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 ElBissati, 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

11 Citations (Scopus)

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.
LanguageEnglish
Pages1138-1160
Number of pages23
JournalChemMedChem
Volume8
Issue number7
Early online date14 Jun 2013
DOIs
Publication statusPublished - Jul 2013

Fingerprint

Triclosan
Acyl Carrier Protein
Toxoplasma
Scaffolds
Inhibitory Concentration 50
Oxidoreductases
Toxoplasmosis
Lead compounds
Enzymes
Pharmaceutical Preparations
Medicine
Toxicity
Assays
Drug Design
Enzyme Assays
Lead

Keywords

  • enoyl reductase
  • inhibitors
  • medicinal chemistry
  • Toxoplasma gondii
  • triclosan

Cite this

Stec, J., Fomovska, A., Afanador, G. A., Muench, S. P., Zhou, Y., Lai, B. S., ... 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
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 ; Roberts, Craig W. ; Rice, David ; Prigge, Sean T. ; Mcleod, Rima ; Kozikowski, Alan P. / Modification of triclosan scaffold in search of improved inhibitors for enoyl-acyl carrier protein (ACP) reductase in Toxoplasma gondii. In: ChemMedChem. 2013 ; Vol. 8, No. 7. pp. 1138-1160.
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Stec, J, Fomovska, A, Afanador, GA, Muench, SP, Zhou, Y, Lai, BS, ElBissati, K, Hickman, MR, Lee, PJ, Leed, SE, Auschwitz, JM, Sommervile, C, Woods, S, Roberts, CW, Rice, D, Prigge, ST, Mcleod, R & Kozikowski, AP 2013, 'Modification of triclosan scaffold in search of improved inhibitors for enoyl-acyl carrier protein (ACP) reductase in Toxoplasma gondii' ChemMedChem, vol. 8, no. 7, pp. 1138-1160. https://doi.org/10.1002/cmdc.201300050

Modification of triclosan scaffold in search of improved inhibitors for enoyl-acyl carrier protein (ACP) reductase in Toxoplasma gondii. / 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; Roberts, Craig W.; Rice, David; Prigge, Sean T.; Mcleod, Rima; Kozikowski, Alan P.

In: ChemMedChem, Vol. 8, No. 7, 07.2013, p. 1138-1160.

Research output: Contribution to journalArticle

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T1 - Modification of triclosan scaffold in search of improved inhibitors for enoyl-acyl carrier protein (ACP) reductase in Toxoplasma gondii

AU - Stec, Jozef

AU - Fomovska, Alina

AU - Afanador, Gustavo A.

AU - Muench, Stephen P.

AU - Zhou, Ying

AU - Lai, Bo Shiun

AU - ElBissati, Kamal

AU - Hickman, Mark R.

AU - Lee, Patty J.

AU - Leed, Susan E.

AU - Auschwitz, Jennifer M.

AU - Sommervile, Caroline

AU - Woods, Stuart

AU - Roberts, Craig W.

AU - Rice, David

AU - Prigge, Sean T.

AU - Mcleod, Rima

AU - Kozikowski, Alan P.

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N2 - 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.

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