Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal.
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.
Molecules. 2019 Feb 7;24(3):587. doi: 10.3390/molecules24030587.
Research on neurodegenerative brain disorders, namely the age-dependent Alzheimer's disease (AD), has been intensified in the last decade due to the absence of a cure and the recognized increasing of life expectancy for populations. To address the multifactorial nature and complexity of AD, a multi-target-directed ligand approach was herein employed, by designing a set of six selected hybrids (⁻) that combine in the same entity two pharmacophores: tacrine (TAC) and 2-phenylbenzothiazole (PhBTA). The compounds contain a methoxy substituent at the PhBTA moiety and have a variable length linker between that and the TAC moiety. The docking studies showed that all the compounds assure a dual-binding mode of acetylcholinesterase (AChE) inhibition, establishing π-stacking and H-bond interactions with aminoacid residues at both active binding sites of the enzyme (CAS and PAS). The bioassays revealed that the designed compounds display excellent AChE inhibitory activity in the sub-micromolar range (0.06⁻0.27 μM) and moderate inhibition values for amyloid-β (Aβ) self-aggregation (27⁻44.6%), compounds and being the lead compounds. Regarding neuroprotective effects in neuroblastoma cells, compounds , and revealed the capacity to prevent Aβ-induced toxicity, but compound showed the highest neuroprotective effect. Overall these hybrid compounds, in particular and , with promising multitarget anti-AD ability, encourage further pursuing studies on this type of TAC-PhBTA derivatives for potential AD therapy.
针对神经退行性脑疾病（即年龄相关性阿尔茨海默病，AD）的研究在过去十年中得到了加强，因为目前还没有治愈方法，而且人们认识到人口预期寿命的延长。为了解决 AD 的多因素性质和复杂性，采用了多靶标导向配体方法，设计了一组 6 种选定的杂合分子（⁻），将两种药效团：他克林（TAC）和 2-苯基苯并噻唑（PhBTA）组合在同一实体中。这些化合物在 PhBTA 部分含有一个甲氧基取代基，并且在该部分和 TAC 部分之间具有可变长度的连接子。对接研究表明，所有化合物都能确保乙酰胆碱酯酶（AChE）抑制的双重结合模式，与酶的两个活性结合位点（CAS 和 PAS）中的氨基酸残基建立π堆积和氢键相互作用。生物测定结果表明，设计的化合物在亚微摩尔范围内表现出优异的 AChE 抑制活性（0.06⁻0.27 μM），并且对淀粉样蛋白-β（Aβ）自聚集具有适度的抑制作用（27⁻44.6%），化合物 和 是先导化合物。关于神经母细胞瘤细胞的神经保护作用，化合物 、 和 具有预防 Aβ 诱导的毒性的能力，但化合物 显示出最高的神经保护作用。总体而言，这些杂合化合物，特别是 、 和 ，具有有希望的多靶标抗 AD 能力，鼓励进一步研究这种 TAC-PhBTA 衍生物，以用于潜在的 AD 治疗。
