Three new ruthenium complexes with bidentate chloroquine analogue ligands, [Ru(η⁶-cym)(L¹)Cl]Cl (1, cym = p-cymene, L¹ = N-(2-((pyridin-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine), [Ru(η⁶-cym)(L²)Cl]Cl (2, L² = N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) and [Ru(η⁶-cym)(L³)Cl] (3, L³ = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine) have been synthesized and characterized. In addition, the X-ray crystal structure of 2 is reported. The antimalarial activity of complexes 1–3 and ligands L¹, L² and L³, as well as the compound N-(2-(bis((pyridin-2-yl)methyl)amino)ethyl)-7-chloroquinolin-4-amine (L⁴), against chloroquine sensitive and chloroquine resistant Plasmodium falciparum malaria strains was evaluated. While 1 and 2 are less active than the corresponding ligands, 3 exhibits high antimalarial activity. The chloroquine analogue L² also shows good activity against both the chloroquine sensitive and the chloroquine resistant strains. Heme aggregation inhibition activity (HAIA) at an aqueous buffer/n-octanol interface (HAIR₅₀) and lipophilicity (D, as measured by water/n-octanol distribution coefficients) have been measured for all ligands and metal complexes. A direct correlation between the D and HAIR₅₀ properties cannot be made because of the relative structural diversity of the complexes, but it may be noted that these properties are enhanced upon complexation of the inactive ligand L³ to ruthenium, to give a metal complex (3) with promising antimalarial activity.

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.

The unsymmetrical dinucleating ligand 2-(N-isopropyl-N-((2-pyridyl)methyl)aminomethyl)-6-(N-(carboxylmethyl)-N-((2-pyridyl)methyl)aminomethyl)-4-methylphenol (IPCPMP or L) has been synthesized to model the active site environment of dinuclear metallohydrolases. It has been isolated as the hexafluorophosphate salt H₄IPCPMP(PF₆)₂·2H₂O (H₄L), which has been structurally characterized, and has been used to form two different Zn(II) complexes, [{Zn₂(IPCPMP)(OAc)}₂][PF₆]₂ (2) and [{Zn₂(IPCPMP)(Piv)}₂][PF₆]₂ (3) (OAc = acetate; Piv = pivalate). The crystal structures of 2 and 3 show that they consist of tetranuclear complexes with very similar structures. Infrared spectroscopy and mass spectrometry indicate that the tetranuclear complexes dissociate into dinuclear complexes in solution. Potentiometric studies of the Zn(II) : IPCPMP system in aqueous solution reveal that a mononuclear complex is surprisingly stable at low pH, even at a 2 : 1 Zn(II) : L ratio, but a dinuclear complex dominates at high pH and transforms into a dihydroxido complex by a cooperative deprotonation of two, probably terminally coordinated, water molecules. A kinetic investigation indicates that one of these hydroxides is the active nucleophile in the hydrolysis of bis(2,4-dinitrophenyl)phosphate (BDNPP) enhanced by complex 2, and mechanistic proposals are presented for this reaction as well as the previously reported transesterification of 2-hydroxypropyl p-nitrophenyl phosphate (HPNP) promoted by Zn(II) complexes of IPCPMP.

Dinuclear carboxylate-bridged zinc complexes of one symmetric and one asymmetric phenolate-based ligand catalyse the transesterification of 2-hydroxypropyl-p-nitrophenyl phosphate (HPNP) at different rates, with an unsymmetrical complex being more active than a symmetric one.