Effect of aliphatic side-chain substituents on the antimalarial activity and on the metabolism of primaquine studied using mitochondria and microsome preparations.

Abstract

The substitution of two deuterium atoms on the alpha-carbon of the primaquine side chain was found to produce a sevenfold decrease in the rate of conversion of primaquine to carboxyprimaquine by enzymatic oxidative deamination, but the deuterium substitution was found to have no significant effect on the in vitro antimalarial activity or on in vitro hepatocyte toxicity. Placing a single methyl group on the alpha-carbon was found to produce only a slight decrease in the rate of oxidative deamination. Although metabolic attack occurred adjacent to either the aniline nitrogen or the aliphatic amine, metabolic attack occurred primarily adjacent to the more basic nitrogen at the 1'-position, even when this position bore a methyl substituent. Primaquine, the alpha-dideutero analogue, and the alpha-methyl analogue were all found to have about the same in vitro antimalarial activity as determined in the liver hepatocyte assay.