Conjugates of salicylaldoximes and peripheral site ligands: Novel efficient nonquaternary reactivators for nerve agent-inhibited acetylcholinesterase

被引:22
|
作者
Wei, Zhao [1 ]
Liu, Yan-qin [2 ]
Wang, Sheng-zheng [1 ]
Yao, Lin [1 ]
Nie, Hui-fang [1 ]
Wang, Yong-an [2 ]
Liu, Xue-ying [1 ]
Zheng, Zhi-bing [3 ]
Li, Song [3 ]
机构
[1] Fourth Mil Med Univ, Sch Pharm, Dept Med Chem, Xian 300071, Shaanxi, Peoples R China
[2] Acad Mil Med Sci, Inst Pharmacol & Toxicol, Dept Mil Toxicol & Biochem Pharmacol, Beijing 100850, Peoples R China
[3] Acad Mil Med Sci, Inst Pharmacol & Toxicol, Dept Med Chem, Beijing 100850, Peoples R China
关键词
Nerve agent; Human acetylcholinesterase; Nonquaternary reactivator; Salicylaldoxime conjugates; Peripheral site ligand; BLOOD-BRAIN-BARRIER; ORGANOPHOSPHORUS COMPOUNDS; UNCHARGED REACTIVATORS; PYRIDINIUM OXIMES; ADMET PREDICTION; CLICK CHEMISTRY; IN-SITU; CHOLINESTERASES; SARIN; ALDOXIME;
D O I
10.1016/j.bmc.2017.06.041
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A new family of nonquaternary reactivators for nerve agent-inhibited human acetylcholinesterase (hAChE) were designed, synthesized and tested in this paper. It was found that salicylaldoximes were able to quickly cleave the P-S bond of organophosphate and avoid the reinhibition phenomenon in the reactivation process, but they lacked reactivating ability due to poor affinity for AChE. Based on a dual site binding strategy, different peripheral site ligands of AChE were introduced to achieve extra affinity. The in vitro reactivation experiments demonstrated that some of the yielding conjugates exhibited similar or even superior ability to reactivate sarin-, VX- or tabun-inhibited hAChE in comparison with the mono-and bis-pyridinium aldoximes currently used. Moreover, due to greatly improved lipophilicity, these nonquaternary conjugates hold promise for the development of efficient centrally activating reactivators. (C) 2017 Elsevier Ltd. All rights reserved.
引用
收藏
页码:4497 / 4505
页数:9
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