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

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.

Potent 3‐Hydroxy‐2‐Pyridine Aldoxime Reactivators of Organophosphate‐Inhibited Cholinesterases with Predicted Blood–Brain Barrier Penetration

“…The activity was corrected for non‐enzymatic substrate degradation by an oxime (oximolysis), and DMSO was kept below 0.15 % to attenuate its inhibitory effect on AChE activity. The K i values were evaluated from the experimental data according to the Hunter–Downs equation and the procedure described previously …”

Different classical hydrogen-bonding patterns in three salicylaldoxime derivatives, 2-HO-4-XC6H3C=NOH (X= Me, OH and MeO)

“…Aldoximes, RCH NOH, are found in many biologically active compounds (Abele et al, 2008;Nikitjuka & Jirgensons 2014), having a diverse range of uses including as anti-tumor agents (Martínez-Pascual et al, 2017;Qin et al, 2017;Canario et al, 2018;Huang et al, 2018), acaricidal and insecticidal agents (Dai et al, 2017), thymidine phosphorylase inhibitors (Zhao et al, 2018), anti-microbial agents (Yadav et al, 2017), bacteriocides (Kozlowska et al, 2017), anti-inflammatory agents (Mohassab et al, 2017) and in the treatment of nervegas poisoning (Lorke et al, 2008;Voicu et al, 2010;Katalinić et al, 2017;Radić et al, 2013). In the plant kingdom, oximes play a vital role in metabolism (Sørensen et al, 2018).…”

Crystal structures and Hirshfeld surfaces of four methoxybenzaldehyde oxime derivatives, 2-MeO-XC6H3C=NOH (X= H and 2-, 3- and 4-MeO): different conformations and hydrogen-bonding patterns

“…In the plant kingdom, oximes play a vital role in metabolism (Sørensen et al, 2018). Aldoximes, RCH NOH, are found in many biologically active compounds (Abele et al, 2008;Nikitjuka & Jirgensons, 2014), having a diverse range of uses including as anti-tumour agents (Martínez-Pascual et al, 2017;Qin et al, 2017;Canario et al, 2018;Huang et al, 2018), acaricidal and insecticidal agents (Dai et al, 2017), thymidine phosphorylase inhibitors (Zhao et al, 2018), anti-microbial agents (Yadav et al, 2017), bacteriocides (Kozlowska et al, 2017), anti-inflammatory agents (Mohassab et al 2017), and in the treatment of nerve-gas poisoning (Lorke et al, 2008;Voicu et al, 2010;Katalinić et al, 2017;Radić et al, 2013).…”