Wang Jin, Wang Zhi-Min, Li Xue-Mei, Li Fan, Wu Jia-Jia, Kong Ling-Yi, Wang Xiao-Bing
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
Bioorg Med Chem. 2016 Sep 15;24(18):4324-4338. doi: 10.1016/j.bmc.2016.07.025. Epub 2016 Jul 15.
A novel series of compounds obtained by fusing the acetylcholinesterase (AChE) inhibitor donepezil and the antioxidant melatonin were designed as multi-target-directed ligands for the treatment of Alzheimer's disease (AD). In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (eqBuChE and hBuChE), and β-amyloid (Aβ) aggregation, and to act as potential antioxidants and biometal chelators. Especially, 4u displayed a good inhibition of AChE (IC50 value of 193nM for eeAChE and 273nM for hAChE), strong inhibition of BuChE (IC50 value of 73nM for eqBuChE and 56nM for hBuChE), moderate inhibition of Aβ aggregation (56.3% at 20μM) and good antioxidant activity (3.28trolox equivalent by ORAC assay). Molecular modeling studies in combination with kinetic analysis revealed that 4u was a mixed-type inhibitor, binding simultaneously to catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4u could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). Taken together, these results strongly indicated the hybridization approach is an efficient strategy to identify novel scaffolds with desired bioactivities, and further optimization of 4u may be helpful to develop more potent lead compound for AD treatment.
通过将乙酰胆碱酯酶（AChE）抑制剂多奈哌齐与抗氧化剂褪黑素融合而获得的一系列新型化合物被设计为用于治疗阿尔茨海默病（AD）的多靶点导向配体。体外试验表明，大多数目标化合物表现出显著的抑制乙酰胆碱酯酶（eeAChE和hAChE）、丁酰胆碱酯酶（eqBuChE和hBuChE）以及β-淀粉样蛋白（Aβ）聚集的能力，并可作为潜在的抗氧化剂和生物金属螯合剂。特别是，4u对AChE具有良好的抑制作用（对eeAChE的IC50值为193nM，对hAChE的IC50值为273nM），对BuChE有强烈抑制作用（对eqBuChE的IC50值为73nM，对hBuChE的IC50值为56nM），对Aβ聚集有中度抑制作用（20μM时为56.3%）且具有良好的抗氧化活性（通过ORAC测定法为3.28trolox当量）。结合动力学分析的分子模拟研究表明，4u是一种混合型抑制剂，同时结合到AChE的催化阴离子位点（CAS）和外周阴离子位点（PAS）。此外，4u可以螯合金属离子，减少氧化应激诱导的PC12细胞死亡并穿透血脑屏障（BBB）。综上所述，这些结果有力地表明杂交方法是鉴定具有所需生物活性的新型支架的有效策略，对4u的进一步优化可能有助于开发更有效的AD治疗先导化合物。
