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 related to amodiaquine, that possess side chain modifications designed to influence both drug pKa and lipophilicity. These compounds have been used to determine the influence of physicochemical properties on antimalarial activity against, and accumulation by, both chloroquine-susceptible and chloroquine-resistant isolates of Plasmodium falciparum. The compounds tested exhibited a 500-fold range of absolute antimalarial potency. Absolute drug potency and drug accumulation were found to be significantly correlated in each of the four isolates of Plasmodium falciparum studied. The level of accumulation was unrelated to lipophilicity and was significantly greater than the predicted levels of accumulation based on drug pKa, compartmental pH, and Henderson-Hasselbach considerations. Further analysis of the relationship between 4-aminoquinoline accumulation and activity implicated the involvement of additional forces in the accumulation process.