A library of 14 mono-oxime quinuclidinium-based compounds with alkyl or benzyl substituent were synthesized and characterized in vitro as potential antidotes for organophosphorus compounds (OP) poisoning treatment. We evaluated their potency for reversible inhibition and reactivation of OP inhibited human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and evaluated interactions by molecular docking studies. The reactivation was notable for both AChE and BChE inhibited by VX, cyclosarin, sarin and paraoxon, if quinuclidinium compounds contained the benzyl group attached to the quinuclidinium moiety. Out of all 14, oxime Q8 [4-bromobenzyl-3-(hydroxyimino)quinuclidinium bromide] was singled out as having the highest determined overall reactivation rate of approximately 20,000 M⁻¹ min⁻¹ for cyclosarin-inhibited BChE. Furthermore, this oxime in combination with BChE exhibited a capability to act as a bioscavenger of cyclosarin, degrading within 2 h up to 100-fold excess of cyclosarin concentration over the enzyme. Molecular modeling revealed that the position of the cyclohexyl moiety conjugated with the active site serine of BChE directs the favorable positioning of the quinuclidinium ring and the bromophenyl moiety of Q8, which makes phosphonylated-serine easily accessible for the nucleophilic displacement by the oxime group of Q8. This result presents a novel scaffold for the development of new BChE-based bioscavengers. Furthermore, a cytotoxic effect was not observed for Q8, which also makes it promising for further in vivo reactivation studies.

合成了具有烷基或苄基取代基的14种单肟基喹啉鎓类化合物的文库，并在体外表征为有机磷化合物（OP）中毒治疗的潜在解毒剂。我们评估了其对OP抑制的人乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）的可逆抑制和激活的潜力，并通过分子对接研究评估了它们之间的相互作用。如果喹喔啉鎓化合物包含与喹喔啉鎓部分相连的苄基，则VCh，环沙林，沙林和对氧磷抑制的AChE和BChE的重新活化均很明显。在所有14种化合物中，肟Q8 [4-溴苄基-3-（羟基亚氨基）奎宁环己溴铵]被选为具有最高确定的总重新活化率，约为20,000 M ^-1对于环沙蛋白抑制的BChE， min ^-1。此外，这种肟与BChE的结合表现出了作为环沙林的生物清除剂的能力，在2小时内降解了环沙林的浓度是酶的100倍以上。分子建模表明，与BChE的活性位点丝氨酸缀合的环己基部分的位置指示了喹啉环和Q8的溴苯基部分的有利位置，这使得磷酰化的丝氨酸易于被Q8的肟基亲核置换。该结果提出了用于开发新的基于BChE的生物清除剂的新型支架。此外，未观察到Q8有细胞毒性作用，这也使得它有可能用于进一步的体内再激活研究。