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.
Highlights
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
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 lM
The potency of the benzimidazole family has been shown for F. tularensis, Escherichia coli, Bacillus anthracis, Yersinia pestis, Staphylococcus aureus and MRSA, but to date no antiparasitic testing has been carried out.[9]
Summary
Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl. There are distinct differences between the eukaryotic and prokaryotic FAS pathways.[1] The Eukaryotic system, termed FAS I, uses one large polypeptide complex, but Prokaryotes use a series of discrete monofunctional enzymes termed the FAS II pathway to achieve the same goal.[2] Enoyl acyl-carrier protein reductase (ENR), which carries out the final stage of FAS II synthesis, has been the main focus of drug development programs in this area This has resulted in a range of potent ENR inhibitors being developed such as isoniazid, the diazaborine family and the common antibacterial triclosan.[3,4,5,6] The potency and easy synthesis of triclosan has resulted in it being found in a range of common household items such as toothpastes, mouthwashes and chopping boards. The same inhibitors show promising activity with a MIC50 value of between 1 and 10 lM against two different strains of T. gondii parasites cultured in vitro The ability of these compounds to curtail T. gondii growth, but not affect ENR activity, suggests that they have an off-target effect. Bond length (Å) Bond angle (deg.) Ramachandran plota Most favoured (%) allowed (%) Generously allowed (%) Disallowed (%) Molecules in asymm. unit Protein atoms Co-factor atoms Water molecules Mean B-values (Å2) Protein Mainchain/sidechain Co-factors Water molecules
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