Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates |
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| Authors: | Dr Francine S Katz Dr Stevan Pecic Dr Timothy H Tran Dr Ilya Trakht Laura Schneider Dr Zhengxiang Zhu Dr Long Ton‐That Dr Michal Luzac Viktor Zlatanic Shivani Damera Dr Joanne Macdonald Prof?Dr Donald W Landry Prof?Dr Liang Tong Prof?Dr Milan N Stojanovic |
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| Affiliation: | 1. Department of Medicine/Division of Experimental Therapeutics, Columbia University Medical Center, New York, NY, USA;2. Department of Biological Sciences, Columbia University, New York, NY, USA;3. Genecology Research Centre, Inflammation and Healing Research Cluster, School of Science and Engineering, University of the Sunshine Coast, Sippy Downs, QLD, Australia;4. Departments of Biomedical Engineering and Systems Biology, Columbia University, New York, NY, USA |
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| Abstract: | Acetylcholinesterase (AChE) that has been covalently inhibited by organophosphate compounds (OPCs), such as nerve agents and pesticides, has traditionally been reactivated by using nucleophilic oximes. There is, however, a clearly recognized need for new classes of compounds with the ability to reactivate inhibited AChE with improved in vivo efficacy. Here we describe our discovery of new functional groups—Mannich phenols and general bases—that are capable of reactivating OPC‐inhibited AChE more efficiently than standard oximes and we describe the cooperative mechanism by which these functionalities are delivered to the active site. These discoveries, supported by preliminary in vivo results and crystallographic data, significantly broaden the available approaches for reactivation of AChE. |
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| Keywords: | drug discovery high-throughput screening medicinal chemistry neurological agents structure– activity relationships |
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