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

doi:10.1016/j.bmcl.2013.12.066

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 journal › Article › peer-review

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 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.

Original language	English
Pages (from-to)	911-916
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
DOIs	https://doi.org/10.1016/j.bmcl.2013.12.066
Publication status	Published - 1 Feb 2014

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Wilkinson, C., McPhillie, M. J., Zhou, Y., Woods, S., Afanador, G. A., Rawson, S., Khaliq, F., Prigge, S. T., Roberts, C. W., Rice, D. W., McLeod, R., Fishwick, C. W., & Muench, S. P. (2014). The benzimidazole based drugs show good activity against T. gondii but poor activity against its proposed enoyl reductase enzyme target. Bioorganic and Medicinal Chemistry Letters, 911-916. https://doi.org/10.1016/j.bmcl.2013.12.066

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

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.",

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

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doi = "10.1016/j.bmcl.2013.12.066",

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Wilkinson, C, McPhillie, MJ, Zhou, Y, Woods, S, Afanador, GA, Rawson, S, Khaliq, F, Prigge, ST, Roberts, CW, Rice, DW, McLeod, R, Fishwick, CW & Muench, SP 2014, 'The benzimidazole based drugs show good activity against T. gondii but poor activity against its proposed enoyl reductase enzyme target', Bioorganic and Medicinal Chemistry Letters, pp. 911-916. https://doi.org/10.1016/j.bmcl.2013.12.066

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T1 - The benzimidazole based drugs show good activity against T. gondii but poor activity against its proposed enoyl reductase enzyme target

AU - Wilkinson, Craig

AU - McPhillie, Martin J.

AU - Zhou, Ying

AU - Woods, Stuart

AU - Afanador, Gustavo A.

AU - Rawson, Shaun

AU - Khaliq, Farzana

AU - Prigge, Sean T.

AU - Roberts, Craig W.

AU - Rice, David W.

AU - McLeod, Rima

AU - Fishwick, Colin W.

AU - Muench, Stephen P.

PY - 2014/2/1

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JO - Bioorganic and Medicinal Chemistry Letters

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ER -

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

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