Benzimidazole based drugs against T. gondii

Bioorg Med Chem Lett. 2013 Dec 22. pii: S0960-894X(13)01450-9. doi: 10.1016/j.bmcl.2013.12.066. [Epub ahead of print]

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

Wilkinson C¹, McPhillie MJ², Zhou Y³, Woods S⁴, Afanador GA⁵, Rawson S¹, Khaliq F⁴, Prigge ST⁵, Roberts CW⁴, Rice DW², McLeod R³, Fishwick CW⁶, Muench SP⁷.

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.
Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

KEYWORDS:

Benzimidazole, Enoyl reductase, Toxoplasma, Triclosan

PMID:

24398298

[PubMed - as supplied by publisher]