Synthesis, Characterization, and in vitro Antimalarial and Antitumor Activity of New Ruthenium(II) Complexes of Chloroquine

Abstract

The new RuII chloroquine complexes [Ru(η6-arene)(CQ)Cl2] (CQ = chloroquine; arene = p-cymene 1, benzene 2), [Ru(η6-p-cymene)(CQ)(H2O)2][BF4]2 (3), [Ru(η6-p-cymene)(CQ)(en)][PF6]2 (en = ethylenediamine) (4), and [Ru(η6-p-cymene)(η6-CQDP)][BF4]2 (5, CQDP = chloroquine diphosphate) have been synthesized and characterized by use of a combination of NMR and FTIR spectroscopy with DFT calculations. Each complex is formed as a single coordination isomer: in compounds 1–4 chloroquine binds to ruthenium in the η1-N mode through the quinoline nitrogen atom whereas in complex 5 an unprecedented η6 bonding through the carbocyclic ring is observed. Compounds 1, 2, 3, and 5 are active against CQ-resistant (Dd2, K1 and W2) and CQ-sensitive (FcB1, PFB, F32 and 3D7) malaria parasites (Plasmodium falciparum); importantly, the potency of these complexes against resistant parasites is consistently higher than that of the standard drug chloroquine diphosphate. Complexes 1 and 5 also inhibit the growth of colon cancer cells, independently of the p53 status and of liposarcoma tumor cell lines with the latter showing increased sensitivity, especially to complex 1 (IC50 8 µM); this is significant because this type of tumor does not respond to currently employed chemotherapies.

Ferrocenyl Derivatives of the Anthelmintic Praziquantel: Design, Synthesis, and Biological Evaluation

“…Of note, Sánchez-Delgado and co-workers reported the preparation of ruthenium half-sandwich analogues of CQ which were found to be highly potent and to overcome the CQ resistance. 28 Organometallic compounds have also been investigated for their activity against other parasites such as the trypanosome Trypanosoma cruzi (T. cruzi) or Echinococcus multilocularis metacestodes. [29][30][31] For example, a ruthenium halfsandwich complex of the antifungal drug clotrimazole was found to be 58 times more potent than the parent drug in vitro against T. cruzi.…”

Chloroquine-based hybrid molecules as promising novel chemotherapeutic agents

“…4) in this series exhibited IC 50 values in the range of 234-906 nM against CQ-R strains. However, the hybrid molecules were less active than CQDP against most CQ-S strains, except the 3D7 CQ-S strain (Rajapakse et al, 2009a). Certain platinum-based organometallic and 4-aminoquinoline hybrids (e.g., 13 in Fig.…”

“…However, they showed low therapeutic index for antimalarial activity due to high cytotoxicity . Rajapakse et al (2009a) reported that the transition metal ruthenium (II) and CQ hybrids possess antimalarial and anticancer activities with good solubility. In addition, the presence of an arene ring in these compounds increase lipophilicity by stabilizing the metal center.…”

“…Both of them have been completed phase 1 clinical trial with encouraging results (Loannis et al, 2007). Rajapakse et al (2009a) synthesized a series of Ru II -CQ hybrids and evaluated them against cancer cells. Two hybrids, 33 [Ru(η 6 -pcymene)(CQ)Cl 2 ] and 34 {[Ru(η 6 -p-cymene)(η 6 -CQDP)][BF 4 ] 2 } Q3 (CQDP¼chloroquine diphosphate) (Fig.…”

Perception and Resistance Mechanism of some Metal-drug Complexes and Their Roles as Antibacterial

“…The reaction of FQ and CQ against P. falciparum strains is quite unique and different in which FQ reveal some high potency in chloroquine-resistant and chloroquine-sensitive P. falciparum strains [26][27][28][29][30][31][32].…”