Hybrid Gold(I) NHC-Artemether Complexes to Target Falciparum Malaria Parasites

• Published in: Molecules (Basel, Switzerland) Vol. 25; no. 12; p. 2817
• Main Authors: Ouji, Manel, Barnoin, Guillaume, Fernández Álvarez, Álvaro, Augereau, Jean-Michel, Hemmert, Catherine, Benoit-Vical, Françoise, Gornitzka, Heinz
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18.06.2020; MDPI
• Subjects: Antimalarial agents; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Antiprotozoal agents; Artemether; Artemether - chemistry; Artemether - pharmacology; Artemisinin; Cancer; Cell cycle; Chemical Sciences; Coordination chemistry; Cross-resistance; Cytotoxicity; Dihydroartemisinin; Drug development; drug resistance; Drugs; Gold; Gold - chemistry; Gold - pharmacology; Health risks; Humans; hybrid molecules; Malaria; Mammalian cells; Mass spectrometry; NHC-ligands; Organogold Compounds - chemical synthesis; Organogold Compounds - chemistry; Organogold Compounds - pharmacology; Parasites; Parasitic diseases; Pharmacokinetics; Plasmodium falciparum; Plasmodium falciparum - growth & development; Public health; Scientific imaging; Vector-borne diseases; gold; Plasmodium falciparum; NHC-ligands; drug resistance; hybrid molecules; malaria; Gold; Malaria; Drug resistance; Hybrid molecules
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25122817

The emergence of parasites, responsible for malaria disease, resistant to antiplasmodial drugs including the artemisinins, represents a major threat to public health. Therefore, the development of new antimalarial drugs or combinations is urgently required. In this context, several hybrid molecules combining a dihydroartemisinin derivative and gold(I) N-heterocyclic carbene (NHC) complexes have been synthesized based on the different modes of action of the two compounds. The antiplasmodial activity of these molecules was assessed in vitro as well as their cytotoxicity against mammalian cells. All the hybrid molecules tested showed efficacy against , in a nanomolar range for the most active, associated with a low cytotoxicity. However, cross-resistance between artemisinin and these hybrid molecules was evidenced. These results underline a fear about the risk of cross-resistance between artemisinins and new antimalarial drugs based on an endoperoxide part. This study thus raises concerns about the use of such molecules in future therapeutic malaria policies.