Optimization of propafenone analogues as antimalarial leads

David J. Lowes, W. Armand Guiguemde, Michele C. Connelly, Fangyi Zhu, Martina S. Sigal, Julie A. Clark, Andrew S. Lemoff, Joseph L. Derisi, Emily B. Wilson, R. Kiplin Guy

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Propafenone, a class Ic antiarrythmic drug, inhibits growth of cultured Plasmodium falciparum. While the drug's potency is significant, further development of propafenone as an antimalarial would require divorcing the antimalarial and cardiac activities as well as improving the pharmacokinetic profile of the drug. A small array of propafenone analogues was designed and synthesized to address the cardiac ion channel and PK liabilities. Testing of this array revealed potent inhibitors of the 3D7 (drug sensitive) and K1 (drug resistant) strains of P. falciparum that possessed significantly reduced ion channel effects and improved metabolic stability. Propafenone analogues are unusual among antimalarial leads in that they are more potent against the multidrug resistant K1 strain of P. falciparum compared to the 3D7 strain.

Original languageEnglish (US)
Pages (from-to)7477-7485
Number of pages9
JournalJournal of Medicinal Chemistry
Volume54
Issue number21
DOIs
StatePublished - Nov 10 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Lowes, D. J., Guiguemde, W. A., Connelly, M. C., Zhu, F., Sigal, M. S., Clark, J. A., Lemoff, A. S., Derisi, J. L., Wilson, E. B., & Guy, R. K. (2011). Optimization of propafenone analogues as antimalarial leads. Journal of Medicinal Chemistry, 54(21), 7477-7485. https://doi.org/10.1021/jm2005546