Discovery of a bulky 2-tert-butyl group containing primaquine analogue that exhibits potent blood-schizontocidal antimalarial activities and complete elimination of methemoglobin toxicity

J Med Chem. 2004 Jan 15;47(2):285-7. doi: 10.1021/jm0304562.

Abstract

To eliminate an unwarranted metabolic pathway of the quinoline ring, a set of two compounds, where C-2 position of the antimalarial drug primaquine is blocked by metabolically stable bulky alkyl group are synthesized. Compound 2 [R = C(CH(3))(3)] of the series has produced excellent antimalarial efficacy against P. berghei and highly virulent multidrug-resistant P. yoelii nigeriensis strain in vivo. Compound 2 was also evaluated for methemoglobin (MetHb) toxicity. This study describes the discovery of a highly potent blood-schizontocidal antimalarial analogue 2, completely devoid of MetHb toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / pharmacology
  • Antimalarials / toxicity
  • Malaria / blood
  • Malaria / mortality
  • Malaria / parasitology
  • Methemoglobin / analysis*
  • Mice
  • Plasmodium berghei / drug effects
  • Plasmodium falciparum / drug effects
  • Plasmodium yoelii / drug effects
  • Primaquine / analogs & derivatives*
  • Primaquine / chemical synthesis*
  • Primaquine / pharmacology
  • Primaquine / toxicity
  • Structure-Activity Relationship

Substances

  • 2-tert-butylprimaquine
  • Antimalarials
  • Methemoglobin
  • Primaquine