Design and synthesis of novel 3,4-dihydrocoumarins as potent and selective monoamine oxidase-B inhibitors with the neuroprotection against Parkinson's disease
Design and synthesis of novel 3,4-dihydrocoumarins as potent and selective monoamine oxidase-B inhibitors with the neuroprotection against Parkinson's disease
复制标题
设计和合成新型 3,4-二氢香豆素作为有效的选择性单胺氧化酶 B 抑制剂，具有针对帕金森病的神经保护作用。
DOI：
10.1016/j.bioorg.2021.104685
复制
发表时间：
2021-02-25
影响因子：
5.1
通讯作者：
Zhang, Tong
中科院分区：
文献类型：
--
作者：
Liu, Li;Chen, Yi;Zhang, Tong
由于帕金森病发病机制复杂，具有神经保护作用的单胺氧化酶-B（MAO-B）抑制剂更适合治疗帕金森病。为了开发具有神经保护作用的新型 hMAO-B 抑制剂，设计了一系列新型 3,4-二氢香豆素作为选择性且可逆的 hMAO-B 抑制剂来治疗 PD。大多数化合物对 hMAO-B 的抑制作用优于 hMAO-A，IC50 值范围为纳摩尔至亚纳摩尔。其中，化合物4d是最有效的hMAO-B抑制剂（IC50 = 0.37 nM），其活性比异丙烟肼高约20783倍，并且对hMAO-B表现出最高的选择性（SI > 270,270）。动力学研究表明，化合物 4d 是 hMAO-B 的可逆竞争性抑制剂。神经保护研究表明，化合物 4d 可以保护 PC12 细胞免受 6-OHDA 和鱼藤酮引起的损伤。此外，化合物4d在剂量高达2500 mg/kg (po)时并未表现出急性毒性，并且在平行的人工膜通透性测定中可以穿过血脑屏障。更重要的是，化合物 4d 能够显着预防 MPTP 诱导的 PD 模型中的运动缺陷。这些结果表明化合物 4d 是一种有效且有前景的抗 PD 候选药物。
The monoamine oxidase-B (MAO-B) inhibitors with neuroprotective effects are better for Parkinson's disease (PD) treatment, due to the complicated pathogenesis of PD. To develop new hMAO-B inhibitors with neuro-protection, a novel series of 3,4-dihydrocoumarins was designed as selective and reversible hMAO-B inhibitors to treat PD. Most compounds showed potent and selective inhibition for hMAO-B over hMAO-A with IC50 values ranging from nanomolar to sub-nanomolar. Among them, compound 4d was the most potent hMAO-B inhibitor (IC50 = 0.37 nM) being about 20783-fold more active than iproniazid, and exhibited the highest selectivity for hMAO-B (SI > 270,270). Kinetic studies revealed that compound 4d was a reversible and competitive inhibitor of hMAO-B. Neuroprotective studies indicated that compound 4d could protect PC12 cells from the damage induced by 6-OHDA and rotenone. Besides, compound 4d did not exhibit acute toxicity at a dose up to 2500 mg/kg (po), and could cross the BBB in parallel artificial membrane permeability assay. More importantly, compound 4d was able to significantly prevent the motor deficits in the MPTP-induced PD model. These results indicate that compound 4d is an effective and promising candidate against PD.