Chandran Namitha, Lee Jiseong, Prabhakaran Prabitha, Kumar Sunil, Sudevan Sachithra Thazhathuveedu, Parambi Della Grace Thomas, Alsahli Tariq G, Pant Manu, Kim Hoon, Mathew Bijo
Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, 682041, India.
Department of Pharmacy, College of Pharmacy, Sunchon National University, Suncheon, 57922, Republic of Korea.
Sci Rep. 2024 Dec 28;14(1):31292. doi: 10.1038/s41598-024-82771-3.
Sixteen thio/semicarbazide-based benzyloxy derivatives (BT1-BT16) were synthesized and evaluated for their inhibitory activities against monoamine oxidases (MAOs). Most compounds showed better inhibitory activity against MAO-B than against MAO-A. BT1, BT3, and BT5 showed the greatest inhibitory activity with an identical IC value of 0.11 µM against MAO-B, followed by BT6 and BT7 (IC = 0.12 µM) and BT2 (IC = 1.68 µM). The selectivity index of BT5 was the highest (363.64) for MAO-B, whereas that of BT1 was 88.73. BT1 and BT5 were reversible MAO-B inhibitors, based on the results of dialysis experiments. In inhibition kinetics, BT1 and BT5 were competitive MAO-B inhibitors with K values of 0.074 ± 0.0020 and 0.072 ± 0.0079 µM, respectively. Additionally, in the in-vitro parallel artificial membrane penetration assay, BT1 and BT5 crossed the blood-brain barrier. Cytotoxicity and possible neuroprotective effects of the lead compounds were assessed using IMR 32 cells. Levels of the antioxidant superoxide dismutase, catalase, and glutathione peroxidase in IMR 32 cells were increased by pretreatment with lead compounds. Five lead molecules (BT1, BT3, BT5, BT6, and BT7) were used for the docking studies. A significant pi-pi interaction with Tyr 326 was observed and molecular dynamics studies were performed for the most promising BT1-MAO-B complex. These results suggested that BT1 and BT5 could be used therapeutically for the treatment of various neurodegenerative diseases.
合成了16种基于硫代/氨基脲的苄氧基衍生物（BT1 - BT16），并评估了它们对单胺氧化酶（MAO）的抑制活性。大多数化合物对MAO - B的抑制活性比对MAO - A的更好。BT1、BT3和BT5对MAO - B表现出最大的抑制活性，其IC值相同，均为0.11 μM，其次是BT6和BT7（IC = 0.12 μM）以及BT2（IC = 1.68 μM）。BT5对MAO - B的选择性指数最高（363.64），而BT1的为88.73。基于透析实验结果，BT1和BT5是可逆的MAO - B抑制剂。在抑制动力学中，BT1和BT5是竞争性的MAO - B抑制剂，K值分别为0.074 ± 0.0020和0.072 ± 0.0079 μM。此外，在体外平行人工膜渗透试验中，BT1和BT5能够穿过血脑屏障。使用IMR 32细胞评估了先导化合物的细胞毒性和可能的神经保护作用。用先导化合物预处理可提高IMR 32细胞中抗氧化超氧化物歧化酶、过氧化氢酶和谷胱甘肽过氧化物酶的水平。使用5种先导分子（BT1、BT3、BT5、BT6和BT7）进行对接研究。观察到与Tyr 326有显著的π - π相互作用，并对最有前景的BT1 - MAO - B复合物进行了分子动力学研究。这些结果表明，BT1和BT5可用于治疗各种神经退行性疾病。
