Modification of triclosan scaffold in search of improved inhibitors for enoyl-acyl carrier protein (ACP) Reductase in Toxoplasma gondii

Jozef Stec, Alina Fomovska, Gustavo A. Afanador, Stephen P. Muench, Ying Zhou, Bo Shiun Lai, Kamal El Bissati, Mark R. Hickman, Patty J. Lee, Susan E. Leed, Jennifer M. Auschwitz, Caroline Sommervile, Stuart Woods, Craig W. Roberts, David Rice, Sean T. Prigge, Rima Mcleod, Alan P. Kozikowski

Research output: Contribution to journalArticle

Abstract

Through our focused effort to discover new and effective agents against toxoplasmosis, a structure-based drug design approach was used to develop a series of potent inhibitors of the enoyl-acyl carrier protein (ACP) reductase (ENR) enzyme in Toxoplasma gondii (TgENR). Modifications to positions 5 and 4′ of the well-known ENR inhibitor triclosan afforded a series of 29 new analogues. Among the resulting compounds, many showed high potency and improved physicochemical properties in comparison with the lead. The most potent compounds 16a and 16c have IC 50 values of 250nM against Toxoplasma gondii tachyzoites without apparent toxicity to the host cells. Their IC 50 values against recombinant TgENR were found to be 43 and 26nM, respectively. Additionally, 11 other analogues in this series had IC 50 values ranging from 17 to 130nM in the enzyme-based assay. With respect to their excellent invitro activity as well as improved drug-like properties, the lead compounds 16a and 16c are deemed to be excellent starting points for the development of new medicines to effectively treat Toxoplasma gondii infections.

Original languageEnglish (US)
Pages (from-to)1138-1160
Number of pages23
JournalChemMedChem
Volume8
Issue number7
DOIs
StatePublished - Jul 1 2013

Keywords

  • Enoyl reductase
  • Inhibitors
  • Medicinal chemistry
  • Toxoplasma gondii
  • Triclosan

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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  • Cite this

    Stec, J., Fomovska, A., Afanador, G. A., Muench, S. P., Zhou, Y., Lai, B. S., El Bissati, K., Hickman, M. R., Lee, P. J., Leed, S. E., Auschwitz, J. M., Sommervile, C., Woods, S., Roberts, C. W., Rice, D., Prigge, S. T., Mcleod, R., & Kozikowski, A. P. (2013). Modification of triclosan scaffold in search of improved inhibitors for enoyl-acyl carrier protein (ACP) Reductase in Toxoplasma gondii. ChemMedChem, 8(7), 1138-1160. https://doi.org/10.1002/cmdc.201300050