Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu 610041, China.
Bioorg Med Chem. 2021 Apr 1;35:116074. doi: 10.1016/j.bmc.2021.116074. Epub 2021 Feb 16.
To discover novel multifunctional agents for the treatment of Alzheimer's disease, a series of 3-benzylidene/benzylphthalide Mannich base derivatives were designed, synthesized and evaluated. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound (Z)-13c raised particular interest because of its excellent multifunctional bioactivities. It displayed excellent EeAChE and HuAChE inhibition (IC = 9.18 × 10 and 6.16 × 10 μM, respectively), good MAO-B inhibitory activity (IC = 5.88 μM) and high antioxidant activity (ORAC = 2.05 Trolox equivalents). Additionally, it also exhibited good antiplatelet aggregation activity, moderate self- and Cu-induced Aβ aggregation inhibitory potency, disaggregation ability on Aβ fibrils, biometal chelating ability, appropriate BBB permeability and significant neuroprotective effect. Furthermore, (Z)-13c can also ameliorate the learning and memory impairment induced by scopolamine in mice. These multifunctional properties highlight compound (Z)-13c as a promising candidate for further development of multifunctional drug against AD.
为了发现治疗阿尔茨海默病的新型多功能试剂，设计、合成并评价了一系列 3-亚苄基/苯酞曼尼希碱衍生物。生物筛选结果表明，这些衍生物大多数具有良好的多功能活性。其中，化合物（Z）-13c 因其出色的多功能生物活性而引起特别关注。它对 EeAChE 和 HuAChE 具有优异的抑制作用（IC=9.18×10 和 6.16×10 μM），良好的 MAO-B 抑制活性（IC=5.88 μM）和较高的抗氧化活性（ORAC=2.05 Trolox 当量）。此外，它还表现出良好的抗血小板聚集活性、适度的自诱导和 Cu 诱导的 Aβ聚集抑制能力、对 Aβ纤维的解聚能力、生物金属螯合能力、适当的 BBB 渗透性和显著的神经保护作用。此外，（Z）-13c 还可以改善东莨菪碱诱导的小鼠学习记忆障碍。这些多功能特性突出了化合物（Z）-13c 作为进一步开发治疗 AD 的多功能药物的有前途的候选物。
