Design, synthesis, and evaluation of novel isoflavone derivatives as multifunctional agents for the treatment of Alzheimer‘s disease
Design, synthesis, and evaluation of novel isoflavone derivatives as multifunctional agents for the treatment of Alzheimer‘s disease
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新型异黄酮衍生物的设计、合成和评估作为治疗阿尔茨海默病的多功能药物
DOI：
10.1016/j.ejmech.2019.02.053
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Zhang tiantai
中科院分区：
文献类型：
--
作者：
Wang dongmei;Hu min;Li xingpeng;Zhang dan;Chen chengjuan;Fu junmin;Shao shuai;Shi gaona;Wu song;Zhang tiantai
设计、合成了一系列新的抗阿尔茨海默病的多靶点配体，体外研究表明，部分配体具有多功能，包括阻断组胺3受体（H3 R）、抑制乙酰胆碱酯酶（AChE）、神经保护作用和抗神经炎症作用。其中化合物9 b对H3 R的阻断能力最强（IC_（50）= 0.27 μM），对AChE的抑制活性也较好（IC_（50）= 0.08 μM）。此外，化合物9 b通过防止铜诱导的神经元损伤而对SH-SY 5 Y显示出明显的神经保护作用，并且通过抑制BV-2细胞上的炎症因子的产生而显示出有效的抗神经炎症活性。分子模拟研究表明，9 bacts是一种同时与H3 R和AChE相互作用的混合型抑制剂。此外，体内数据显示，化合物9 b在高达1000 mg/kg的剂量下在小鼠中不引起急性毒性，并且具有期望的药代动力学性质，以及良好的血脑屏障（BBB）渗透性（log BB = 1.24 ± 0.07）。进一步的研究表明，长期口服9 b显著改善东莨菪碱诱导的AD小鼠在跳台被动回避试验中的认知功能障碍。综上所述，本研究表明化合物9 bis是一种有希望的治疗阿尔茨海默病的多功能候选药物。
A series of novel isoflavone analogs were designed, synthesized, and evaluated as multitarget-directed ligands for the treatment of Alzheimer's disease.In vitroevaluations revealed that some ligands had multifunctional profiles, including potent blockage of histamine 3 receptor (H3R), excellent inhibition of acetylcholinesterase (AChE), neuroprotective effects and anti-neuroinflammatory properties. Among these derivatives, compound9bexhibited the highest ability to block H3R (IC50= 0.27 μM) and good inhibitory activity against AChE (IC50= 0.08 μM). Additionally, compound9bshowed obvious neuroprotective effect on SH-SY5Y by preventing copper-induced neuronal damage and potent anti-neuroinflammatory activity by inhibiting the production of inflammatory factors on BV-2 cells. A molecular modeling study revealed that9bacts as a mixed-type inhibitor that interacts simultaneously with H3R and AChE. Moreover,in vivodata revealed that compound9bdid not cause acute toxicity in mice at doses up to 1000 mg/kg, and had desirable pharmacokinetic properties, as well as a good blood-brain barrier (BBB) permeability (log BB = 1.24 ± 0.07). Further studies demonstrated that chronic oral treatment with9bsignificantly improved cognitive dysfunction in scopolamine-induced AD mice in the step-down passive avoidance test. Taken together, the present study showed that compound9bis a promising multifunctional drug candidate for the treatment of Alzheimer's disease.