian cells. This drug retained
its activity on several multiresistant field isolates from Cambodia
and Guiana, exhibited no cross-resistance to artemisinin, and is also
very active against the quiescent stage of the artemisinin-resistant
parasites, three features that constitute the gold standard for new
antimalarial drugs. In vivo, emoquine-1 is active
against Plasmodium vinckei petteri
at 25 mg/kg/d per os and by the intraperitoneal route at 1–5
mg/kg/d, with total cure at 10 mg/kg/d, making emoquine-1 an ideal
candidate to fight Plasmodium parasites resistant
to artemisinin-based combination therapies (ACTs) with a capacity
to eliminate persistent parasites.