Carbon isosteres of the 4-aminopyridine substructure of chloroquine: Effects on pKa, hematin binding, inhibition of hemozoin formation, and parasite growth

Srinivasa R. Cheruku, Souvik Maiti, Arnulf Dorn, Bernard Scorneaux, Apurba K. Bhattacharjee, William Y. Ellis, Jonathan L. Vennerstrom

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3166-3169
Number of pages4
JournalJournal of Medicinal Chemistry
Volume46
Issue number14
DOIs
StatePublished - Jul 3 2003

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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