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

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...

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Published in:Chemical science (Cambridge) 2023-11, Vol.14 (45), p.12941-12952
Main Authors: Herrmann, Lars, Leidenberger, Maria, Sacramento de Morais, Adrielle, Mai, Christina, Çapci, Aysun, da Cruz Borges Silva, Mariana, Plass, Fabian, Kahnt, Axel, Moreira, Diogo R. M., Kappes, Barbara, Tsogoeva, Svetlana B.
Format: Article
Language:English
Subjects:
Antiparasitic agents
Coumarin
Drugs
Erythrocytes
Fluorescence
Image resolution
In vivo methods and tests
Lead compounds
Malaria
Natural products
Time dependence
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Summary: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 Artemisia annua 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 in vitro against CQ-resistant and multidrug-resistant P. falciparum 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 in vitro potency and in vivo 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 via time-dependent imaging resolution in living P. falciparum-infected red blood cells.
ISSN:2041-6520
2041-6539
DOI:10.1039/d3sc03661h