Leong Sze Wei, Abas Faridah, Lam Kok Wai, Shaari Khozirah, Lajis Nordin H
Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.
Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia; Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.
Bioorg Med Chem. 2016 Aug 15;24(16):3742-51. doi: 10.1016/j.bmc.2016.06.016. Epub 2016 Jun 9.
In the present study, a series of 2-benzoyl-6-benzylidenecyclohexanone analogs have been synthesized and evaluated for their anti-cholinesterase activity. Among the forty-one analogs, four compounds (38, 39, 40 and 41) have been identified as lead compounds due to their highest inhibition on both AChE and BChE activities. Compounds 39 and 40 in particular exhibited highest inhibition on both AChE and BChE with IC50 values of 1.6μM and 0.6μM, respectively. Further structure-activity relationship study suggested that presence of a long-chain heterocyclic in one of the rings played a critical role in the dual enzymes' inhibition. The Lineweaver-Burk plots and docking results suggest that both compounds could simultaneously bind to the PAS and CAS regions of the enzyme. ADMET analysis further confirmed the therapeutic potential of both compounds based upon their high BBB-penetrating. Thus, 2-benzoyl-6-benzylidenecyclohexanone containing long-chain heterocyclic amine analogs represent a new class of cholinesterase inhibitor, which deserve further investigation for their development into therapeutic agents for cognitive diseases such as Alzheimer.
在本研究中，合成了一系列2-苯甲酰基-6-亚苄基环己酮类似物，并对其抗胆碱酯酶活性进行了评估。在41种类似物中，有4种化合物（38、39、40和41）因其对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）活性的最高抑制作用而被确定为先导化合物。特别是化合物39和40对AChE和BChE均表现出最高抑制作用，其半数抑制浓度（IC50）值分别为1.6μM和0.6μM。进一步的构效关系研究表明，其中一个环中存在长链杂环在双重酶抑制中起关键作用。Lineweaver-Burk图和对接结果表明，这两种化合物都能同时结合到酶的外周阴离子位点（PAS）和催化活性位点（CAS）区域。药物代谢动力学（ADMET）分析进一步证实了这两种化合物基于其高血脑屏障穿透性的治疗潜力。因此，含有长链杂环胺类似物的2-苯甲酰基-6-亚苄基环己酮代表了一类新型胆碱酯酶抑制剂，值得进一步研究以开发成治疗阿尔茨海默病等认知疾病的治疗药物。
