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Coumarin-dithiocarbamate hybrids as novel multitarget AChE and MAO-B inhibitors against Alzheimer’s disease: Design, synthesis and biological evaluation
Bioorganic Chemistry ( IF 5.1 ) Pub Date : 2018-09-11 , DOI: 10.1016/j.bioorg.2018.09.010
Qi He , Jing Liu , Jin-Shuai Lan , Jiaoli Ding , Yongbing Sun , Yuanying Fang , Neng Jiang , Zunhua Yang , Liyuan Sun , Yi Jin , Sai-Sai Xie

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 μM and 0.0089 μM 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 µM for hAChE; 0.101 µM 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.



中文翻译:

香豆素-二硫代氨基甲酸酯杂化物作为新型多靶点AChE和MAO-B抑制剂,可预防阿尔茨海默氏病:设计,合成和生物学评估

设计并合成了一系列新的香豆素-二硫代氨基甲酸酯杂化物作为多靶点药物,用于治疗阿尔茨海默氏病。它们中的大多数显示出对AChE和MAO-B的有效且明显的选择性抑制。在这些化合物中,化合物8f表现出对AChE的最强抑制作用,eeAChE和hAChE的IC 50值分别为0.0068μM和0.0089μM。化合物8g被认为是hMAO-B的最有效抑制剂,同时也是hAChE和hMAO-B的良好且平衡的抑制剂(hAChE为0.114 µM; hMAO-B为0.101 µM)。动力学和分子模型研究表明8g是AChE的双重结合位点抑制剂,也是MAO-B的竞争性抑制剂。进一步的研究表明8g可穿透血脑屏障,对SH-SY5Y神经母细胞瘤细胞无毒性。更重要的是,剂量高达2500 mg / kg的8g小鼠没有表现出任何急性毒性,并且可以逆转东pol碱诱导的AD小鼠的认知功能障碍。总体而言,这些结果突出了8g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。

更新日期:2018-09-11
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