空军军医大学学报2023，Vol.44Issue(12)：1155-1163,9.DOI:10.13276/j.issn.2097-1656.2023.12.004
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
摘要
Abstract
Objective To screen more efficient non-oxime acetylcholinesterase(AChE)reactivators for organophosphorus poisoning.Methods The highly active non-oxime reactivator L1OR1 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 L1OR1 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Key words
organophosphate agents/acetylcholinesterase/reactivator/non-oxime/Mannich base分类
医药卫生引用本文复制引用
魏朝,姜茹,王平安,张东旭,郑志兵,刘雪英..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[J].空军军医大学学报,2023,44(12):1155-1163,9.基金项目
国家自然科学基金(81703413) （81703413）
陕西省重点研发计划项目(2022SF-017) （2022SF-017）
