Autofluorescent antimalarials by hybridization of artemisinin and coumarin: <i>in vitro</i>/<i>in vivo</i> studies and live-cell imaging

Abstract

Malaria is one of our planet's most widespread and deadliest diseases, and there is an ever-consistent need for new and improved pharmaceuticals. Natural products have been an essential source of hit and lead compounds for drug discovery. Antimalarial drug artemisinin (ART), a highly effective natural product, is an enantiopure sesquiterpene lactone and occurs in <i>Artemisia annua</i> L. The development of improved antimalarial drugs, which are highly potent and at the same time inherently fluorescent is particularly favorable and highly desirable since they can be used for live-cell imaging, avoiding the requirement of the drug's linkage to an external fluorescent label. Herein, we present the first antimalarial autofluorescent artemisinin-coumarin hybrids with high fluorescence quantum yields of up to 0.94 and exhibiting excellent activity <i>in vitro</i> against CQ-resistant and multidrug-resistant <i>P. falciparum</i> strains (IC₅₀ (Dd2) down to 0.5 nM; IC₅₀ (K1) down to 0.3 nM) compared to reference drugs CQ (IC₅₀ (Dd2) 165.3 nM; IC₅₀ (K1) 302.8 nM) and artemisinin (IC₅₀ (Dd2) 11.3 nM; IC₅₀ (K1) 5.4 nM). Furthermore, a clear correlation between <i>in vitro</i> potency and <i>in vivo</i> efficacy of antimalarial autofluorescent hybrids was demonstrated. Moreover, deliberately designed autofluorescent artemisinin-coumarin hybrids, were not only able to overcome drug resistance, they were also of high value in investigating their mode of action <i>via</i> time-dependent imaging resolution in living <i>P. falciparum</i>-infected red blood cells.