Copper (I)-Chloroquine Complexes: Interactions with DNA and Ferriprotoporphyrin, Inhibition of β-Hematin Formation and Relation to Antimalarial Activity

Abstract

A new Cu(I)-chloroquine (CQ) complex [Cu(CQ)(PPh3)2]NO3 (1) was synthesized and characterized, and its mechanism of action studied concomitant with the previously reported complex [Cu(CQ)2]Cl (2). These copper (I) coordination compounds can be considered as potential antimalarial agents because they show better inhibition of the CQ-resistant strain in in vitro studies than CQ alone. In comparison with other metal-CQ complexes, only the gold complex was similar to (1), i.e., more active than CQ against both CQ-susceptible (3D7) and CQ-resistant strains (W2). These two copper (I)-compounds also demonstrated higher antiplasmodial activity against W2 than other copper complexes reported to date. This suggests that the incorporation of the copper metal center enhanced the biological activity of CQ. To better understand their significant growth inhibition of the Plasmodium falciparum parasite, the interaction with two essential molecular targets for the survival and proliferation of the malarial parasite were studied. These were the ferriprotoporphyrin group and the DNA, both important targets for current antimalarial drugs at the asexual erythrocytic stages. Both compounds (1,2) exhibited significant interactions with these targets. In particular, interactions with the DNA were dominated by the intercalator properties of the CQ ligand but may have also been affected by the presence of copper. Overall, these compounds were better parasitic inhibitors than chloroquine diphosphate (CQDP) alone or other previously reported metal-CQ complexes such as platinum, ruthenium and gold.

Copper(I)‐Thiosemicarbazone Complexes with Dual Anticancer and Antiparasitic Activity

“…Amongst the several reports on the anticancer and antiparasitic potential of copper complexes, only a small number of them include Cu(I) as central ion, mainly due to the difficulty to stabilize copper(I) species. However several examples of Cu(I) complexes involving P‐donor ligands and N,N‐diimine chelates have shown high stability and antineoplastic activity in vitro against several tumor cell lines [32,37–46] . In fact, due to the soft nature of the P‐donor and S‐donor atoms, the use of phosphane and sulfur ligands can be an efficient way to stabilize Cu(I)‐d 10 metal centers [46] …”

“…Some of us have been focused on the search for new Cu(I)–phosphane compounds with several heteroaromatic ligands as anticancer agents. Several complexes of general formula [Cu(PP)(LL)][BF 4 ] in which PP represents mono/bidentate phosphane ligands and LL represents N,N‐, N,O‐ or N,S‐heteroaromatic bidentate ligands were designed and synthesized [18,44–46] . Most of these compounds present high cytotoxic activities in vitro against several human cancer cell lines (e. g. A2780, MCF7, MDAMB231, HCT116 and HCT116 DOXR), in most cases, showing lower IC 50 values than cisplatin [18,44–46] …”

“…However several examples of Cu(I) complexes involving P-donor ligands and N,N-diimine chelates have shown high stability and antineoplastic activity in vitro against several tumor cell lines. [32,[37][38][39][40][41][42][43][44][45][46] In fact, due to the soft nature of the P-donor and S-donor atoms, the use of phosphane and sulfur ligands can be an efficient way to stabilize Cu(I)-d 10 metal centers. [46] Some of us have been focused on the search for new Cu(I)phosphane compounds with several heteroaromatic ligands as anticancer agents.…”

“…Several complexes of general formula [Cu-(PP)(LL)][BF 4 ] in which PP represents mono/bidentate phosphane ligands and LL represents N,N-, N,O-or N,S-heteroaromatic bidentate ligands were designed and synthesized. [18,[44][45][46] Most of these compounds present high cytotoxic activities in vitro against several human cancer cell lines (e. g. A2780, MCF7, MDAMB231, HCT116 and HCT116 DOXR), in most cases, showing lower IC 50 values than cisplatin. [18,[44][45][46] Our ongoing interest in this area and the similarities between parasites and cancer have inspired us to develop Cu(I)-phosphane complexes containing previously reported antiparasitic 5-nitrofuryl-thiosemicarbazone derivatives as bioactive ligands to explore the interface between these two fields.…”

New N4-Donor Ligands as Supramolecular Guests for DNA and RNA: Synthesis, Structural Characterization, In Silico, Spectrophotometric and Antimicrobial Studies

“…Cu(I) coordination compounds, despite the oxidative instability of the ions [ 19 ], have been studied as potential antitumor [ 20 ] and antimicrobial agents as well [ 16 , 17 ]. For instance, in 2022, Villarreal et al presented the synthesis, structural, and biological studies of a new Cu(I) complex that was shown to be a potential antimalarial drug [ 21 ].…”