Study of Huperzine A derivatives with extended protection against soman intoxication

索曼 石杉碱甲 乙酰胆碱酯酶 化学 神经毒剂 药理学 阿切 体内 乙酰胆碱酯酶抑制剂 IC50型 立体化学 急性毒性 解毒剂 毒性 毒理 生物化学 体外 医学 有机化学 生物 生物技术
作者
Yalan Cui,Xuejun Chen,Jingjing Shi,Qian Jin,Ruihua Zhang,Tong Shi,Chen Wang,Liqin Li
出处
期刊:Toxicology and Applied Pharmacology [Elsevier]
卷期号:475: 116646-116646
标识
DOI:10.1016/j.taap.2023.116646
摘要

Pre-administration of huperzine A (Hup A) was validated to prevent poisoning from exposure to nerve agents (NAs) by reversibly inhibiting acetylcholinesterase (AChE). However, like the currently commonly used reversible inhibitors, Hup A has a short half-life and is unable to produce a long-term preventative effect. To extend the protective time of Hup A against NAs, 42 derivatives with a CN bond were designed based on the structure of Hup A in this study. All designed derivatives showed good binding capability with AChE via molecular docking. Six compounds (H3, H4, H11, H14, H16, and H25) with representative structures were selected for synthesis by Schiff base reaction, and their structures were stable. The modified Ellman's method showed the six compounds concentration-dependently inhibited AChE, and the half maximal inhibitory concentration (IC50) were higher than that of Hup A. Pretreatment of AChE with the derivatives significantly increased the IC50 of soman. In vivo experiments demonstrated H3, H4, H14, H16, and H25 had longer protective capacities against 1 × LD95 soman-induced death in mice than Hup A. The 12 h protective index showed that the protective ratios of H3, H4, H14 and H16 were 2.31, 1.85, 2.23 and 1.99 respectively, better than that of Hup A. The extended protection of the derivatives against soman may be explained by their transformation to Hup A in vivo. Furthermore, all six compounds showed lower acute oral toxicity than Hup A. Overall, our study provided an optional strategy to acquire pretreatment agents for NAs with extended action and low toxicity.
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