A Chemically Stable Fluorescent Mimic of Dihydroartemisinin, Artemether, and Arteether with Conserved Bioactivity and Specificity Shows High Pharmacological Relevance to the Antimalarial Drugs.

Abstract

Three novel tracers designed as fluorescent surrogates of artemisinin-derived antimalarial drugs (i.e., dihydroartemisinin, artemether, arteether, and artemisone) were synthesized from dihydroartemisinin. One of these tracers, corresponding to a dihydroartemisinin/artemether/arteether mimic, showed a combination of excellent physicochemical and biological properties such as hydrolytic stability, high inhibitory potency against blood-stage parasites, similar ring-stage survival assay values than the clinical antimalarials, high cytopermeability and specific labeling of live P. falciparum cells, alkylation of heme, as well as specific covalent labeling of drug-sensitive and drug-resistant P. falciparum proteomes at physiological concentrations, consistent with a multitarget action of the drugs. Our study demonstrates that probes containing the complete structural core of clinical artemisinin derivatives can be stable in biochemical and cellular settings, and recapitulate the complex mechanisms of these frontline, yet threatened, antimalarial drugs.