Makhaeva Galina F, Grishchenko Maria V, Kovaleva Nadezhda V, Boltneva Natalia P, Rudakova Elena V, Astakhova Tatiana Y, Timokhina Elena N, Pronkin Pavel G, Lushchekina Sofya V, Khudina Olga G, Zhilina Ekaterina F, Shchegolkov Evgeny V, Lapshina Maria A, Dubrovskaya Elena S, Radchenko Eugene V, Palyulin Vladimir A, Burgart Yanina V, Saloutin Victor I, 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.
Postovsky Institute of Organic Synthesis, Urals Branch of the Russian Academy of Sciences, Ekaterinburg, Russia.
Arch Pharm (Weinheim). 2025 Jan;358(1):e2400819. doi: 10.1002/ardp.202400819.
New conjugates of amiridine and salicylic derivatives (salicylamide, salicylimine, and salicylamine) with different lengths of alkylene spacers were designed, synthesized, and evaluated as potential multifunctional central nervous system therapeutic agents for Alzheimer's disease (AD). Conjugates demonstrated high acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition (IC: AChE, 0.265-4.24 μM; BChE, 0.01-0.64 μM) but poor activity against off-target carboxylesterase (CES). Specifically, conjugates with a (CH) spacer showed the highest AChE and BChE inhibition: 3-16 times more effective than amiridine. Salicylamides 7b and 7c had the maximum BChE/AChE selectivity ratios: 193 and 138, respectively. Conjugates were mixed-type reversible inhibitors of both cholinesterases and displaced propidium from the AChE peripheral anionic site (PAS) at the level of donepezil. All conjugates inhibited Aβ self-aggregation in the thioflavin test; inhibition increased with spacer elongation, being greatest for (CH). The results agreed with molecular docking to AChE, BChE, and Aβ. Conjugates exhibited high 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)-scavenging activity comparable to the standard antioxidant Trolox, and they showed the ability to bind Cu, Fe, and Zn. Conjugates had favorable predicted intestinal absorption and blood-brain barrier permeability. Altogether, the results indicate that the new conjugates possess potential for further development as multifunctional anti-AD drug candidates.
设计、合成并评估了具有不同长度亚烷基间隔基的阿米啶与水杨酸衍生物（水杨酰胺、水杨基亚胺和水杨胺）的新型共轭物，将其作为治疗阿尔茨海默病（AD）的潜在多功能中枢神经系统治疗剂。共轭物表现出高乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）抑制活性（IC：AChE为0.265 - 4.24μM；BChE为0.01 - 0.64μM），但对非靶标羧酸酯酶（CES）活性较差。具体而言，具有(CH)间隔基的共轭物表现出最高的AChE和BChE抑制活性：比阿米啶有效3 - 16倍。水杨酰胺7b和7c具有最大的BChE/AChE选择性比率，分别为193和138。共轭物是两种胆碱酯酶的混合型可逆抑制剂，并且在多奈哌齐水平从AChE外周阴离子位点（PAS）置换碘化丙啶。在硫黄素试验中，所有共轭物均抑制Aβ自聚集；抑制作用随间隔基延长而增加，对于(CH)间隔基最大。结果与对AChE、BChE和Aβ的分子对接结果一致。共轭物表现出与标准抗氧化剂Trolox相当的高2,2'-联氮-双-(3-乙基苯并噻唑啉-6-磺酸)（ABTS）清除活性，并且它们显示出结合Cu、Fe和Zn的能力。共轭物具有良好的预测肠道吸收和血脑屏障通透性。总之，结果表明新型共轭物作为多功能抗AD药物候选物具有进一步开发的潜力。
