Organometallic complexes with antimalarial properties
Sammanfattning: Malaria is a serious disease that causes around 800 000 deaths per year. Current malaria control efforts are hampered by the widespread resistance to common antimalarial drugs, such as the 4-aminoquinoline derivative called chloroquine. Previous research has shown that specific modifications of chloroquine, including inclusion of organometallic fragments into the organic framework, can result in compounds that are able to circumvent resistance. In the case of ferroquine, a ferrocene analogue of chloroquine, excellent results against both chloroquine sensitive and chloroquine resistant malaria parasites have been achieved and the drug has completed phase II clinical trials. This thesis describes the synthesis and evaluation of antimalarial activity of metal chloroquine analogues with an integrated “half sandwich” unit (an organometallic moiety with an aromatic π-system and three additional ligands). These complexes can be divided into two groups in which the side chain of the 4-aminoquinoline group is either covalently bound to the aromatic ring of the half sandwich unit or coordinated to the metal in the half sandwich unit. Organometallic complexes based on chromium, manganese, rhenium, ruthenium and osmium are presented. In the case of chromium, manganese and osmium, these are the first reported organometallic complexes with antimalarial activity. The chromium complex η6-N-(7-chloroquinolin-4-yl)-N′-(2-dimethylamino-methylbenzyl)-ethane-1,2-diamine tricarbonylchromium showed high antimalarial activity against both a chloroquine sensitive and a chloroquine resistant P. falciparum malaria strain and was more active than the corresponding organic ligand against resistant parasites. The manganese complexes N-(2-(7-chloroquinolin-4-ylamino)ethyl)-4-cymantrenylbutanamide and N-(7-chloroquinolin-4-yl)-N’-(cymantrenylmethyl)ethane-1,2-diamine, and the rhenium complex N-(2-(7-chloroquinolin-4-ylamino)ethyl)-4-cyrhetrenyl butanamide, all of which lack a terminal tertiary amine, were significantly less active. The ruthenium and osmium complexes RuCl(η6-p-cymene)(L1)Cl (L1 = N-(2-((pyridin-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) and MCl(η6-p-cymene)(L2)Cl (M = Ru, Os; L2 = N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) were less active than their corresponding ligands against both the chloroquine sensitive and the chloroquine resistant parasite strain. In contrast, the complexes MCl(η6-p-cymene)(L3) (M = Ru, Os; HL3 = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine) were significantly more active than the ligand alone against both parasite strains. Overall, osmium complexes appear to exhibit higher activity than their ruthenium counterparts.
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