Antimalarial activity of ruthenium(ii) and osmium(ii) arene complexes with mono- and bidentate chloroquine analogue ligands

Abstract

Eight new ruthenium and five new osmium p-cymene half-sandwich complexes have been synthesized, characterized and evaluated for antimalarial activity. All complexes contain ligands that are based on a 4-chloroquinoline framework related to the antimalarial drug chloroquine. Ligands HL^1–8 are salicylaldimine derivatives, where HL¹ = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine, and HL^2–8 contain non-hydrogen substituents in the 3-position of the salicylaldimine ring, viz. F, Cl, Br, I, NO₂, OMe and ^tBu for HL^2–8, respectively. Ligand HL⁹ is also a salicylaldimine-containing ligand with substitutions in both 3- and 5-positions of the salicylaldimine moiety, i.e. N-(2-((2-hydroxy-3,5-di-tert-butylphenyl)methyl-imino)ethyl)-7-chloroquinolin-4-amine, while HL¹⁰ is N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) The half sandwich metal complexes that have been investigated are [Ru(η⁶-cym)(L^1–8)Cl] (Ru-1–Ru-8, cym = p-cymene), [Os(η⁶-cym)(L^1–3,5,7)Cl] (Os-1–Os-3, Os-5, and Os-7), [M(η⁶-cym)(HL⁹)Cl₂] (M = Ru, Ru-HL⁹; M = Os, Os-HL⁹) and [M(η⁶-cym)(L¹⁰)Cl]Cl (M = Ru, Ru-10; M = Os, Os-10). In complexes Ru-1–Ru-8 and Ru-10, Os-1–Os-3, Os-5 and Os-7 and Os-10, the ligands were found to coordinate as bidentate N,O- and N,N-chelates, while in complexes Ru-HL⁹ and Os-HL⁹, monodentate coordination of the ligands through the quinoline nitrogen was established. The antimalarial activity of the new ligands and complexes was evaluated against chloroquine sensitive (NF54 and D10) and chloroquine resistant (Dd2) Plasmodium falciparum malaria parasite strains. Coordination of ruthenium and osmium arene moieties to the ligands resulted in lower antiplasmodial activities relative to the free ligands, but the resistance index is better for the ruthenium complexes compared to chloroquine. Overall, osmium complexes appeared to be less active than the corresponding ruthenium complexes.