脱氧鸭嘴花酮碱二聚体的设计合成及生物活性研究

Design,synthesis and biological evaluation of deoxyvasicinone dimers

目的设计合成乙酰胆碱酯酶(AChE)双位点抑制剂。方法以天然活性化合物脱氧鸭嘴花酮碱为先导化合物,根据AChE的晶体结构特征,设计合成了22个脱氧鸭嘴花酮碱二聚体,通过1H-NMR、13C-NMR和HRMS谱对目标化合物结构进行了确证,并测试了化合物对AChE和Aβ1-42聚集的抑制活性。结果与结论合成的22个二聚体化合物均未见文献报道,其中19个化合物对AChE的抑制活性明显优于脱氧鸭嘴花酮碱,10个化合物对AChE的抑制活性优于阳性对照他克林,2个化合物对Aβ1-42聚集的抑制活性优于阳性对照姜黄素,特别是化合物9b,对AChE(IC50=8.2 nmol·L-1)和Aβ1-42(IC50=12.7μmol·L-1)聚集的抑制活性分别强于阳性对照多奈哌齐(IC50=17.4 nmol·L-1)和姜黄素(IC50=14.4μmol·L-1),具有深入研究价值。

Alzheimer′s disease(AD)is a serious threat to the elderly health and life.Searching for multiple targets anti-AD lead compounds from natural active components is an important basis of developing medicines for AD.Twenty-two deoxyvasicinone dimers were designed,synthesized and evaluated as multifunctional agents for the treatment of AD.The results of biological assays indicated that most of them showed potent inhibitory activities against acetylcholinesterase(AChE),and could inhibitβ-amyloid(Aβ)self-aggregation.Especially,compound 9 b presented the highest inhibitory ability to hAChE(IC50=8.2 nmol·L-1)and potential inhibition of Aβ1-42 aggregation(IC50=12.7μmol·L-1).The preliminary structure-activity relationships(SARs)of these compounds indicated that the carbonyl group on deoxyvasicinone decreased the inhibitory activity for hAChE.The piperazine group of the linker was favorable for increasing the inhibitory activity.The length of the linker had a great influence on hAChE inhibition.Molecular modeling studies revealed that compound 9 b could interact simultaneously with the catalytic active site and peripheral anionic site of AChE ■.