针对有机磷中毒的新型非肟类乙酰胆碱酯酶重活化剂的筛选  

Screening of novel non-oxime acetylcholinesterase reactivators for organophosphorus poisoning

作　　者：魏朝 姜茹 王平安 张东旭 郑志兵 刘雪英 WEI Zhao;JIANG Ru;WANG Ping an;ZHANG Dongxu;ZHENG Zhibing;LIU Xueying(Department of Medicinal Chemistry and Pharmaceutical Analysis,School of Pharmacy,Air Force Medical University,Xi'an 710032,China;Institute of Toxicology and Pharmacology,Academy of Military Medical Sciences,Academy of Military Sciences,Beijing 100850,China)

机构地区：[1]空军军医大学药学系药物化学与药物分析学教研室,陕西西安710032 [2]军事科学院军事医学研究院毒物药物研究所,北京100850

出　　处：《空军军医大学学报》2023年第12期1155-1163,共9页Journal of Air Force Medical University

基　　金：国家自然科学基金(81703413);陕西省重点研发计划项目(2022SF-017)。

摘　　要：目的筛选针对有机磷毒剂中毒乙酰胆碱酯酶(AChE)更高效的非肟类重活化剂。方法以前期研究发现的高活性非肟类重活化剂L10R1为先导,通过基于片段药物设计策略构建系列含有曼尼希碱结构的非肟类重活化剂,通过核磁、质谱验证结构;用5,5’二硫双(2硝基苯甲酸)法测试该系列化合物对维埃克斯、沙林、塔崩、梭曼、对氧磷、对硫磷和敌敌畏等抑制AChE的重活率,并优选高活性化合物动态测试其重活化速率;基于活性测试结果进行构效关系分析。结果成功构建了全新结构的非肟类化合物21个并完成了结构确证,筛选出了对维埃克斯、沙林、对氧磷和对硫磷中毒AChE重活化能力较好的非肟类化合物L49R1和L51R1,L49R1对有机磷农药对氧磷和对硫磷中毒酶重活化效能优于先导L10R1。结论在曼尼希碱结构中引入磺胺类活性片段未能得到高效重活化剂,但引入三氮唑并嘧啶酮(L51R1)或硝基噻唑(L49R1)片段可得到广谱且相对高效的重活化剂,并以硝基噻唑结构最佳,本研究为开发更高效的全新非肟类重活化剂奠定了良好基础。Objective To screen more efficient non-oxime acetylcholinesterase(AChE)reactivators for organophosphorus poisoning.Methods The highly active non-oxime reactivator L10R1 found in previous studies was chosen as a lead,a series of non-oxime reactivators containing Mannich base were constructed through fragment-based drug design strategy,and structures of these newly synthesized compounds were confirmed by nuclear magnetic resonance and high-resolution mass spectrometry.DTNB method was used to test the reactivation rate of these compounds for inhibited AChEs such as VX,sarin,tabun,soman,paraoxon,parathion and dichlorvos,and highly active compounds were selected to test their reactivation rate dynamically.Structure-activity relationship was analyzed according to the results of reactivating experiments.Results A total of 21 non-oxime compounds with new structures were successfully constructed and their structures were confirmed.Non-oxime compounds L49R1 and L51R1 were screened as efficient reactivators for inhibited AChEs such as VX,sarin,paraoxon and parathion,and L49R1 exhibited higher reactivating ability than the lead compound L10R1 for inhibited AChEs such as paraoxon and parathion.Conclusion The introduction of active sulfonamide fragments into the Mannich base can not produce efficient reactivators,but introduction of triazolopyrimidinone(L51R1)or nitrothiazole(L49R1)fragments can yield broad-spectrum and relatively efficient reactivators,and nitrothiazole was proven as the most efficient fragment in this study.This study lays a good foundation for the development of more efficient non-oxime reactivators.

关 键 词：有机磷毒剂 乙酰胆碱酯酶 重活化剂 非肟类 曼尼希碱 

分 类 号：R91[医药卫生—药学]