胆碱酯酶抑制剂他克林-单甲氧芳基杂合物的设计、合成及活性评价

Design, synthesis and evaluation of tacrine-methoxybenzene hybrids as cholinesterases inhibitors

摘要:
本文设计合成了一系列他克林−单甲氧芳基杂合物 (5a～5i) 作为胆碱酯酶抑制剂, 并对其进行了活性评价。结果表明该类化合物比他克林具有更好的胆碱酯酶抑制活性, IC₅₀值均达到纳摩尔级, 其中化合物5h对乙酰胆碱酯酶的抑制活性最强, IC₅₀值为6.74 nmol·L⁻¹, 5f对丁酰胆碱酯酶的活性最强, IC₅₀值为3.83 nmol·L⁻¹。酶动力学及分子对接表明该类杂合物能够同时作用于AChE的催化活性位点和外周结合位点。

Abstract:
A series of tacrine-methoxybenzene hybrids (5a−5i) were designed, synthesized and evaluated as inhibitors of cholinesterases (ChEs). All the compounds had better ChEs inhibitory activities than tacrine with IC₅₀ values at the nanomolar range. Compound 5h exhibited the strongest inhibition on acetylcholinesterase (AChE) with an IC₅₀ value of 6.74 nmol·L⁻¹ and compound 5f showed the most potent inhibition on butyrylcholinesterase with IC₅₀ value of 3.83 nmol·L⁻¹. Kinetic and molecular modeling studies showed that these hybrids targeted both the catalytic active site and the peripheral anionic site of AChE.