State Key Laboratory of Functions and Applications of Medicinal Plants, School of Basic Medical Sciences, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, China.
Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):1375-1388. doi: 10.1080/14756366.2022.2073442.
Herein, a series of novel -alkyl ferulamide derivatives were designed and synthesised through the multi-target-directed ligands (MTDLs) strategy. The biological activities showed that compounds , , , , and indicated significantly selective MAO-B inhibitory potency (IC = 0.32, 0.56, 0.54, 0.73, and 0.86 μM, respectively) and moderate antioxidant activity. Moreover, compounds , , , , and showed potent anti-inflammatory properties, remarkable effects on self-induced A aggregation, and potent neuroprotective effect on A-induced PC12 cell injury. Furthermore, compounds , , , , and presented good blood-brain barrier permeation and drug-like properties. More interesting, the PET/CT images with [C] demonstrated that [C] could penetrate the BBB with a high brain uptake and exhibited good brain clearance kinetic property. Therefore, compound would be a promising multi-functional agent for the treatment of AD.
本文通过多靶点导向配体（MTDLs）策略设计和合成了一系列新型 - 烷基阿魏酰胺衍生物。生物活性研究表明，化合物 、 、 、 、 对 MAO-B 具有显著的选择性抑制作用（IC = 0.32、0.56、0.54、0.73、0.86 μM），具有中等的抗氧化活性。此外，化合物 、 、 、 、 表现出较强的抗炎作用、对自身诱导的 A 聚集有显著影响，对 A 诱导的 PC12 细胞损伤有较强的神经保护作用。进一步的，化合物 、 、 、 、 具有良好的血脑屏障通透性和类药性。更有趣的是，[C]的 PET/CT 图像显示 [C]可以穿透 BBB，具有较高的脑摄取率，并表现出良好的脑清除动力学特性。因此，化合物 可能是一种有前途的治疗 AD 的多功能药物。
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