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.

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。