MANIPULATION OF THE N-ALKYL SUBSTITUENT IN AMODIAQUINE TO OVERCOME THE VERAPAMIL-SENSITIVE CHLOROQUINE RESISTANCE COMPONENT

Aminoquinoline resistance correlates with lipid solubility at pH 7.2. Consequently, the in vivo dealkylation of amodiaquine, to the less lip id-soluble desethylamodiaquine, is a likely contributor to therapeutic failure in vivo, Therefore, 4-aminoquinoline drugs with lipid solubil ities similar to that of amodiaquine, but which are not subject to sid e chain modification in vivo, should be superior antimalarial agents, In this study, we have identified amopyroquine and N-tertbutylamodiaqu ine as two such compounds. The values for the logarithms of the partit ion coefficients for amopyroquine and N-tertbutylamodiaquine are betwe en those for amodiaquine and its dealkylated metabolite, desethylamodi aquine. Both amopyroquine and N-tertbutylamodiaquine possess levels of antimalarial activity greater than that of desethylamodiaquine and si gnificantly reduced cross-resistance patterns; i.e., the former two co mpounds are not subject to the verapamil-sensitive resistance mechanis m, Simple in vitro markers of direct toxicity and potential reactive m etabolite formation suggest that these two compounds are no more toxic than amodiaquine and desethylamodiaquine.