Institute for Medical Research and Occupational Health, Ksaverska cesta 2, 10000, Zagreb, Croatia.
University of Belgrade, Institute of Chemistry, Technology and Metallurgy, Studentski trg 12-16, 11000, Beograd, Serbia; Centre of Excellence in Environmental Chemistry and Engineering, ICTM, 11000, Belgrade, Serbia.
Chem Biol Interact. 2023 Sep 1;382:110620. doi: 10.1016/j.cbi.2023.110620. Epub 2023 Jul 3.
The most successful therapeutic strategy in the treatment of Alzheimer's disease (AD) is directed toward increasing levels of the neurotransmitter acetylcholine (ACh) by inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), the enzymes responsible for its hydrolysis. In this paper, we extended our study on 4-aminoquinolines as human cholinesterase inhibitors on twenty-six new 4-aminoquinolines containing an n-octylamino spacer on C(4) and different substituents on the terminal amino group. We evaluated the potency of new derivatives to act as multi-targeted ligands by determining their inhibition potency towards human AChE and BChE, ability to chelate biometals Fe, Cu and Zn, ability to inhibit the action of β-secretase 1 (BACE1) and their antioxidant capacity. All of the tested derivatives were very potent inhibitors of human AChE and BChE with inhibition constants (K) ranging from 0.0023 to 1.6 μM. Most of the compounds were estimated to be able to cross the blood-brain barrier (BBB) by passive transport and were nontoxic to human neuronal, kidney and liver cells in concentrations in which they inhibit cholinesterases. Generally, newly synthesised compounds were weak reductants compared to standard antioxidants, but all possessed a certain amount of antioxidant activity compared to tacrine. Of the eleven most potent cholinesterase inhibitors, eight compounds also inhibited BACE1 activity at 10-18%. Based on our overall results, compounds 8 with 3-fluorobenzyl, 11 with 3-chlorobenzyl and 17 with 3-metoxy benzyl substituents on the terminal amino group stood out as the most promising for the treatment of AD; they strongly inhibited AChE and BChE, were non-toxic on HepG2, HEK293 and SH-SY5Y cells, had the potential to cross the BBB and possessed the ability to chelate biometals and/or inhibit the activity of BACE1 within a range close to the therapeutically desired degree of inhibition.
最成功的治疗阿尔茨海默病（AD）的治疗策略是通过抑制乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）来增加神经递质乙酰胆碱（ACh）的水平，这两种酶负责其水解。在本文中，我们将 4-氨基喹啉作为人类胆碱酯酶抑制剂的研究扩展到了 26 种新的 4-氨基喹啉上，这些喹啉在 C（4）上含有一个正辛基氨基间隔基，在末端氨基上有不同的取代基。我们通过测定它们对人乙酰胆碱酯酶和丁酰胆碱酯酶的抑制能力、与生物金属 Fe、Cu 和 Zn 的螯合能力、抑制β-分泌酶 1（BACE1）的能力以及它们的抗氧化能力，评估了新衍生物作为多靶点配体的效力。所有测试的衍生物都是人类乙酰胆碱酯酶和丁酰胆碱酯酶的非常有效的抑制剂，其抑制常数（K）范围从 0.0023 到 1.6 μM。大多数化合物被估计能够通过被动转运穿过血脑屏障（BBB），并且在抑制胆碱酯酶的浓度下对人神经元、肾和肝细胞没有毒性。一般来说，与标准抗氧化剂相比，新合成的化合物是较弱的还原剂，但与他克林相比，所有化合物都具有一定的抗氧化活性。在 11 种最有效的胆碱酯酶抑制剂中，有 8 种化合物在 10-18%的浓度下也抑制了 BACE1 的活性。根据我们的综合结果，在末端氨基上具有 3-氟苄基、11-3-氯苄基和 17-3-甲氧基苄基取代基的化合物 8、11 和 17 作为 AD 治疗的最有前途的化合物脱颖而出；它们强烈抑制乙酰胆碱酯酶和丁酰胆碱酯酶，对 HepG2、HEK293 和 SH-SY5Y 细胞无毒，有穿过血脑屏障的潜力，并且具有螯合生物金属和/或抑制 BACE1 活性的能力，其抑制程度接近治疗所需的程度。
