New ruthenium (II)-chloroquine complexes and metal-free aminoquinolines: Synthesis, antimalarial activity and mechanism of biological action

Malaria is widespread in many tropical and subtropical regions and causes between one and three million deaths annually. The disease is caused by a protozoan parasite of the genus Plasmodium that is transmitted primarily by the female Anopheles mosquito. Chloroquine (CQ) is the most commonly used antimalarial drug, but resistant strains of P. falciparum have emerged and thus improved chemotherapies are required. Modifications of the molecular structure of chloroquine led to other effective quinoline based drugs but unfortunately, resistance to these drugs is now also common in many parts of the world.;The success of cisplatin and other platinum anticancer drugs has stimulated a renaissance of inorganic medicinal chemistry and the search for complexes of other transition metals with better biological properties. Among them, ruthenium complexes are attracting increasing attention as potential chemotherapeutic agents against a variety of diseases.;Complexation of CQ to Ru has been previously shown by our group to enhance the activity against resistant strains of the malaria parasite, as for instance the complex [RuCl2(CQ)]2. In the first phase of this thesis we adopted a molecular design based on Ru(II) forming coordinate bonds to CQ through one of the basic nitrogen atoms. A series of new organo-Ru II-CQ complexes were synthesized and characterized by use of a combination of NMR and FTIR spectroscopy with DFT calculations.;All the new complexes were 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 (CQDP). In order to understand the origin of the improved antimalarial activity, we have measured water/n-octanol partition coefficients, pKa values, heme binding constants, and heme aggregation inhibition activity of the new (pi-arene)-Ru-CQ complexes. Measurements of heme aggregation inhibition activity of the metal complexes atq water/n-octanol interfaces qualitatively predict their superior antiplasmodial action against resistant parasites, in relation to CQ. Some interesting tendencies emerge from our data, indicating that the antiplasmodial activity is related to a balance of effects associated with the lipophilicity, basicity, and structural details of the compounds studied.;We concluded that the increase in the lipophilicity of CQ caused by coordination to the Ru-containing fragments is beneficial for overcoming resistance but the reduction in basicity due to the blocking of one active nitrogen atom by the metal limits the therapeutic potential of the complexes.;Therefore, new compounds combining the desired basicity and lipophilicity are needed. Based on this new model, two new metal free 4-aminoquinoline derivatives were synthesized and characterized by 1D/2D NMR spectroscopy, elemental analysis and mass spectrometry. Both compounds are highly active in vitro against CQ-resistant strains of P. falciparum (K1, K14 and Dd2) as well as a CQ-sensitive strain (D6). Both compounds are more basic and more lipophilic than the standard drug CQ. Our mechanistic studies demonstrate the validity of our hypothesis: that the structural and physicochemical modifications of 4-aminoquinoline imposed by the presence of the lipophilic substituent as a side chain lead to an enhanced activity against malaria parasites, while retaining heme aggregation as the main target of action.