MMSL 2011, 80(4):178-186 | DOI: 10.31482/mmsl.2011.024

OXIMES AS INHIBITORS OF ACETYLHOLINESTERASE - A STRUCTURE-ACTIVITY RELATIONSHIP (SAR) STUDYOriginal article

Vendula ©epsová1*, Jana ®ďárová Karasová ORCID...2, Filip Zemek1, Brian J. Bennion3, Kamil Kuča ORCID...4
1 Department of Toxicology, Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic
2 Department of Public Health, Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic
3 Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, 7000 East Ave, Livermore CA 94550, USA
4 Center of Advances Studies, Faculty of Military Health Sciences, University of Defence, , Czech Republic

Acetylcholinesterase (AChE) reactivators (oximes) are generally used as antidotes in case of nerve agent poisoning. Because of their affinity to AChE, they may also act as weak inhibitors of AChE. Their inhibition potency against AChE was determined by an in vitro method based on the interaction between AChE and oxime reactivator in the concentration range 10-1 to 10-8 M. We used eel AChE for these assays. We found that AChE inhibition strongly depends on the oxime structure. The aim of the present study is to describe the structure-activity relationship (SAR) between oxime structure and inhibition of AChE. AChE reactivators tested include both monoquaternary and bisquaternary structures with the oxime group in different positions on the pyridine ring and with changes in the connecting linker in the case of the bisquaternary compounds.We found AChE inhibition to be highest in bisquaternary oximes that have a longer linker length and have the oxime group in the ortho position. Increased AChE inhibition in monoquaternary oximes was highest when the meta position was occupied by the oxime nucleophile. In addition, different substituents in the connecting chain (in case of bisquaternary oximes) modulated their inhibition potency.

Keywords: acetylcholinesterase; inhibitor; reactivator; oxime; structure-activity relationship (SAR); antidote

Received: October 18, 2011; Revised: November 25, 2011; Published: December 9, 2011  Show citation

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©epsová, V., ®ďárová Karasová, J., Zemek, F., Bennion, B.J., & Kuča, K. (2011). OXIMES AS INHIBITORS OF ACETYLHOLINESTERASE - A STRUCTURE-ACTIVITY RELATIONSHIP (SAR) STUDY. MMSL, 80(4), 178-186. doi: 10.31482/mmsl.2011.024
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