Chloroquine free base (CQ) reacts with [Rh(COD)Cl]2 (COD = 1,5-cyclooctadiene) and RuCl3.-3H2O/Zn to yield Rh(COD)(CQ)Cl (1) and [RuCl2(CQ)]2 (2), respectively. The two novel metal- CQ complexes, which were characterized mainly by 1D and 2D NMR spectroscopy, were tested against Plasmodium berghei. The in vitro activity of 1 was comparable to that of chloroquine diphosphate (CQDP), whereas 2 was about 5 times more active. In in vivo tests at equivalent concentrations of free CQ, CQDP reduced the parasitemia by 55%, while for complexes 1 and 2 the reduction reached 73% and 94%, respectively, without any sign of acute toxicity being observed up to 30 days after treatment. The Ru derivative 2 was further evaluated against two chloroquine-resistant strains of Plasmodium falciparum, and it was found to be 2-5 times more active than CQDP.

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.