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Pharmaceutical Research

, Volume 7, Issue 1, pp 91–95 | Cite as

Effect of Aliphatic Side-Chain Substituents on the Antimalarial Activity and on the Metabolism of Primaquine Studied Using Mitochondria and Microsome Preparations

  • John K. Baker
  • Robert H. Yarber
  • N. P. D. Nanayakkara
  • James D. McChesney
  • Frederic Homo
  • Irene Landau
Article

Abstract

The substitution of two deuterium atoms on the α-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 α-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 l′-position, even when this position bore a methyl substituent. Primaquine, the α-dideutero analogue, and the α-methyl analogue were all found to have about the same in vitro antimalarial activity as determined in the liver hepatocyte assay.

malaria drug metabolism deuterium isotope effect cytotoxicity, quinocide 

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Copyright information

© Plenum Publishing Corporation 1990

Authors and Affiliations

  • John K. Baker
    • 1
  • Robert H. Yarber
    • 1
  • N. P. D. Nanayakkara
    • 2
  • James D. McChesney
    • 2
  • Frederic Homo
    • 3
  • Irene Landau
    • 3
  1. 1.Department of Medicinal Chemistry, School of PharmacyUniversity of Mississippi
  2. 2.Department of Pharmacognosy, School of PharmacyUniversity of Mississippi
  3. 3.Laboratoire De Zoologie (Vers)Museum National d'Histoire NaturelleParis Cedex 05France

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