a State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University , People's Republic of China.
J Enzyme Inhib Med Chem. 2016;31(sup3):41-53. doi: 10.1080/14756366.2016.1201814. Epub 2016 Jul 7.
In a continuing effort to develop multitargeted compounds as potential treatment agents against Alzheimer's disease (AD), a series of donepezil-like compounds were designed, synthesized and evaluated. In vitro studies showed that most of the designed compounds displayed potent inhibitory activities toward AChE, BuChE, MAO-B and MAO-A. Among them, w18 was a promising agent with balanced activities, which exhibited a moderate cholinesterase inhibition (IC, 0.220 μM for eeAChE; 1.23 μM for eqBuChE; 0.454 μM for hAChE) and an acceptable inhibitory activity against monoamine oxidases (IC, 3.14 μM for MAO-B; 13.4 μM for MAO-A). Moreover, w18 could also be a metal-chelator, and able to cross the blood-brain barrier with low cell toxicity on PC12 cells. Taken together, these results suggested that w18 might be a promising multitargeted compound for AD treatment.
为了开发多靶标化合物作为治疗阿尔茨海默病（AD）的潜在药物，设计、合成并评价了一系列类似多奈哌齐的化合物。体外研究表明，大多数设计的化合物对 AChE、BuChE、MAO-B 和 MAO-A 均显示出很强的抑制活性。其中，w18 是一种具有平衡活性的很有前途的药物，其表现出中等的胆碱酯酶抑制活性（eeAChE 的 IC 为 0.220 μM；eqBuChE 的 IC 为 1.23 μM；hAChE 的 IC 为 0.454 μM），对单胺氧化酶也有可接受的抑制活性（MAO-B 的 IC 为 3.14 μM；MAO-A 的 IC 为 13.4 μM）。此外，w18 还可能是一种金属螯合剂，能够穿过血脑屏障，对 PC12 细胞的细胞毒性低。综上所述，这些结果表明 w18 可能是一种很有前途的治疗 AD 的多靶标化合物。
