Synthesis, biological evaluation and molecular modeling of new tetrahydroacridine derivatives as potential multifunctional agents for the treatment of Alzheimer's disease
Synthesis, biological evaluation and molecular modeling of new tetrahydroacridine derivatives as potential multifunctional agents for the treatment of Alzheimer's disease
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DOI：
10.1016/j.bmc.2015.07.029
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发表时间：
2015-09-01
影响因子：
3.5
通讯作者：
Szymanski, Pawel
中科院分区：
文献类型：
--
作者：
Bajda, Marek;Jonczyk, Jakub;Szymanski, Pawel
合成了一系列具有 4-二甲基氨基苯甲酸部分的新型 9-氨基-1,2,3,4-四氢吖啶衍生物，并测试了其对胆碱酯酶和淀粉样蛋白 β 聚集的抑制作用。目标化合物被设计为双结合位点胆碱酯酶抑制剂，能够结合酶的催化位点和外围位点，因此可能具有其他特性。获得的衍生物是两种胆碱酯酶（EeAChE、EqBChE）的非常有效的抑制剂，IC50值范围从亚纳摩尔到纳摩尔范围，并且最有前途的药物的抑制效力高于参考药物（卡巴拉汀和他克林）。最活跃的化合物 3a 的动力学研究揭示了 AChE 抑制的竞争类型。此外，所有目标化合物都是比他克林更有效的人类 AChE 抑制剂，其中化合物 3b 的活性最强 (IC50 = 19 nM)。还测试了化合物3a，并显示出对AChE诱导的Aβ1-42聚集的抑制效力（在50μM和100μM筛选浓度下分别为80.6％和91.3％）。此外，对 A549 细胞进行的细胞毒性测定并未表明该药物具有毒性。化合物 3a 是进一步开发治疗 AD 的新型多功能药物的有希望的候选者。 (C) 2015 Elsevier Ltd. 保留所有权利。
A novel series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with 4-dimethylaminobenzoic acid moiety was synthesized and tested towards inhibition of cholinesterases and amyloid beta aggregation. Target compounds were designed as dual binding site cholinesterase inhibitors able to bind to both the catalytic and the peripheral site of the enzyme and therefore potentially endowed with other properties. The obtained derivatives were very potent inhibitors of both cholinesterases (EeAChE, EqBChE) with IC50 values ranging from sub-nanomolar to nanomolar range, and the inhibitory potency of the most promising agents was higher than that of the reference drugs (rivastigmine and tacrine). The kinetic studies of the most active compound 3a revealed competitive type of AChE inhibition. Moreover, all target compounds were more potent inhibitors of human AChE than tacrine with the most active compound 3b (IC50 = 19 nM). Compound 3a was also tested and displayed inhibitory potency against AChE-induced A beta 1-42 aggregation (80.6% and 91.3% at 50 mu M and 100 mu M screening concentration, respectively). Moreover, cytotoxicity assay performed on A549 cells did not indicate toxicity of this agent. Compound 3a is a promising candidate for further development of novel multi-functional agents in the therapy of AD. (C) 2015 Elsevier Ltd. All rights reserved.