THERMODYNAMIC FACTORS CONTROLLING THE INTERACTION OF QUINOLINE ANTIMALARIAL-DRUGS WITH FERRIPROTOPORPHYRIN-IX

The interaction of a variety of quinoline antimalarial drugs as well a s other quinoline derivatives with strictly monomeric ferriprotoporphy rin IX [Fe(III)PPIX] has been investigated in 40% aqueous DMSO solutio n. At an apparent pH of 7.5 and 25 degrees C, log K values for bonding are 5.52 +/- 0.03 (chloroquine), 5.39 +/- 0.04 (amodiaquine), 4.10 +/ - 0.02 (quinine), 4.04 +/- 0.03 (9-epiquinine), and 3.90 +/- 0.08 (mef loquine). Primaquine, 8-hydroxyquinoline, 5-aminoquinoline, 6-aminoqui noline, 8-aminoquinoline, and quinoline exhibit no evidence of interac tion with Fe(III)PPIX. The enthalpy and entropy changes for the intera ction of quinolines with Fe(III)PPIX, as determined from the temperatu re dependence of the log K values, exhibit a compensation phenomenon t hat is suggestive of hydrophobic interaction. This is supported by the finding that the interactions of chloroquine and quinine with Fe(III) PPIX are weakened by increasing concentrations of acetonitrile. Intera ctions of chloroquine, quinine, and 9-epiquinine with Fe(lll)PPIX are shown to remain strong at pH 5.6, the approximate pH of the food vacuo le of the malaria parasite which is believed to be the locus of drug a ctivity. Implications for the design of antimalarial drugs are briefly discussed. (C) 1997 Elsevier Science Inc.