Makhaeva Galina F, Kovaleva Nadezhda V, Rudakova Elena V, Boltneva Natalia P, Lushchekina Sofya V, Astakhova Tatiana Yu, Timokhina Elena N, Serebryakova Olga G, Shchepochkin Alexander V, Averkov Maxim A, Utepova Irina A, Demina Nadezhda S, Radchenko Eugene V, Palyulin Vladimir A, Fisenko Vladimir P, Bachurin Sergey O, Chupakhin Oleg N, Charushin Valery N, Richardson Rudy J
Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka, Russia.
Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, Russia.
Front Pharmacol. 2023 Aug 9;14:1219980. doi: 10.3389/fphar.2023.1219980. eCollection 2023.
We investigated the inhibitory activities of novel 9-phosphoryl-9,10-dihydroacridines and 9-phosphorylacridines against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CES). We also studied the abilities of the new compounds to interfere with the self-aggregation of β-amyloid (Aβ) in the thioflavin test as well as their antioxidant activities in the ABTS and FRAP assays. We used molecular docking, molecular dynamics simulations, and quantum-chemical calculations to explain experimental results. All new compounds weakly inhibited AChE and off-target CES. Dihydroacridines with aryl substituents in the phosphoryl moiety inhibited BChE; the most active were the dibenzyloxy derivative and its diphenethyl bioisostere (IC = 2.90 ± 0.23 µM and 3.22 ± 0.25 µM, respectively). Only one acridine, , an analog of dihydroacridine, , was an effective BChE inhibitor (IC = 6.90 ± 0.55 μM), consistent with docking results. Dihydroacridines inhibited Aβ self-aggregation; and were the most active (58.9% ± 4.7% and 46.9% ± 4.2%, respectively). All dihydroacridines demonstrated high ABTS-scavenging and iron-reducing activities comparable to Trolox, but acridines were almost inactive. Observed features were well explained by quantum-chemical calculations. ADMET parameters calculated for all compounds predicted favorable intestinal absorption, good blood-brain barrier permeability, and low cardiac toxicity. Overall, the best results were obtained for two dihydroacridine derivatives and with dibenzyloxy and diphenethyl substituents in the phosphoryl moiety. These compounds displayed high inhibition of BChE activity and Aβ self-aggregation, high antioxidant activity, and favorable predicted ADMET profiles. Therefore, we consider and as lead compounds for further in-depth studies as potential anti-AD preparations.
我们研究了新型9-磷酰基-9,10-二氢吖啶和9-磷酰基吖啶对乙酰胆碱酯酶（AChE）、丁酰胆碱酯酶（BChE）和羧酸酯酶（CES）的抑制活性。我们还研究了这些新化合物在硫黄素试验中干扰β-淀粉样蛋白（Aβ）自聚集的能力，以及它们在ABTS和FRAP试验中的抗氧化活性。我们使用分子对接、分子动力学模拟和量子化学计算来解释实验结果。所有新化合物对AChE和脱靶的CES均有微弱抑制作用。磷酰基部分带有芳基取代基的二氢吖啶抑制BChE；活性最高的是二苄氧基衍生物 及其二苯乙基生物电子等排体 （IC分别为2.90±0.23 μM和3.22±0.25 μM）。只有一种吖啶，即二氢吖啶 的类似物 ，是一种有效的BChE抑制剂（IC = 6.90±0.55 μM），与对接结果一致。二氢吖啶抑制Aβ自聚集； 和 活性最高（分别为58.9%±4.7%和46.9%±4.2%）。所有二氢吖啶 均表现出与Trolox相当的高ABTS清除活性和铁还原活性，但吖啶 几乎没有活性。量子化学计算很好地解释了观察到的特征。为所有化合物计算的ADMET参数预测其具有良好的肠道吸收、良好的血脑屏障通透性和低心脏毒性。总体而言，磷酰基部分带有二苄氧基和二苯乙基取代基的两种二氢吖啶衍生物 和 取得了最佳结果。这些化合物对BChE活性和Aβ自聚集具有高度抑制作用，具有高抗氧化活性，并且预测的ADMET谱良好。因此，我们认为 和 是作为潜在抗阿尔茨海默病制剂进行进一步深入研究的先导化合物。
