Synthesis and biological activity of diaryl ether inhibitors of malarial enoyl acyl carrier protein reductase. Part 2: 2′-Substituted triclosan derivatives

Joel S. Freundlich, Min Yu, Edinson Lucumi, MacK Kuo, Han Chun Tsai, Juan Carlos Valderramos, Luchezar Karagyozov, William R. Jacobs, Guy A. Schiehser, David A. Fidock, David P. Jacobus, James C. Sacchettini

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

2′-Substituted analogs of triclosan have been synthesized to target inhibition of the key malarial enzyme Plasmodium falciparum enoyl acyl carrier protein reductase (PfENR). Many of these compounds exhibit good potency (EC 50 < 500 nM) against in vitro cultures of drug-resistant and drug-sensitive strains of the P. falciparum parasite and modest (IC50 = 1-20 μM) potency against purified PfENR enzyme. Compared to triclosan, this survey of 2′-substituted derivatives has afforded gains in excess of 20- and 30-fold versus the 3D7 and Dd2 strains of parasite, respectively.

Original languageEnglish (US)
Pages (from-to)2163-2169
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume16
Issue number8
DOIs
StatePublished - Apr 15 2006

Keywords

  • Antimalarial
  • Diaryl ether
  • Phenol

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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    Freundlich, J. S., Yu, M., Lucumi, E., Kuo, M., Tsai, H. C., Valderramos, J. C., Karagyozov, L., Jacobs, W. R., Schiehser, G. A., Fidock, D. A., Jacobus, D. P., & Sacchettini, J. C. (2006). Synthesis and biological activity of diaryl ether inhibitors of malarial enoyl acyl carrier protein reductase. Part 2: 2′-Substituted triclosan derivatives. Bioorganic and Medicinal Chemistry Letters, 16(8), 2163-2169. https://doi.org/10.1016/j.bmcl.2006.01.051