Half-sandwich complexes with amino-quinoline ligands - synthesis, antiplasmodial and antimycobacterial activities

Sammanfattning: Malaria and tuberculosis are two of the most deadly infectious diseases that exist. Both diseases predominantly affect the most vunerable parts of society. Additionally the treatment of both diseases are complicated by growing and spreading resistance against the drugs used to treat them. Chloroquine was once described as a wonder drug for its combination of efficacy, low price and tolerable side effects. Most P. falciparum malaria today is resistant against chloroquine and in many areas of the world its usage has been discontinued. Ferroquine is a chloroquine derivative that overcomes chloroquine resistance by incorporation of a ferrocene moiety into the chloroquine side chain. This thesis deals with attempts to overcome chloroquine resistance by incorporation of half-sandwich moieties. In Paper I, eight of new 4-aminoquinoline-based ligands and a large number of ruthenium and osmium half sandwichcomplexes with these ligands are prepared and tested for antimalarial activity. The ligands are highly active against a chloroquine sensitive strain of P. falciparum, but exhibit cross-resistance with chloroquine. The ruthenium and osmium complexes are less active than the free ligands and do not overcome chloroquine resistance. The antimalarial activity of the ligands correlates with electronic properties of substituents on a phenol ring. In Paper II, the same ligand family as in Paper I are used to prepare 20 new rhodium and iridium pentamethylcyclopentadienyl complexes. The rhodium comlexes are more active than iridium complexes, and both are more active than ruthenium or osmium complexes. Only occasionally though are a metal complex more active than the free ligands, but complexes share the cross-resistance of the free ligands. The correlation between ligand substituents and antimalarial activity extends to the rhodium and iridium complexes. Paper III introduces a 4-aminoquinoline-pyrazinamide hybrid which has limited antimalarial and antimycobacterial acitivity. Metal complexes are more active against M. tuberculosis. Paper IV examines the effect of halide ligands in complexes from earlier papers. No clear conclusion can be drawn, although halide exchange can affect antimalarial activity. Paper V introduces 2 pyrazole-based 4-aminoquinoline ligands. Ligands and half sandwich complexes are reasonably active against CQS parasites, Pd and Pt complexes are much less active.