Synthesis, biological activity, and X-ray crystal structural analysis of diaryl ether inhibitors of malarial enoyl acyl carrier protein reductase. Part 1: 4′-Substituted triclosan derivatives

Joel S. Freundlich, John W. Anderson, Dimitri Sarantakis, Hong Ming Shieh, Min Yu, Juan Carlos Valderramos, Edinson Lucumi, MacK Kuo, William R. Jacobs, David A. Fidock, Guy A. Schiehser, David P. Jacobus, James C. Sacchettini

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

A structure-based approach has been taken to develop 4′-substituted analogs of triclosan that target the key malarial enzyme Plasmodium falciparum enoyl acyl carrier protein reductase (PfENR). Many of these compounds exhibit nanomolar potency against purified PfENR enzyme and modest (2-10 μM) potency against in vitro cultures of drug-resistant and drug-sensitive strains of the P. falciparum parasite. X-ray crystal structures of nitro 29, aniline 30, methylamide 37, and urea 46 demonstrate the presence of hydrogen-bonding interactions with residues in the active site and point to future rounds of optimization to improve compound potency against purified enzyme and intracellular parasites.

Original languageEnglish (US)
Pages (from-to)5247-5252
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume15
Issue number23
DOIs
StatePublished - Dec 1 2005

Keywords

  • Anti-malarial
  • 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., Anderson, J. W., Sarantakis, D., Shieh, H. M., Yu, M., Valderramos, J. C., Lucumi, E., Kuo, M., Jacobs, W. R., Fidock, D. A., Schiehser, G. A., Jacobus, D. P., & Sacchettini, J. C. (2005). Synthesis, biological activity, and X-ray crystal structural analysis of diaryl ether inhibitors of malarial enoyl acyl carrier protein reductase. Part 1: 4′-Substituted triclosan derivatives. Bioorganic and Medicinal Chemistry Letters, 15(23), 5247-5252. https://doi.org/10.1016/j.bmcl.2005.08.044