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Bioorg Med Chem Lett. 2014 Feb 1;24(3):911-6. doi: 10.1016/j.bmcl.2013.12.066. Epub 2013 Dec 22.

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

Author information

1
School of Biomedical Sciences, University of Leeds, Leeds, UK.
2
Department of Molecular Biology and Biotechnology, The University of Sheffield, Sheffield, UK.
3
Department of Ophthalmology and Visual Sciences, Pediatrics (Infectious Diseases), Committees on Genetics, Immunology, and Molecular Medicine, Institute of Genomics and Systems Biology, and The College, The University of Chicago, Chicago, IL 60637, United States.
4
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
5
Johns Hopkins School of Public Health, Rm. E5132, 615 N. Wolfe St., Baltimore, MD 21205, United States.
6
School of Chemistry, University of Leeds, Leeds, UK.
7
School of Biomedical Sciences, University of Leeds, Leeds, UK. Electronic address: s.p.muench@leeds.ac.uk.

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.

KEYWORDS:

Benzimidazole; Enoyl reductase; Toxoplasma; Triclosan

PMID:
24398298
PMCID:
PMC3966656
DOI:
10.1016/j.bmcl.2013.12.066
[Indexed for MEDLINE]
Free PMC Article

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