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.
authors.affiliation: School of Biomedical Sciences, University of Leeds, Leeds, UK.
authors.forename: Craig
authors.initials: C
authors.lastname: Wilkinson
authors.affiliation: Department of Molecular Biology and Biotechnology, The University of Sheffield, Sheffield, UK.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: McPhillie
authors.affiliation: 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.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Woods
authors.affiliation: Johns Hopkins School of Public Health, Rm. E5132, 615 N. Wolfe St., Baltimore, MD 21205, United States.
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Afanador
authors.affiliation: School of Biomedical Sciences, University of Leeds, Leeds, UK.
authors.forename: Shaun
authors.initials: S
authors.lastname: Rawson
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
authors.forename: Farzana
authors.initials: F
authors.lastname: Khaliq
authors.affiliation: Johns Hopkins School of Public Health, Rm. E5132, 615 N. Wolfe St., Baltimore, MD 21205, United States.
authors.forename: Sean T
authors.initials: ST
authors.lastname: Prigge
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Roberts
authors.affiliation: Department of Molecular Biology and Biotechnology, The University of Sheffield, Sheffield, UK.
authors.forename: David W
authors.initials: DW
authors.lastname: Rice
authors.affiliation: 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.
authors.forename: Rima
authors.initials: R
authors.lastname: McLeod
authors.affiliation: School of Chemistry, University of Leeds, Leeds, UK.
authors.forename: Colin W
authors.initials: CW
authors.lastname: Fishwick
authors.affiliation: School of Biomedical Sciences, University of Leeds, Leeds, UK. Electronic address: s.p.muench@leeds.ac.uk.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Muench
mesh_terms: D000977:Antiparasitic Agents / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D016503:Drug Delivery Systems; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation / Q000187:drug effects; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D014122:Toxoplasma / Q000187:drug effects*
chemical_list: D000977:Antiparasitic Agents; D001562:Benzimidazoles; C031000:benzimidazole; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
keywords: Benzimidazole; Enoyl reductase; Toxoplasma; Triclosan