Although the mechanism by which squaric derivatives reported
herein act as antiplasmodial agents is unknown, there is strong
evidence that 4-aminoquinolines, such as chloroquine, exert their
main activity by interfering with heme detoxification in the acidic
digestive vacuole (DV) of erythrocytic parasites [2,25,26]. This
process requires a proper balance between charged and uncharged
molecular species to allow the appropriate diffusion of the uncharged
form at physiologic pH (7.4) and the retention of the
charged counterpart in the DV (pH ¼ 5.2). To test whether our
compounds might in fact satisfy these requirements, we determined
in silico the pH-dependent distribution of base between