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

Abstract

The emergence of Plasmodium falciparum 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 P. falciparum, 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.

Metallodrug Profiling against SARS‐CoV‐2 Target Proteins Identifies Highly Potent Inhibitors of the S/ACE2 interaction and the Papain‐like Protease PLpro

“…Some tested compounds are commercially available and they were purchased from Sigma Aldrich (sodium aurothiomalate hydrate, gold(III) chloride hydrate, chloro(triethylphosphine)gold(I), chloro(triphenylphosphine)gold(I), thiomersal), Acros Organics (silver sulfadiazine, titanocene dichoride, cisplatin, disulfiram), Adipogen‐Biomol (chloroquine diphosphate) and Enzo Life Sciences (auranofin). The following complexes were prepared as previously described in the literature: Au‐7 [51] , Au‐8 [52] , Au‐9 , Au‐11 [53] , Au10 [54] , Au‐12 , Au‐13 [55] , Au‐15 [52] , Au‐20 , Au‐25 , Au‐26 [56] , Au‐27 [57] , Au‐31 – Au‐32 [55] , Au‐33 , Au‐34 [58] , Ru‐1 , Ru‐4 – Ru‐8 , [59] , Ru‐10 [60] , Ru‐11 [61] , Ru‐12 [62] , Ru‐13 [63] , Ru‐14 , Ru‐15 , Ru‐16 [64] , Mn‐1 , Mn‐2 [65] , Re‐1 [66] , Re‐2 [67] , Pt‐2 [68] , Pt‐3 , Pt‐4 , Pd‐1 , Pd‐2 [69] , Fe‐1 , Fe‐2 , Fe‐3 , Fe‐4 [70] , Fe‐5 [71] , Fe‐6 [72] , Fe‐7 , Fe‐8 [73] Fe‐9 [74] , Fe‐10 [75] , Fe‐11 [76] , Fe‐13 [77] , POM‐1 , POM‐2 [27] , POM‐3 [28] , POM‐4 [29] , POM‐5 [30] , POM‐6 , POM7 [31] , POM‐8 , POM‐9 , POM‐10 [32] , POM‐11 [33] . For preparation and characterization of all other complexes see the supporting information.…”

The antimalarial activity of 1,2,4‐trioxolane/trioxane hybrids and dimers: A review

“…[67] The activity of ART dimer gold(I) complex 51 (IC 50 : 9.0 nM) was twice higher than that of ART (IC 50 : 18 nM) against CQS 3D7 strain and this complex displayed acceptable cytotoxicity (IC 50 : 1.0 µM) towards normal VERO cells. [68] The ART dimer 52 could inhibit the 40% CQS 3D7 strain of P. falciparum at the concentration of 100 nM and the activity was slightly less potent than that of ART (58.2% inhibition rate). [69] The ART dimer 53 (EC 50 : 7.97 nM) was highly potent against ARTresistant clone 4G strain of P. falciparum, implying that this dimer may possess a novel mechanism of action and it could also overcome ART resistance.…”

Biological Activity of Gold Compounds against Viruses and Parasitosis: A Systematic Review

“…Gold(I) complexes with N-heterocyclic carbene (NHC) or gold(III)-dithiocarbamato complexes [40] Plasmonium falciparum and Leishmania infantum Gold(I) complexes combined with triclosan [41,42] Protozoa and Helminth infections Gold(I) complex [43] Leishmania major, Toxoplasma gondii and Trypanosoma Gold(I)-carbene complexes [44] [40]…”