AdditiveIn VitroAntiplasmodial Effect ofN-Alkyl andN-Benzyl-1,10-Phenanthroline Derivatives and Cysteine Protease Inhibitor E64

[摘要] Potential new targets for antimalarial chemotherapy include parasite proteases, which are required for several cellular functions during thePlasmodium falciparumlife cycle. Four new derivatives ofN-alkyl andN-benzyl-1,10-phenanthrolinehave been synthesized. Those are(1)-N-methyl-1,10-phenanthrolinium sulfate, (1)-N-ethyl-1,10-phenanthrolinium sulfate, (1)-N-benzyl-1,10-phenanthrolinium chloride, and (1)-N-benzyl-1,10-phenanthrolinium iodide. Those compounds had potential antiplasmodial activity with IC50values from 260.42 to 465.38 nM.Cysteine proteinase inhibitor E64 was used to investigate the mechanism of action ofN-alkyl andN-benzyl-1,10-phenanthroline derivatives. A modified fixed-ratio isobologram method was used to study thein vitrointeractions between the newcompounds with either E64 or chloroquine. The interaction betweenN-alkyl andN-benzyl-1,10-phenanthroline derivatives and E64 was additiveas well as their interactions withchloroquine were also additive. Antimalarial mechanism of chloroquine is mainly on the inhibition of hemozoin formation. As the interaction of chloroquine and E64 was additive, the results indicated that these new compounds had a mechanism of action byinhibitingPlasmodiumproteases.

[学科分类] 传染病学