Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan.
Department of Pharmacy, Abdul Wali Khan University, Mardan, Pakistan.
Drug Dev Res. 2019 Aug;80(5):595-605. doi: 10.1002/ddr.21537. Epub 2019 Apr 9.
Novel bioactive compounds as synthetic analogs of the potent herbal medicines can be optimized as potential drug candidates for various neurologic disorders. This study was performed to investigate the newly synthesized dibenzylidene ketone derivatives: (2E,6E)-2,6-dibenzylidene cyclohexanone (A1K1) and (1E,4E)-5-(2,3-dichlorophenyl)-1-(4-methoxyphenyl)-2-methylpenta-1,4-diene-3-one (A2K2) and evaluate its potential anti-Alzheimer's and anti-depressant properties. Both the derivatives are chemically characterized by using HNMR and CNMR techniques. Auto Dock Vina program was used to investigate ligand-protein affinity. Forced swim test, tail suspension test, open field test, Y-maze test, and Morris water maze test (MWM) models were employed to evaluate anti-depressant and anti-Alzheimer's activity of dibenzylidene ketone derivatives in mice. Both A1K1 and A2K2 showed high binding affinities against various proteins involved in depression and Alzheimer's mechanisms like monoamine oxidase B, acetylcholinesterase, norepinephrine transporter 2, serotonin transporter, dopamine receptor, serotonin receptor modulator, and beta-amyloid targets. A1K1 and A2K2 dose-dependently (0.1-1 mg/kg) decreased immobility time, while increased swimming and climbing time of mice in forced swim test (FST). A1K1 and A2K2 decreased animal immobility time in TST. In the open field test, both A1K1 and A2K2 increased the number of ambulations and rearings. A1K1 and A2K2 dose-dependently (0.5-1.0 mg/kg) increased spontaneous alternation behavior (%) and the number of entries of mice in Y-maze test. In the MWM test, A1K1 and A2K2 decreased escape latency time. Overall, both in-silico and in-vivo investigations of A1K1 and A2K2, report their therapeutic potential for antidepressant and anti-Alzheimer properties. Hence, these compounds possess potent neuroprotective properties and may be further evaluated for their therapeutic potential in various neurological disorders.
新型生物活性化合物作为强效草药的合成类似物，可以被优化为治疗各种神经紊乱的潜在药物候选物。本研究旨在研究新合成的二苄基甲酮衍生物：（2E,6E）-2,6-二苄基环己酮（A1K1）和（1E,4E）-5-（2,3-二氯苯基）-1-（4-甲氧基苯基）-2-甲基戊-1,4-二烯-3-酮（A2K2），并评估其潜在的抗阿尔茨海默病和抗抑郁特性。这两种衍生物均通过 HNMR 和 CNMR 技术进行化学表征。Auto Dock Vina 程序用于研究配体-蛋白亲和力。强迫游泳试验、悬尾试验、旷场试验、Y 迷宫试验和 Morris 水迷宫试验（MWM）模型用于评估二苄基甲酮衍生物在小鼠中的抗抑郁和抗阿尔茨海默病活性。A1K1 和 A2K2 均对涉及抑郁和阿尔茨海默病机制的多种蛋白质表现出高结合亲和力，如单胺氧化酶 B、乙酰胆碱酯酶、去甲肾上腺素转运体 2、血清素转运体、多巴胺受体、血清素受体调节剂和β-淀粉样蛋白靶标。A1K1 和 A2K2 剂量依赖性（0.1-1mg/kg）降低了强迫游泳试验（FST）中小鼠的不动时间，同时增加了游泳和攀爬时间。A1K1 和 A2K2 降低了 TST 中小鼠的不动时间。在旷场试验中，A1K1 和 A2K2 均增加了动物的走动和后肢次数。A1K1 和 A2K2 剂量依赖性（0.5-1.0mg/kg）增加了 Y 迷宫试验中小鼠的自发交替行为（%）和进入次数。在 MWM 试验中，A1K1 和 A2K2 降低了逃避潜伏期时间。总的来说，A1K1 和 A2K2 的体内外研究报告了它们在抗抑郁和抗阿尔茨海默病方面的治疗潜力。因此，这些化合物具有潜在的神经保护特性，可能会进一步评估它们在各种神经紊乱中的治疗潜力。
