The benzimidazole based drugs show good activity against T. gondii but poor activity against its proposed enoyl reductase enzyme target

Craig Wilkinson, Martin J McPhillie, Ying Zhou, Stuart Woods, Gustavo A Afanador, Shaun Rawson, Farzana Khaliq, Sean T Prigge, Craig W Roberts, David W Rice, Rima McLeod, Colin W Fishwick, Stephen P Muench

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The enoyl acyl-carrier protein reductase (ENR) enzyme of the apicomplexan parasite family has been intensely studied for antiparasitic drug design for over a decade, with the most potent inhibitors targeting the NAD(+) bound form of the enzyme. However, the higher affinity for the NADH co-factor over NAD(+) and its availability in the natural environment makes the NADH complex form of ENR an attractive target. Herein, we have examined a benzimidazole family of inhibitors which target the NADH form of Francisella ENR, but despite good efficacy against Toxoplasma gondii, the IC50 for T. gondii ENR is poor, with no inhibitory activity at 1μM. Moreover similar benzimidazole scaffolds are potent against fungi which lack the ENR enzyme and as such we believe that there may be significant off target effects for this family of inhibitors.
Original languageEnglish
Pages (from-to)911-916
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number3
Early online date22 Dec 2013
DOIs
Publication statusPublished - 1 Feb 2014

Keywords

  • enoyl reductase
  • triclosan
  • toxoplasma
  • benzimidazole

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