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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 the Wittig reaction, converted to aldehydes by Vilsmeier formylation, and transformed to the corresponding uncharged oximes 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, and in silico evaluated ADME properties regarding lipophilicity and CNS activity, these compounds present a new class of oximes with the potential for further development of CNS-active therapeutics in OP poisoning.