论文部分内容阅读
本文在先前的虚拟筛选发现的命中化合物B51 (IC50 =37.4 μM)的结构基础上,设计并合成了一系列新型甲基异噁唑/异噻唑衍生物类BACE1抑制剂.分子对接结果显示,将B51结构中的氰基嘧啶酮片段转化为甲基异恶唑/异噻唑,同时缩短连接氰基嘧啶酮环和酰胺键另一侧咪唑环之间的连接链长度,可以使分子与BACE1的S1’和S2’口袋的契合程度更好,从而提高活性.因此本文设计合成了20个甲基异噁唑/异噻唑类衍生物并对其抑制BACEl酶活性进行了初步构效关系研究.在这些化合物中,5t显示出比B51提高了近10倍的效力.SPR实验结果显示,其与BACE1结合动力学呈现“快结合,慢解离”的特征.所获得的活性甲基异噻唑类化合物分子量小,对正常细胞安全无毒,经PAMPA实验测试具有透过BBB的可能,可作为BACE1抑制剂类抗AD药物设计的新结构骨架.“,”Based on the structure of compound B51 (IC50 =37.4 μM),which was discovered as hit in a previous virtual screen,a series of methylisoxazole/isothiazole amide derivatives were designed and synthesized as BACE1 inhibitors.The methoxyphenylpyrimidone fragment of B51 was transformed into a methoxyphenylmethylisoxazole/isothiazole moiety to reduce the molecular weight while retaining the ability to fit into the S1’and S2’subpocket of BACE1 as predicted by docking studies.The effects of BACE1 inhibition and the structure-activity relationships were analyzed.Among all 20 designed compounds,5t exhibited almost 10-fold improved potency (IC50 =5.33 μM) compared to B51 in the BACE1 inhibition assay.Additionally,it has exhibited “rapid binding,slow dissociation” kinetics in SPR analysis,suggesting a longer inhibitory effect than B51.All acquired methylisoxazole/isothiazole derivatives were small in size and safe to normal cells,which allow them represent a novel scaffold for BACEI inhibitor design.