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Molecules 2017, 22(7), 1234; doi:10.3390/molecules22071234

New Cinchona Oximes Evaluated as Reactivators of Acetylcholinesterase and Butyrylcholinesterase Inhibited by Organophosphorus Compounds

1
Institute for Medical Research and Occupational Health, POB 291, HR-10001 Zagreb, Croatia
2
Department of Chemistry, Faculty of Science, University of Zagreb, HR-10001 Zagreb, Croatia
*
Authors to whom correspondence should be addressed.
Received: 30 June 2017 / Revised: 18 July 2017 / Accepted: 19 July 2017 / Published: 22 July 2017
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Abstract

For the last six decades, researchers have been focused on finding efficient reactivators of organophosphorus compound (OP)-inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). In this study, we have focused our research on a new oxime scaffold based on the Cinchona structure since it was proven to fit the cholinesterases active site and reversibly inhibit their activity. Three Cinchona oximes (C1, C2, and C3), derivatives of the 9-oxocinchonidine, were synthesized and investigated in reactivation of various OP-inhibited AChE and BChE. As the results showed, the tested oximes were more efficient in the reactivation of BChE and they reactivated enzyme activity to up to 70% with reactivation rates similar to known pyridinium oximes used as antidotes in medical practice today. Furthermore, the oximes showed selectivity towards binding to the BChE active site and the determined enzyme-oxime dissociation constants supported work on the future development of inhibitors in other targeted studies (e.g., in treatment of neurodegenerative disease). Also, we monitored the cytotoxic effect of Cinchona oximes on two cell lines Hep G2 and SH-SY5Y to determine the possible limits for in vivo application. The cytotoxicity results support future studies of these compounds as long as their biological activity is targeted in the lower micromolar range. View Full-Text
Keywords: nerve agents; pesticides; alkaloids; cytotoxicity; reversible inhibition nerve agents; pesticides; alkaloids; cytotoxicity; reversible inhibition
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Katalinić, M.; Zandona, A.; Ramić, A.; Zorbaz, T.; Primožič, I.; Kovarik, Z. New Cinchona Oximes Evaluated as Reactivators of Acetylcholinesterase and Butyrylcholinesterase Inhibited by Organophosphorus Compounds. Molecules 2017, 22, 1234.

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