Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, School of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, People's Republic of China.
Key Laboratory of Pesticide, College of Plant Protection, Nanjing Agricultural University, Nanjing 210095, China.
Fitoterapia. 2024 Apr;174:105867. doi: 10.1016/j.fitote.2024.105867. Epub 2024 Feb 19.
The concept of multi-target-directed ligands offers fresh perspectives for the creation of brand-new Alzheimer's disease medications. To explore their potential as multi-targeted anti-Alzheimer's drugs, eighteen new bakuchiol derivatives were designed, synthesized, and evaluated. The structures of the new compounds were elucidated by IR, NMR, and HRMS. Eighteen compounds were assayed for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in vitro using Ellman's method. It was shown that most of the compounds inhibited AChE and BuChE to varying degrees, but the inhibitory effect on AChE was relatively strong, with fourteen compounds showing inhibition of >50% at the concentration of 200 μM. Among them, compound 3g (IC = 32.07 ± 2.00 μM) and compound 3n (IC = 34.78 ± 0.34 μM) showed potent AChE inhibitory activities. Molecular docking studies and molecular dynamics simulation showed that compound 3g interacts with key amino acids at the catalytically active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase and binds stably to acetylcholinesterase. On the other hand, compounds 3n and 3q significantly reduced the pro-inflammatory cytokines TNF-α and IL-6 released from LPS-induced RAW 264.7 macrophages. Compound 3n possessed both anti-acetylcholinesterase activity and anti-inflammatory properties. Therefore, an in-depth study of compound 3n is expected to be a multi-targeted anti-AD drug.
多靶标导向配体的概念为开发全新的阿尔茨海默病药物提供了新的视角。为了探索它们作为多靶标抗阿尔茨海默病药物的潜力，设计、合成并评价了 18 种新的补骨脂素衍生物。新化合物的结构通过 IR、NMR 和 HRMS 进行了阐明。采用 Ellman 法测定了 18 种化合物对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）的体外活性。结果表明，大多数化合物对 AChE 和 BuChE 均有不同程度的抑制作用，但对 AChE 的抑制作用相对较强，有 14 种化合物在 200 μM 浓度下的抑制率>50%。其中，化合物 3g（IC = 32.07 ± 2.00 μM）和化合物 3n（IC = 34.78 ± 0.34 μM）表现出较强的 AChE 抑制活性。分子对接研究和分子动力学模拟表明，化合物 3g 与乙酰胆碱酯酶的催化活性位点（CAS）和外周阴离子位点（PAS）的关键氨基酸相互作用，并与乙酰胆碱酯酶稳定结合。另一方面，化合物 3n 和 3q 显著降低了 LPS 诱导的 RAW 264.7 巨噬细胞释放的促炎细胞因子 TNF-α和 IL-6。化合物 3n 具有抗乙酰胆碱酯酶活性和抗炎特性。因此，深入研究化合物 3n 有望成为一种多靶标抗 AD 药物。
