Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye, Ankara, Turkey.
Turkish Medicines and Medical Devices Agency, Analyses and Control Laboratories, 06100 Ankara, Turkey.
J Med Chem. 2021 Feb 25;64(4):1989-2009. doi: 10.1021/acs.jmedchem.0c01504. Epub 2021 Feb 3.
Thirty compounds having 1-[2-(5-substituted-2-benzoxazolinone-3-yl) acetyl]-3,5-disubstitutedphenyl-2-pyrazoline structure and nine compounds having '-(1,3-disubstitutedphenylallylidene)-2-(5-substituted-2-benzoxazolinone-3-yl)acetohydrazide skeleton were synthesized and evaluated as monoamine oxidase (MAO) inhibitors. All of the compounds exhibited selective MAO-A inhibitor activity in the nanomolar or low micromolar range. The results of the molecular docking for hydrazone derivatives supported the results. Five compounds, (0.008 μM, Selectivity Index (SI): 9.70 × 10), (0.009 μM, SI: 4.55 × 10), (0.001 μM, SI: 8.00 × 10), (0.009 μM, SI: 1.37 × 10), and (0.010 μM, SI: 5.40 × 10), exhibiting the highest inhibition and selectivity toward hMAO-A and nontoxic to hepatocytes were assessed for antidepressant activity as acute and subchronic in mice. All of these five compounds showed significant antidepressant activity with subchronic administration consistent with the increase in the brain serotonin levels and the compounds crossed the blood-brain barrier according to parallel artificial membrane permeation assay. Compounds , and exhibited an MAO-A profile, which is highly consistent with the data.
合成了 30 种具有 1-[2-(5-取代-2-苯并恶唑啉酮-3-基)乙酰基]-3,5-二取代苯基-2-吡唑啉结构的化合物和 9 种具有'-(1,3-二取代苯基丙烯酰基)-2-(5-取代-2-苯并恶唑啉酮-3-基)乙二酰肼骨架的化合物，并将它们作为单胺氧化酶（MAO）抑制剂进行了评估。所有化合物均在纳摩尔或低微摩尔范围内表现出对 MAO-A 的选择性抑制活性。肼衍生物的分子对接结果支持了这一结果。5 种化合物， （0.008 μM，选择性指数（SI）：9.70 × 10）， （0.009 μM，SI：4.55 × 10）， （0.001 μM，SI：8.00 × 10）， （0.009 μM，SI：1.37 × 10）和 （0.010 μM，SI：5.40 × 10），对 hMAO-A 的抑制作用最高且选择性最强，对肝细胞无毒性，被评估为急性和亚慢性抗抑郁作用。所有这 5 种化合物在亚慢性给药时均表现出显著的抗抑郁作用，与脑内 5-羟色胺水平的升高一致，并且根据平行人工膜渗透测定，这些化合物均能穿过血脑屏障。化合物 、 和 表现出与 数据高度一致的 MAO-A 特征。
