2’,4’,6’-三羟基查尔酮衍生物合成及抗抑郁活性研究

Synthesis and studies on antidepressant activity of 2',4',6'-trihydroxychalcone derivatives

目的本文设计合成了11个2’,4’,6’-三羟基查尔酮衍生物,并对所合成的目标化合物进行抗抑郁活性研究,探讨其可能的作用机制。方法以2’,4’,6’-三羟基苯乙酮为起始原料。经过羟基保护、醇醛缩合、水解三步反应得到目标化合物3a^3k。其结构经IR、1H-NMR和MS等确证。对所合成的目标化合物采用经典抗抑郁模型"小鼠强迫游泳实验"和"小鼠悬尾实验"进行抗抑郁活性研究。采用开放性实验评价化合物3h抗抑郁活性。建立5-羟色氨酸(5-HTP)诱导小鼠甩头和育亨宾小鼠致死增强模型,观察化合物3h对诱导小鼠甩头行为和对小鼠皮下注射(sc)育亨宾致死增强的影响。结果实验结果表明有6个化合物在10 mg/kg剂量下均能明显缩短小鼠强迫游泳不动时间,初步断定其具有抗抑郁活性。其中化合物3h显示最好抗抑郁活性,与氟西汀相似。另外化合物3h在3种不同剂量下(10 mg/kg、20 mg/kg和40 mg/kg)均明显缩短小鼠强迫游泳和小鼠悬尾的不动时间,显示较强的抗抑郁活性,其中在20 mg/kg剂量下显示抗抑郁活性最好。化合物3h也能显著增加5-HTP诱导的小鼠甩头次数,对育亨宾诱导的小鼠致死量没有显著影响。结论 6个查尔酮化合物显示具有明确的抗抑郁作用,其作用机制可能与5-HT系统有关。

Objective To synthesize 2＇ ,4＇ ,6＇ -trihydroxychalcone derivatives and study their antidepressant activity and mechanism. Methods The 2＇ ,4＇ ,6＇-trihydroxyacetophenone was used as the starting material;by hydroxyl protection, alodl condensation reaction and hydrolysis reactions ,we get the target compounds 3a- 3k, its structure was confirmed by IR, 1HNMR and MS. The antidepressant activities of the target compounds were evaluated by using the forced swim test （FST） and tail suspension test（TST） in rats. The 5-HTP induced head-twitch and yohimbine-induced lethality tests were used to observe the impact of the synthesized compound 3h on the head-twitch and yohimbine-induced lethality in mice. Results The resuhs showed that all six compounds significantly reduced the immobihty times during the FST at a dose of 10 mg/kg,indicative of antidepressant activity. The compound 3h showed the most antidepressant activity. In addition, compound 3h showed antidepressant activity at three doses of 10 mg/kg,20 mg/kg and 40 mg/kg, significantly reduced immobility times in FST and TST in mice. It was found to be the most antidepressant activity at 20 mg/kg. The compound 3h increased the head-twitch and had not raised the mortality of mice. Conclusion Six compounds showed significantly the antidepressant activity. The mechanism may be related to the system of 5-HT in central nervous system.