Komatović Katarina, Matošević Ana, Terzić-Jovanović Nataša, Žunec Suzana, Šegan Sandra, Zlatović Mario, Maraković Nikola, Bosak Anita, Opsenica Dejan M
Faculty of Chemistry, University of Belgrade, Studentski trg 16, 11000 Belgrade, Serbia.
Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10 000 Zagreb, Croatia.
Pharmaceutics. 2022 Jun 20;14(6):1305. doi: 10.3390/pharmaceutics14061305.
Considering that acetylcholinesterase (AChE) inhibition is the most important mode of action expected of a potential drug used for the treatment of symptoms of Alzheimer's disease (AD), our previous pilot study of 4-aminoquinolines as potential human cholinesterase inhibitors was extended to twenty-two new structurally distinct 4-aminoquinolines bearing an adamantane moiety. Inhibition studies revealed that all of the compounds were very potent inhibitors of AChE and butyrylcholinesterase (BChE), with inhibition constants () ranging between 0.075 and 25 µM. The tested compounds exhibited a modest selectivity between the two cholinesterases; the most selective for BChE was compound , which displayed a 10 times higher preference, while compound was a 5.8 times more potent inhibitor of AChE. Most of the compounds were estimated to be able to cross the blood-brain barrier (BBB) by passive transport. Evaluation of druglikeness singled out fourteen compounds with possible oral route of administration. The tested compounds displayed modest but generally higher antioxidant activity than the structurally similar AD drug tacrine. Compound showed the highest reducing power, comparable to those of standard antioxidants. Considering their simple structure, high inhibition of AChE and BChE, and ability to cross the BBB, 4-aminoquinoline-based adamantanes show promise as structural scaffolds for further design of novel central nervous system drugs. Among them, two compounds stand out: compound as the most potent inhibitor of both cholinesterases with a constant in low nano molar range and the potential to cross the BBB, and compound , which met all our requirements, including high cholinesterase inhibition, good oral bioavailability, and antioxidative effect. The QSAR model revealed that AChE and BChE inhibition was mainly influenced by the ring and topological descriptors MCD, Nnum, RP, and RSIpw3, which defined the shape, conformational flexibility, and surface properties of the molecules.
鉴于乙酰胆碱酯酶（AChE）抑制作用是用于治疗阿尔茨海默病（AD）症状的潜在药物预期的最重要作用方式，我们先前对作为潜在人类胆碱酯酶抑制剂的4-氨基喹啉的初步研究扩展至二十二种新的结构不同的带有金刚烷部分的4-氨基喹啉。抑制研究表明，所有化合物都是AChE和丁酰胆碱酯酶（BChE）的非常有效的抑制剂，抑制常数（）介于0.075和25μM之间。测试的化合物在两种胆碱酯酶之间表现出适度的选择性；对BChE最具选择性的是化合物，其偏好性高10倍，而化合物是AChE的强效抑制剂，效力高5.8倍。大多数化合物估计能够通过被动转运穿过血脑屏障（BBB）。类药性质评估选出了十四种可能具有口服给药途径的化合物。测试的化合物显示出适度但通常比结构相似的AD药物他克林更高的抗氧化活性。化合物表现出最高的还原能力，与标准抗氧化剂相当。考虑到它们的简单结构、对AChE和BChE的高抑制作用以及穿过BBB的能力，基于4-氨基喹啉的金刚烷作为新型中枢神经系统药物进一步设计的结构骨架显示出前景。其中，两种化合物脱颖而出：化合物是两种胆碱酯酶的最有效抑制剂，抑制常数在低纳摩尔范围内，并且有可能穿过BBB；化合物满足了我们所有的要求，包括高胆碱酯酶抑制作用、良好的口服生物利用度和抗氧化作用。QSAR模型表明，AChE和BChE抑制作用主要受环和拓扑描述符MCD、Nnum、RP和RSIpw3的影响，这些描述符定义了分子的形状、构象灵活性和表面性质。
