3′,4′-亚乙二氧基查尔酮类MAO-B抑制剂的设计、合成及活性评价  

Design,Synthesis and Evaluation of 3′,4′-Ethylendioxy Chalcone Derivatives as Potent Monoamine Oxidase B Inhibitors

作　　者：孔卓 孙德萌 江艳梅 胡云 KONG Zhuo;SUN Demeng;JIANG Yanmei;HU Yun(School of Bioengineering,Zunyi Medical University,Zhuhai 519041,China)

机构地区：[1]遵义医科大学生物工程学院,广东珠海519041

出　　处：《中国药学杂志》2024年第22期2116-2125,共10页Chinese Pharmaceutical Journal

基　　金：国家自然科学基金项目资助(81560562,21762055)。

摘　　要：目的设计合成一类3′,4′-亚乙二氧基查尔酮类衍生物作为单胺氧化酶B(MAO-B)抑制剂。方法通过Claisen-Schmidt缩合反应,合成目标化合物,测定其对人的单胺氧化酶(hMAO-B)的抑制作用。分析活性化合物抑制hMAO-B的选择性、作用类型和可逆性。探讨活性化合物与hMAO-B的结合模式。评价活性化合物对小鼠BV2细胞的增殖抑制作用。结果成功合成16个化合物。多数化合物对hMAO-B具有良好的抑制活性和选择性,代表性化合物9和13的IC50值分别为0.021和0.042μmol·L-1。二者均为MAO-B的竞争型可逆性抑制剂,与hMAO-B的结合作用力主要为疏水作用力和氢键。活性最好的化合物9对小鼠BV2小胶质细胞株表现出较低水平的细胞毒性。结论3′,4′-亚乙二氧基查尔酮类化合物是一类高效的hMAO-B抑制剂,具有进一步研究价值。OBJECTIVE To design,synthesize and evaluate a series of 3′,4′-ethylendioxy chalcone derivatives as monoamine oxidase B(MAO-B)inhibitors,and summarize the structure-activity relationship(SAR).METHODS The targeted compounds were synthesized via Claisen-Schmidt condensation reaction starting from 6-acetyl-1,4-benzodioxan and corresponding benzaldehydes.The inhibition of these compounds on human MAO-B(hMAO-B)was determined,and the inhibiting selectivity,dynamics and reversibility were investigated as well.The binding mode between active compounds and hMAO-B was revealed by molecular docking study.Additionally,the inhibitory effect of active compounds on the proliferation of BV2 cell line was determined by MTT assay.RESULTS Sixteen targeted compounds were successfully prepared.Most compounds showed good inhibitory effects on hMAO-B.Representative compounds 9 and 13 exhibited IC50 values of 0.021 and 0.042μmol·L-1,respectively,which showed high inhibiting selectivity towards hMAO-B.Both compounds acted as competitive and reversible hMAO-B inhibitors.The main interactions between active compounds and hMAO-B were hydrophobic interaction and hydrogen bond.The most active compound 9 exhibited low cytotoxicity in BV2 cells.CONCLUSION This class of 3′,4′-ethylendioxy chalcone derivatives represent potential novel inhibitors of hMAO-B,and compound 9 could be further investigated as a potent lead for future studies.

关 键 词：神经退行性疾病 单胺氧化酶B抑制剂 查尔酮 构效关系 

分 类 号：R914[医药卫生—药物化学]