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

Stec, Jozef and Fomovska, Alina and Afanador, Gustavo A. and Muench, Stephen P. and Zhou, Ying and Lai, Bo Shiun and ElBissati, Kamal and Hickman, Mark R. and Lee, Patty J. and Leed, Susan E. and Auschwitz, Jennifer M. and Sommervile, Caroline and Woods, Stuart and Roberts, Craig W. and Rice, David and Prigge, Sean T. and Mcleod, Rima and Kozikowski, Alan P. (2013) Modification of triclosan scaffold in search of improved inhibitors for enoyl-acyl carrier protein (ACP) reductase in Toxoplasma gondii. ChemMedChem, 8 (7). pp. 1138-1160. ISSN 1860-7179

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Official URL: https://doi.org/10.1002/cmdc.201300050

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 16 a and 16 c have IC50 values of 250 nM against Toxoplasma gondii tachyzoites without apparent toxicity to the host cells. Their IC50 values against recombinant TgENR were found to be 43 and 26 nM, respectively. Additionally, 11 other analogues in this series had IC50 values ranging from 17 to 130 nM in the enzyme-based assay. With respect to their excellent in vitro activity as well as improved drug-like properties, the lead compounds 16 a and 16 c are deemed to be excellent starting points for the development of new medicines to effectively treat Toxoplasma gondii infections.

Author(s):	Stec, Jozef, Fomovska, Alina, Afanador, Gustavo A., Muench, Stephen P., Zhou, Ying, Lai, Bo Shiun, ElBissati, Kamal, Hickman, Mark R., Lee, Patty J., Leed, Susan E., Auschwitz, Jennifer M., Sommervile, Caroline, Woods, Stuart ORCID: https://orcid.org/0000-0002-3798-2074, Roberts, Craig W. ORCID: https://orcid.org/0000-0002-0653-835X, Rice, David, Prigge, Sean T., Mcleod, Rima and Kozikowski, Alan P.
Item type:	Article
ID code:	44274
Notes:	Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Keywords:	enoyl reductase, inhibitors, medicinal chemistry, Toxoplasma gondii, triclosan, Pharmacy and materia medica, Organic Chemistry, Molecular Medicine, Pharmacology, Toxicology and Pharmaceutics(all)
Subjects:	Medicine > Pharmacy and materia medica
Department:	Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences University of Strathclyde > University of Strathclyde
Depositing user:	Pure Administrator
Date deposited:	03 Jul 2013 10:35
Last modified:	11 Oct 2019 04:36
Related URLs:	Scopus publication
URI:	https://strathprints.strath.ac.uk/id/eprint/44274
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