THE ROLE OF DRUG ACCUMULATION IN 4-AMINOQUINOLINE ANTIMALARIAL POTENCY - THE INFLUENCE OF STRUCTURAL SUBSTITUTION AND PHYSICOCHEMICAL PROPERTIES

We have investigated a series of novel 4-aminoquinoline analogues rela ted to amodiaquine, that possess side chain modifications designed to influence both drug pKa and lipophilicity. These compounds have been u sed to determine the influence of physicochemical properties on antima larial activity against, and accumulation by, both chloroquine-suscept ible and chloroquine-resistant isolates of Plasmodium falciparum. The compounds tested exhibited a 500-fold range of absolute antimalarial p otency. Absolute drug potency and drug accumulation were found to be s ignificantly correlated in each of the four isolates of Plasmodium fal ciparum studied. The level of accumulation was unrelated to lipophilic ity and was significantly greater than the predicted levels of accumul ation based on drug pKa, compartmental pc, and Henderson-Hasselbach co nsiderations. Further analysis of the relationship between 4-aminoquin oline accumulation and activity implicated the involvement of addition al forces in the accumulation process.