Purgatorio Rosa, Kulikova Larisa N, Pisani Leonardo, Catto Marco, de Candia Modesto, Carrieri Antonio, Cellamare Saverio, De Palma Annalisa, Beloglazkin Andrey A, Reza Raesi Ghulam, Voskressensky Leonid G, Altomare Cosimo D
Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125, Bari, Italy.
Organic Chemistry Department, Peoples' Friendship University of Russia (RUDN), 6 Miklukho-Maklaya St., Moscow, 117198, Russia.
ChemMedChem. 2020 Oct 19;15(20):1947-1955. doi: 10.1002/cmdc.202000468. Epub 2020 Sep 4.
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 (IC =0.89 μM), proved to be a safe neuroprotectant in a human neuroblastoma cell line (SH-SY5Y) by improving viability impaired by Aβ and pro-oxidant insult. Furthermore, structure-activity relationships (SARs) and docking models were derived in order to assist further hit-to-lead optimization stage.
已经合成了多种1,2,3,4-四氢色烯并[3,2-c]吡啶-10-酮衍生物，并针对与阿尔茨海默病（AD）的发生和发展相关的不同靶点进行了筛选，这些靶点包括乙酰胆碱酯酶和丁酰胆碱酯酶（AChE和BChE）、单胺氧化酶A和B（MAO A和B）、β-淀粉样蛋白（Aβ）的聚集以及活性氧（ROS）的产生。衍生物1 c、3 b、4和5 a表现出多方面有前景的抗AD特性，并且具有平衡良好的多靶点抑制活性。此外，化合物1 f是一种强效且选择性的人MAO B抑制剂（IC =0.89 μM），通过提高因Aβ和促氧化剂损伤而受损的活力，在人神经母细胞瘤细胞系（SH-SY5Y）中被证明是一种安全的神经保护剂。此外，还推导了构效关系（SARs）和对接模型，以辅助进一步的从命中物到先导物的优化阶段。
