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

DOI: 10.1016/j.bmcl.2013.12.066 DOI Help
PMID: 24398298 PMID Help

Authors: Craig Wilkinson (University of Leeds) , Martin J. Mcphillie (The University of Sheffield) , Ying Zhou (The University of Chicago) , Stuart Woods (University of Strathclyde) , Gustavo A. Afanador (Johns Hopkins School of Public Health) , Shaun Rawson (University of Leeds) , Farzana Khaliq (University of Strathclyde) , Sean T. Prigge (Johns Hopkins School of Public Health) , Craig W. Roberts (University of Strathclyde) , David W. Rice (The University of Sheffield) , Rima Mcleod (The University of Chicago) , Colin W. Fishwick (University of Leeds) , Stephen Muench (University of Leeds)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry Letters

State: Published (Approved)
Published: December 2013

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 1 μM. 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.

Journal Keywords: Benzimidazoles; Crystallography; X-Ray; Drug; Enoyl-(Acyl-Carrier-Protein); Enzyme; Inhibitory; Microbial; Molecular; Toxoplasma

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography