将 NSAIDs 与多奈哌齐联合作为治疗阿尔茨海默病的多靶点定向配体。
Combination of NSAIDs with donepezil as multi-target directed ligands for the treatment of Alzheimer's disease.
机构信息
Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin 541004, China.
Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
出版信息
Bioorg Med Chem Lett. 2022 Nov 1;75:128976. doi: 10.1016/j.bmcl.2022.128976. Epub 2022 Sep 5.
To search for multi-target directed ligands for the treatment of Alzheimer's disease (AD), eight hybrid compounds from the combination of non-steroidal anti-inflammatory drugs with donepezil were designed and synthesized. The enzyme test revealed that the synthesized compounds had remarkable inhibitory activity towards both AChE and BChE. The IC values of the most active compound 3a reached 0.015 and 0.80 μM for AChE and BChE, respectively, much lower than that of donepezil. Besides, the anti-inflammatory assays showed that the target compounds could effectively inhibit COX-1 and COX-2, and prevent the secretion of proinflammatory cytokines (TNF-α and IL-1β) induced by LPS. Moreover, the target compound could also protect the neuron cells from the damage caused by Aβ42 in vitro. All the results suggest that the hybrid compounds, in particular compound 3a, can be considered as potential candidates for the treatment of AD.
为了寻找治疗阿尔茨海默病（AD）的多靶标导向配体，设计并合成了 8 种将非甾体抗炎药与多奈哌齐结合的杂合化合物。酶测试表明，所合成的化合物对 AChE 和 BChE 均具有显著的抑制活性。最活性化合物 3a 的 IC 值分别为 0.015 和 0.80 μM，均明显低于多奈哌齐。此外，抗炎测定表明，这些目标化合物可以有效抑制 COX-1 和 COX-2，并防止 LPS 诱导的促炎细胞因子（TNF-α和 IL-1β）的分泌。此外，该目标化合物还可以保护神经元细胞免受 Aβ42 在体外造成的损伤。所有结果表明，这些杂合化合物，特别是化合物 3a，可以被认为是治疗 AD 的潜在候选药物。
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