Evranos-Aksoz Begum, Ucar Gulberk, Tas Sadik Taskin, Aksoz Erkan, Yelekci Kemal, Erikci Acelya, Sara Yildirim, Iskit Alper Bektas
Medicines and Medical Devices Agency, Analyses and Control Laboratories, Sıhhiye 06100, Ankara, Turkey.
Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, Sıhhıye 06100, Ankara, Turkey.
Comb Chem High Throughput Screen. 2017;20(6):461-473. doi: 10.2174/1386207320666170504113158.
Depression is a momentous disease that can greatly reduce the quality of life and cause death. In depression, neurotransmitter levels such as serotonine, dopamine and noradrenaline are impaired. Monoamine oxidases (MAO) are responsible for oxidative catalysis of these monoamine neurotransmitters. Because of this relation, MAO-A inhibitors show antidepressant activity by regulating neurotransmitter levels. This study was carried out to investigate the design, synthesis and activity of new antidepressant compounds in pyrazoline and hydrazone structure.
Chalcones and hydrazides were heated under reflux to give new pyrazoline and hydrazone derivatives. Docking simulations were performed using AutoDock4.2. hMAO activities were determined by a fluorimetric method. To determine cell viability, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used. Behavioral activities of the three compounds were determined by using Forced Swim Test, Step-Through Passive Avoidance Test, Elevated Plus Maze and Open Field Arena Tests.
According to in vitro tests, all of the synthesized compounds were found more potent than moclobemide and six of the synthesized compounds were found more selective than moclobemide. Three of the synthesized compounds were investigated for their behavioral activities comparing with moclobemide after 7 days of i.p. treatment at 30 mg/kg. One of the three compounds elicited significant antidepressant properties.
All of the synthesized compounds were found potent hMAO-A inhibitors in in vitro screening tests. Only one of the in vivo tested three compounds, (3-(2-hydroxy-5-methylphenyl)-5- p-tolyl-4,5-dihydropyrazol-1-yl)(pyridin-4-yl) methanone indicated significant antidepressant activity. This article opens a window for further development of new pyrazoline and hydrazone derivatives as antidepressant agents.
抑郁症是一种严重的疾病，会极大地降低生活质量并导致死亡。在抑郁症中，血清素、多巴胺和去甲肾上腺素等神经递质水平会受损。单胺氧化酶（MAO）负责这些单胺神经递质的氧化催化。由于这种关系，MAO - A抑制剂通过调节神经递质水平显示出抗抑郁活性。本研究旨在研究具有吡唑啉和腙结构的新型抗抑郁化合物的设计、合成及活性。
将查尔酮和酰肼在回流条件下加热，得到新型吡唑啉和腙衍生物。使用AutoDock4.2进行对接模拟。通过荧光法测定人MAO活性。使用3 -（4,5 - 二甲基噻唑 - 2 - 基）- 2,5 - 二苯基四氮唑溴盐（MTT）试验来测定细胞活力。通过强迫游泳试验、穿梭箱被动回避试验、高架十字迷宫试验和旷场试验来测定这三种化合物的行为活性。
根据体外试验，发现所有合成化合物均比吗氯贝胺更有效，且六种合成化合物比吗氯贝胺更具选择性。在以30mg/kg腹腔注射治疗7天后，对三种合成化合物与吗氯贝胺的行为活性进行了比较研究。这三种化合物中的一种表现出显著的抗抑郁特性。
在体外筛选试验中，发现所有合成化合物均为有效的人MAO - A抑制剂。在体内试验的三种化合物中，只有一种，即（3 -（2 - 羟基 - 5 - 甲基苯基）- 5 - 对甲苯基 - 4,5 - 二氢吡唑 - 1 - 基）（吡啶 - 4 - 基）甲酮表现出显著的抗抑郁活性。本文为进一步开发新型吡唑啉和腙衍生物作为抗抑郁药打开了一扇窗口。
