Coumarin-dithiocarbamate hybrids as novel multitarget AChE and MAO-B inhibitors against Alzheimer's disease: Design, synthesis and biological evaluation
Coumarin-dithiocarbamate hybrids as novel multitarget AChE and MAO-B inhibitors against Alzheimer's disease: Design, synthesis and biological evaluation
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香豆素-二硫代氨基甲酸酯杂合体作为新型多靶点 AChE 和 MAO-B 抑制剂对抗阿尔茨海默病：设计、合成和生物学评价
DOI：
10.1016/j.bioorg.2018.09.010
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发表时间：
2018-12-01
影响因子：
5.1
通讯作者：
Xie, Sai-Sai
中科院分区：
文献类型：
--
作者：
He, Qi;Liu, Jing;Xie, Sai-Sai
设计并合成了一系列新的香豆素-二硫代氨基甲酸酯杂合物，作为治疗阿尔茨海默病的多靶点药物。大多数化合物对AChE和MAO-B有明显的选择性抑制作用。在这些化合物中，化合物8 f显示出对AChE最有效的抑制作用，其对eeAChE和hAChE的IC 50值分别为0.0068 μ M和0.0089 μ M。化合物8 g被鉴定为对hMAO-B最有效的抑制剂，并且它也是对hAChE和hMAO-B两者的良好且平衡的抑制剂（对于hAChE为0.114 μ M;对于hMAO-B为0.101 μ M）。动力学和分子模拟研究表明，8 g是AChE的双结合位点抑制剂和MAO-B的竞争性抑制剂。进一步的研究表明，8 g可穿透血脑屏障，对SH-SY 5 Y神经母细胞瘤细胞无毒性。更重要的是，在高达2500 mg/kg的剂量下，8 g在小鼠中未显示出任何急性毒性，并且可以逆转东莨菪碱诱导的AD小鼠的认知功能障碍。总体而言，这些结果强调了8 g作为AD治疗的潜在多靶点药物，并为设计基于二硫代氨基甲酸酯支架的新型多靶点AChE/MAO-B抑制剂提供了起点。
A series of new coumarin-dithiocarbamate hybrids were designed and synthesized as multitarget agents for the treatment of Alzheimer's disease. Most of them showed potent and clearly selective inhibition towards AChE and MAO-B. Among these compounds, compound 8f demonstrated the most potent inhibition to AChE with IC50 values of 0.0068 mu M and 0.0089 mu M for eeAChE and hAChE, respectively. Compound 8g was identified as the most potent inhibitor to hMAO-B, and it is also a good and balanced inhibitor to both hAChE and hMAO-B (0.114 mu M for hAChE; 0.101 mu M for hMAO-B). Kinetic and molecular modeling studies revealed that 8g was a dual binding site inhibitor for AChE and a competitive inhibitor for MAO-B. Further studies indicated that 8g could penetrate the BBB and exhibit no toxicity on SH-SY5Y neuroblastoma cells. More importantly, 8g did not display any acute toxicity in mice at doses up to 2500 mg/kg and could reverse the cognitive dysfunction of scopolamine-induced AD mice. Overall, these results highlighted 8g as a potential multitarget agent for AD treatment and offered a starting point for design of new multitarget AChE/MAO-B inhibitors based on dithiocarbamate scaffold.