Carbon isosteres of the 4-aminopyridine substructure of chloroquine: effects on pK(a), hematin binding, inhibition of hemozoin formation, and parasite growth

J Med Chem. 2003 Jul 3;46(14):3166-9. doi: 10.1021/jm030038x.

Abstract

Unlike diprotic chloroquine (CQ), its two 4-aminoquinoline carbon isosteres (1, 2) are monoprotic at physiological pH. Compared to CQ, hematin binding affinity of 1 decreased 6.4-fold, and there was no measurable binding for 2. Although 1 was a weak inhibitor of hemozoin formation, neither isostere inhibited P. falciparum in vitro. Evidently, the CQ-hematin interaction is largely a function of its pyridine substructure, but inhibition of hemozoin formation and parasite growth depends on its 4-aminopyridine substructure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Aminopyridine / analogs & derivatives*
  • 4-Aminopyridine / chemical synthesis*
  • 4-Aminopyridine / pharmacology
  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / pharmacology
  • Chloroquine / chemistry*
  • Hemin / chemistry*
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / growth & development
  • Structure-Activity Relationship
  • Thermodynamics

Substances

  • Antimalarials
  • Hemin
  • Chloroquine
  • 4-Aminopyridine