有机磷类毒剂包括神经性毒剂和有机磷农药，它们中毒发生率高，致死率高，严重威胁人类生命，其通过不可逆抑制乙酰胆碱酯酶(AChE)，导致神经系统中毒，且中枢中毒是致死的主因。季铵盐肟类氯解磷定等是目前可用的AChE重活化剂，但它们血脑屏障通过率低，中枢解毒能力不足。非季铵盐重活化剂有望克服这一缺陷，但季铵盐结构缺失导致它们和酶结合能力下降，重活化能力严重不足。研究表明，在非季铵盐肟类结构中引入可与AChE活性部位外周位点结合的配体，其体外重活化能力会明显提升，但体内活性尚无报道，且相关研究仅限于神经性毒剂中毒。本课题拟采用双位点结合策略，首次重点针对有机磷农药中毒设计合成全新非季铵盐肟类重活化剂，测定体外重活化率及速率常数，通过动力学手段分析重活化机制，再优选化合物深入体内测试中枢解毒能力，分析构效关系，以期获得结构新颖、合成可行、中枢解毒高效的苗头化合物2-3个，为开发新型重活化剂奠定基础。

Organophosphate (OP, including nerve agents and organophosphorus pesticides ) poisoning is featured as high poisoning incidence and high mortality, posing great threats to the military and the public. Organophosphate agents exert their acute toxicology through irreversible inhibition of acetylcholinesterase (AChE) both in the central and peripheral nervous system, while early death is mainly due to central poisoning. Currently available reactivators for OP poisoning are pyridinium oximes (such as 2-PAM), whereas the pyridinium oximes provide little or no protection against neurological effects of OP exposure in the central nervous system (CNS), because the permanent charges seriously limit their blood-brain barrier (BBB) penetration. It was proven that nonionic reactivators would facilitate the BBB penetration as a result of increased lipophilicity, and they showed obvious superiority to charged 2-PAM as antidotes for CNS poisoning. Nevertheless, the absence of charge will cause decreasing reactivation potency because the uncharged reactivators don’t properly bind to the active site of AChE. It was found that the reactivation ability of nonquaternary oximes can be greatly improved if peripheral ligands of AChE were introduced, but the reactivation ability in vivo was still unknow and no organophosphorus pesticides had ever been studied in the experiment. According to the previous study, a dual-site binding strategy is used and novel nonquaternary reactivators will be designed and synthesized in this project. We will measured their reactivation rate constant Kr、dissociation constant KD and second order reactivation rate constant Kr2 mainly for organophosphorus pesticides poisoning in vitro, and analyze the reactivation mechanism through a dynamic way. Then the reactivation potency of selected compounds in the CNS will be evaluated in vivo, and the structure-activity relationships will be built. It was expected that 2-3 compounds featured as high CNS antidotal potency, structure novelty and synthesis feasibility would be found, laying foundation for the development of new efficient reactivators.