Teke Tuncel Senel, Erol Gunal Sule, Demir İlke, Baysal İpek, Erdem Safiye Sag, Telli Gökçen, Ucar Gulberk, Dogan Ilknur, Kelekci Nesrin Gokhan
Bogazici University, Department of Chemistry, Bebek, 34342, Istanbul, Turkey; İstanbul Arel University, Department of Molecular Biology and Genetics, 34537, Istanbul, Turkey.
İstanbul University-Cerrahpaşa, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Istanbul, Turkey.
Eur J Med Chem. 2025 Nov 15;298:117986. doi: 10.1016/j.ejmech.2025.117986. Epub 2025 Jul 23.
Neurodegenerative diseases are multifactorial disorders characterized by protein misfolding, oxidative stress, and neuroinflammation, finally resulting in neuronal loss and cognitive dysfunctions. Nowadays, an attractive strategy to improve the classical treatments is the development of multitarget-directed molecules able to synergistically interact with different enzymes and/or receptors. A novel series of chiral carbamate and carbamothioate derivatives were designed, synthesized, and investigated as inhibition of cholinesterases and monoamine oxidases, anti-β-amyloid aggregation and antioxidant activities against Alzheimer's disease. The enzymatic activity of butyrylcholinesterase (BChE) in the brain increases with the progression of Alzheimer's disease, thus classifying BChE as a promising drug target in advanced Alzheimer's disease. Two compounds, 4a-S and 4a-R, showed excellent and selective inhibitory activities against BChE (IC: 0.051 μM; IC: 0.059 μM). Compound 4a-S also exhibited selective hMAO-B (IC = 0.45 ± 0.02 μM) inhibitory activities. The molecular docking and dynamic simulations of compounds 4a-R and 4a-S in human BChE revealed that the piperidine and propargyl groups play crucial roles for the inhibition. Compound 1d-R had the greatest ability to hMAO-B inhibition (IC = 0.09 μM). Compound 2b exhibited significant ability to inhibit self-induced β-amyloid (Aβ; IC: 0.97 μM). Achiral carbamate derivatives 2c, 2j and 2a act as potential antioxidants. Among the compounds, 2c, 2i, 2j, 4a-S were selected for the PAMPA-BBB test. These compounds demonstrated excellent penetration into the central nervous system. Compounds 1d-R, 2b, 2c, 4a-S and 4a-R were assessed in vivo with Aluminium chloride induced Alzheimer mice model. Compounds 1d-R, 2b, and 4a-S increased learning according to Morris Water Maze test. Our preliminary findings may open-up the way for developing innovative carbamate and carbamothioate derivatives against neurodegenerative diseases.
神经退行性疾病是多因素疾病，其特征在于蛋白质错误折叠、氧化应激和神经炎症，最终导致神经元丧失和认知功能障碍。如今，一种改进传统治疗方法的有吸引力的策略是开发能够与不同酶和/或受体协同相互作用的多靶点导向分子。设计、合成并研究了一系列新型手性氨基甲酸酯和氨基甲硫酯衍生物，以抑制胆碱酯酶和单胺氧化酶、抗β-淀粉样蛋白聚集以及针对阿尔茨海默病的抗氧化活性。随着阿尔茨海默病的进展，大脑中丁酰胆碱酯酶（BChE）的酶活性增加，因此将BChE归类为晚期阿尔茨海默病中有前景的药物靶点。两种化合物，4a-S和4a-R，对BChE表现出优异的选择性抑制活性（IC：0.051 μM；IC：0.059 μM）。化合物4a-S还表现出选择性hMAO-B（IC = 0.45 ± 0.02 μM）抑制活性。化合物4a-R和4a-S在人BChE中的分子对接和动力学模拟表明，哌啶和炔丙基对抑制起关键作用。化合物1d-R对hMAO-B的抑制能力最强（IC = 0.09 μM）。化合物2b表现出显著的抑制自身诱导的β-淀粉样蛋白（Aβ；IC：0.97 μM）的能力。非手性氨基甲酸酯衍生物2c、2j和2a作为潜在的抗氧化剂。在这些化合物中，选择2c、2i、2j、4a-S进行PAMPA-BBB测试。这些化合物表现出优异的中枢神经系统渗透性。用氯化铝诱导的阿尔茨海默病小鼠模型对化合物1d-R、2b、2c、4a-S和4a-R进行体内评估。根据莫里斯水迷宫测试，化合物1d-R、2b和4a-S提高了学习能力。我们的初步研究结果可能为开发针对神经退行性疾病的创新氨基甲酸酯和氨基甲硫酯衍生物开辟道路。
