Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6/Selmi 3, 40126 Bologna, Italy; Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czechia.
Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6/Selmi 3, 40126 Bologna, Italy.
Eur J Med Chem. 2017 Feb 15;127:250-262. doi: 10.1016/j.ejmech.2016.12.048. Epub 2016 Dec 26.
Multi-target drug discovery is one of the most followed approaches in the active central nervous system (CNS) therapeutic area, especially in the search for new drugs against Alzheimer's disease (AD). This is because innovative multi-target-directed ligands (MTDLs) could more adequately address the complexity of this pathological condition. In a continuation of our efforts aimed at a new series of anti-AD MTDLs, we combined the structural features of the cholinesterase inhibitor drug tacrine with that of resveratrol, which is known for its purported antioxidant and anti-neuroinflammatory activities. The most interesting hybrid compounds (5, 8, 9 and 12) inhibited human acetylcholinesterase at micromolar concentrations and effectively modulated Aβ self-aggregation in vitro. In addition, 12 showed intriguing anti-inflammatory and immuno-modulatory properties in neuronal and glial AD cell models. Importantly, the MTDL profile is accompanied by high-predicted blood-brain barrier permeability, and low cytotoxicity on primary neurons.
多靶点药物发现是积极中枢神经系统（CNS）治疗领域中最受关注的方法之一，特别是在寻找针对阿尔茨海默病（AD）的新药方面。这是因为创新的多靶点定向配体（MTDL）可以更充分地解决这种病理状况的复杂性。作为我们旨在开发一系列新型抗 AD MTDL 的努力的延续，我们将胆碱酯酶抑制剂药物他克林的结构特征与众所周知的具有抗氧化和抗神经炎症活性的白藜芦醇结合在一起。最有趣的杂合化合物（5、8、9 和 12）在微摩尔浓度下抑制人乙酰胆碱酯酶，并有效调节体外 Aβ 自聚集。此外，12 在神经元和神经胶质 AD 细胞模型中表现出有趣的抗炎和免疫调节特性。重要的是，MTDL 特征伴随着高预测的血脑屏障通透性和对原代神经元的低细胞毒性。
