Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Faculty of Pharmacy, Medical University of Lodz, Muszyńskiego 1, 90-151 Lodz, Poland.
Department of Medicinal Chemistry, Faculty of Pharmacy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland.
Int J Mol Sci. 2020 May 26;21(11):3765. doi: 10.3390/ijms21113765.
A series of new tetrahydroacridine and 3,5-dichlorobenzoic acid hybrids with different spacers were designed, synthesized, and evaluated for their ability to inhibit both cholinesterase enzymes. Compounds , , , and exhibited selective butyrylcholinesterase (BuChE) inhibition with IC values ranging from 24 to 607 nM. Among them, compound 3b was the most active (IC = 24 nM). Additionally, 3c (IC for AChE = 25 nM and IC for BuChE = 123 nM) displayed dual cholinesterase inhibitory activity and was the most active compound against acetylcholinesterase (AChE). Active compound 3c was also tested for the ability to inhibit Aβ aggregation. Theoretical physicochemical properties of the compounds were calculated using ACD Labs Percepta and Chemaxon. A Lineweaver-Burk plot and docking study showed that 3c targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Moreover, 3c appears to possess neuroprotective activity and could be considered a free-radical scavenger. In addition, 3c did not cause DNA damage and was found to be less toxic than tacrine after oral administration; it also demonstrated little inhibitory activity towards hyaluronidase (HYAL), which may indicate that it possesses anti-inflammatory properties. The screening for new in vivo interactions between 3c and known receptors was realized by yeast three-hybrid technology (Y3H).
一系列具有不同间隔基的新型四氢吖啶和 3,5-二氯苯甲酸杂合体被设计、合成并评估了它们抑制两种胆碱酯酶的能力。化合物 、 、 、 和 对丁酰胆碱酯酶（BuChE）表现出选择性抑制，IC 值范围为 24 至 607 nM。其中，化合物 3b 最为活跃（IC = 24 nM）。此外，3c（对 AChE 的 IC = 25 nM 和对 BuChE 的 IC = 123 nM）表现出双重胆碱酯酶抑制活性，是对乙酰胆碱酯酶（AChE）最活跃的化合物。活性化合物 3c 还被测试了抑制 Aβ 聚集的能力。使用 ACD Labs Percepta 和 Chemaxon 计算了化合物的理论物理化学性质。Lineweaver-Burk 图和对接研究表明，3c 靶向 AChE 的催化活性位点（CAS）和外周阴离子位点（PAS）。此外，3c 似乎具有神经保护活性，可以被认为是自由基清除剂。此外，3c 不会引起 DNA 损伤，且经口给药后毒性低于他克林；它对透明质酸酶（HYAL）的抑制活性也较小，这可能表明它具有抗炎特性。通过酵母三杂交技术（Y3H）实现了 3c 与已知受体之间新的体内相互作用的筛选。
