Interactions of quinoline antimalarial drugs with ferrihaem : structural and kinetic insights into the inhibition of malaria pigment formation

[摘要] ENGLISH ABSTRACT: The work in this dissertation provides structural and kinetic insight into the mechanism ofaction of quinoline antimalarial drugs which may aid rational drug design. Quinolineantimalarial drug-ferrihaem (Fe(III)PPIX) complexes were investigated. Single crystal Xraydiffraction (SCD) structures of the complexes formed between Fe(III)PPIX and thequinoline methanol antimalarials quinine, quinidine and mefloquine have been determined,and are the first observed structures of complexes formed between free Fe(III)PPIX andquinoline antimalarial compounds. Quinine, quinidine and mefloquine are shown to have athree-point binding mode to Fe(III)PPIX, which comprises direct coordination of the drugto the Fe(III) centre through its benzylic alcohol functionality, π-stacking between the drugand porphyrin aromatic systems, and intramolecular hydrogen bond formation between theporphyrin propionate group and the protonated quinuclidine nitrogen atom of the drug inthe case of quinine and quinidine, and formation of an intramolecular hydrogen bondingnetwork in the case of mefloquine. Extended X-ray absorption fine structure spectroscopy(EXAFS) was use to elucidate structural information of Fe(III)PPIX-drug complexes insolution, and indicates that coordination persists in solution.The protocol for lipid-mediated formation of β-haematin, where monopalmitic glycerolwas used as a model lipid, was successfully modified to incorporate antimalarial drugs intothe aqueous layer in order to investigate drug activity under biologically-relevantconditions. Four compounds were chosen, namely chloroquine and amodiaquine, both 4-aminoquinolines and quinine and quinidine. IC50 values for the inhibition of β-haematinformation show good correlation with biological activities determined against achloroquine-sensitive Plasmodium falciparum strain. The lipid-water interface system wasfurther used to investigate the effects of quinine, quinidine chloroquine and amodiaquineon the kinetics of β-haematin formation. The results led to the development of a kineticmodel based on the Avrami equation and the Langmuir isotherm. The data strongly supporta mechanism of antimalarial drug action by adsorption to the growing face of haemozoin,with precipitation of Fe(III)PPIX at high drug concentrations accounting for decreasedyields. Adsorptions constants (log Kads) determined for each drug show a strong correlationwith biological activity. Finally, the first SCD structure of the μ-propionato dimer ofFe(III)PPIX, the structural unit of haemozoin, has been determined as its DMSO solvate.EXAFS suggests that this species is only formed upon nucleation, with the π-π dimerspecies being favoured in solution.

[发布机构] Stellenbosch University