Design, Synthesis and Efficacy of Hybrid Triclosan‐gold Based Molecules on Artemisinin‐resistant Plasmodium falciparum and Leishmania infantum Parasites

Abstract

One molecule to target two pathologies. In the fight against major parasite diseases such as malaria and leishmaniasis, novel drugs active against drug-resistant parasites are needed. Hybrid molecules combining triclosan and gold(I) complexes appear as a promising avenue.

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

“…Among the 29 compounds tested, ten gold(I) complexes have shown high antiplasmodial activities, with IC 50 values less than 50 nM and very low cytotoxicity, with selectivity indexes up to 294. However, even though a simple gold(I) bis(NHC) had shown in a previous work [20] no cross-resistance with artemisinins, the presence of this metal could not prevent cross-resistance in the hybrid gold(I)-DHA complexes Aubis(3-Me), Aubis(4-Me) and Aubis(5-Me) tested. These data confirm that the presence of an endoperoxide moiety whatever the structure and the other parts of the hybrid molecules tested leads to artemisinins cross-resistance.…”

“…All compounds were characterized by 1 H-and 13 C-NMR spectroscopy, high-resolution mass spectrometry and elemental analysis. 13 C-NMR spectroscopy unequivocally evidences the formation of the cationic gold(I) complexes Aubis(n-R) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) with resonance of the carbenic carbons located at 181.8-183.9 ppm. In the case of mono-NHC complexes Au(n-R)Cl (27)(28)(29), the most characteristic features in 13 C NMR spectra are the C2 peaks at 173.3, 174.5 and 173.7 ppm for Au(3-iPr)Cl (27), Au(3-Bn)Cl (28) and Au(3-Quin)Cl (29), respectively.…”

“…In the case of mono-NHC complexes Au(n-R)Cl (27)(28)(29), the most characteristic features in 13 C NMR spectra are the C2 peaks at 173.3, 174.5 and 173.7 ppm for Au(3-iPr)Cl (27), Au(3-Bn)Cl (28) and Au(3-Quin)Cl (29), respectively. The elemental analysis for the gold(I) complexes correspond to the general formula [AuL2][Cl] (except for Aubis(L3-Me) (14) with nitrate anion) for the bis(NHC) complexes Aubis(n-R) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) and AuLCl for the mono(NHC) complexes Au(n-R)Cl (27)(28)(29). The high resolution mass spectra (ESI + ) HRMS spectra of all gold(I) complexes exhibit the classical peak m/z for the cationic fragment [M-X − ] + .…”

“…Our chemical research is mainly focused on the design of bioactive gold(I) NHC complexes for parasitic diseases, P. falciparum [18][19][20] and Leishmania infantum [21,22], and anticancer applications [23][24][25]. Moreover, in the field of anticancer metal-based agents, the ubiquitous selenoenzyme thioredoxin reductase (TrxR), responsible for cell homeostasis regulation, is considered as one of the most relevant targets for gold(I) complexes and inhibition of TrxR could lead to apoptosis though a mitochondrial pathway [24][25][26].…”

A “Golden Age” for the discovery of new antileishmanial agents: Current status of leishmanicidal gold complexes and prospective targets beyond the trypanothione system

“…Recently, Ouji et al. evaluated the inhibitory activity of cationic bis‐ N ‐triclosan‐NHC‐gold(I) series 16 against promastigotes and amastigotes of L. infantum [77] . In this work, they compared the results with auranofin reported by Sharlow et al [67] .…”