一类“非季铵型重活化剂”的构效关系及其作用机理的研究

Studies on structure-activity relationship and mechanism of nonquaternary AChE reactivators

乙酰胆碱酯酶的叔胺型重活化剂一直被认为是比较理想的重活化剂,但是,由于缺少明确的理论指导,国际上探索了20多年仍未见有明显进展。本研究对文献报道的“非季铵型”重活化剂,通过分子力学(MMPM程序)和量子化学(MNDO程序)计算,进行构效关系分析,讨论其作用机理,并根据我们自己的重活化剂作用机理,设计了新型重活化剂的基本分子结构,可供药物合成参考。

AChE reactivators of tertiary amines have been considered as ideal antidotes oftoxic organophosphorus esters for a long time. No significant progress has been made in the studyof these compounds for more than 20 years because of the lack of theoretical guidance. A series ofS-dialkylaminoalkyl esters of α-keto thiohydroximic acid were reported. In this paper, on basis ofBedford's results, SAR and mechanism of these AChE reactivators were discussed in theory ofquantum medicinal chemistry. A general molecular structure of new reactivators is designed.