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Scouting around 1,2,3,4-Tetrahydrochromeno[3,2-c]pyridin-10-ones for Single- and Multitarget Ligands Directed towards Relevant Alzheimer's Targets.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-07-27 , DOI: 10.1002/cmdc.202000468
Rosa Purgatorio 1 , Larisa N Kulikova 2 , Leonardo Pisani 1 , Marco Catto 1 , Modesto de Candia 1 , Antonio Carrieri 1 , Saverio Cellamare 1 , Annalisa De Palma 3 , Andrey A Beloglazkin 2 , Ghulam Reza Raesi 2 , Leonid G Voskressensky 2 , Cosimo D Altomare 1
Affiliation  

A number of 1,2,3,4‐tetrahydrochromeno[3,2‐c]pyridin‐10‐one derivatives have been synthesized and screened against different targets involved in the onset and progression of Alzheimer's disease (AD), such as acetyl‐ and butyrylcholinesterase (AChE and BChE), monoamine oxidases A and B (MAO A and B), aggregation of β‐amyloid (Aβ) and reactive oxygen species (ROS) production. Derivatives 1 c, 3 b, 4 and 5 a showed multifaceted profiles of promising anti‐AD features and returned well‐balanced multitargeting inhibitory activities. Moreover, compound 1 f, a potent and selective human MAO B inhibitor (IC50=0.89 μM), proved to be a safe neuroprotectant in a human neuroblastoma cell line (SH‐SY5Y) by improving viability impaired by Aβ1–42 and pro‐oxidant insult. Furthermore, structure–activity relationships (SARs) and docking models were derived in order to assist further hit‐to‐lead optimization stage.

中文翻译:

围绕 1,2,3,4-Tetrahydrochromeno[3,2-c]pyridin-10-ones 寻找针对相关阿尔茨海默氏症靶标的单靶点和多靶点配体。

许多 1,2,3,4-四氢色基 [3,2- c ]pyridin-10-one 衍生物已被合成并针对参与阿尔茨海默病 (AD) 发病和进展的不同靶点进行筛选,例如乙酰-和丁酰胆碱酯酶(AChE 和 BChE)、单胺氧化酶 A 和 B(MAO A 和 B)、β-淀粉样蛋白 (Aβ) 的聚集和活性氧 (ROS) 的产生。衍生物1c3b45a显示出有前景的抗 AD 特征的多方面特征,并返回了均衡的多靶点抑制活性。此外,化合物1f是一种有效且选择性的人 MAO B 抑制剂(IC 50=0.89 μM),通过改善 Aβ 1-42和促氧化损伤损害的活力,被证明是人神经母细胞瘤细胞系 (SH-SY5Y) 中的安全神经保护剂。此外,还推导出了构效关系(SAR)和对接模型,以帮助进一步的“先导优化”阶段。
更新日期:2020-07-27
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