Design, synthesis, and characterization of novel, nonquaternary reactivators of GF-inhibited human acetylcholinesterase

The goal of this research was to identify structurally novel, non-quaternarypyridinium reactivators of GF (cyclosarin)-inhibited hAChE that possess the capacity to mediate in vitro reactivation of GF-inhibited human acetylcholinesterase (hAChE). New compounds were designed, synthesized and assessed...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2014-04, Vol.24 (7), p.1711-1714
Main Authors: McHardy, Stanton F., Bohmann, Jonathan A., Corbett, Michael R., Campos, Bismarck, Tidwell, Michael W., Thompson, Paul Marty, Bemben, Chris J., Menchaca, Tony A., Reeves, Tony E., Cantrell, William R., Bauta, William E., Lopez, Ambrosio, Maxwell, Donald M., Brecht, Karen M., Sweeney, Richard E., McDonough, John
Format: Article
Language:English
Subjects:
Acetylcholinesterase
Acetylcholinesterase - metabolism
Cholinesterase Inhibitors - chemical synthesis
Cholinesterase Inhibitors - chemistry
Cholinesterase Inhibitors - pharmacology
Cyclosarin (GF)
Dose-Response Relationship, Drug
Drug Design
GF-inhibited hAChE
Heteroaryl keto-oximes
Humans
Molecular Structure
Organophosphorus Compounds - chemical synthesis
Organophosphorus Compounds - chemistry
Organophosphorus Compounds - pharmacology
Reactivation
Structure-Activity Relationship
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Summary:The goal of this research was to identify structurally novel, non-quaternarypyridinium reactivators of GF (cyclosarin)-inhibited hAChE that possess the capacity to mediate in vitro reactivation of GF-inhibited human acetylcholinesterase (hAChE). New compounds were designed, synthesized and assessed in GF-inhibited hAChE assays. Structure activity relationships for AChE binding and reactivation of GF-inhibited hAChE were developed. Lead compounds from two different chemical series, represented by compounds 17 and 38, displayed proficient in vitro reactivation of GF-inhibited hAChE, while also possessing low inhibition of native enzyme.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2014.02.049