engleski

New Uncharged 2-Thienostilbenes Oximes as Reactivators of cholinesterases

Oximes, the symptomatic drugs currently were used as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the treatment of neurological disorders such as Alzheimer’s and Parkinson’s disease. The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by organophosphates (OPs) as nerve agents and pesticides compromises normal cholinergic nerve signal transduction in the peripheral and central nervous systems (CNS) leading to cholinergic crisis. The treatment comprises an antimuscarinic drug and an oxime reactivator of the inhibited enzyme. Oximes in use have quaternary nitrogens, and therefore poorly cross the brain–blood barrier. In this work, we synthesized novel uncharged thienostilbene oximes by sequence of three reactions in very high yields. Eight trans, anti- and trans, syn-isomers of oximes were tested as reactivators of nerve-agent- inhibited AChE and BChE. Four derivatives reactivated cyclosarin-inhibited BChE up to 70% in two hours of reactivation, and docking studies confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on the moderate binding affinity of both AChE and BChE for all selected oximes, these compounds present a new class of oximes with the potential for further development of CNS-active therapeutics in OP poisoning.

AChE ; BChE ; reactivation ; heterostilbenes ; spectroscopy ; docking

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