含吡唑甲酰胺结构的硫醇类HDAC6抑制剂的设计、合成及神经保护作用研究  

Design,synthesis and neuroprotective effect of thiol HDAC6 inhibitors containing pyrazolformamide

作　　者：秦汉 罗美迪 王思远 赵临襄[1] 闻家辰[1] 刘丹[1] QIN Han;LUO Meidi;WANG Siyuan;ZHAO Linxiang;WEN Jiachen;LIU Dan(Key Laboratory of Structure-Based Drug Design and Discovery(Shenyang Pharmaceutical University),Ministry of Education,Shenyang 110016,China)

机构地区：[1]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016

出　　处：《中国药物化学杂志》2024年第6期421-433,共13页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(81473086);沈阳药科大学“优青”托举计划项目(YQ202207);沈阳药科大学创新创业训练计划项目(202310163022)。

摘　　要：目的设计并合成一系列含吡唑甲酰胺结构骨架的硫醇类化合物,以期获得高活性和高选择性的HDAC6抑制剂。方法以前期合成的硫醇类HDAC抑制剂B-4和E-15k为结构基础,运用计算机辅助药物设计方法,将先导化合物中苯环与吡唑环通过脂肪碳链相连,构建体积增大的三环结构以配适HDAC6蛋白活性口袋,并在此结构基础上引入不同取代基合成一系列含吡唑甲酰胺结构的新型HDAC6抑制剂,对所合成的目标化合物进行体外靶点抑制活性评价和神经细胞保护作用评价。结果与结论共合成了14个未见文献报道的化合物,其结构均经质谱、核磁共振谱确证。实验结果表明,化合物17a~17c对HDAC6表现出强效的抑制作用和选择性。同时,化合物17b表现出一定的体外神经细胞保护作用。Computer-aided drug design methods were used to connect the benzene ring with the pyrazole ring via an aliphatic carbon chain in the lead compounds based on the thiols-containing HDAC inhibitors B-4 and E-15k.This created an enlarged tricyclic structure to fit the active site pocket of the HDAC6 protein.On this structural basis,various substituents were introduced to synthesize a series of novel HDAC6 inhibitors containing a pyrazolecarboxamide structure.A total of 14 compounds were synthesized,and their structures were confirmed by mass spectrometry and nuclear magnetic resonance spectroscopy.The target inhibitory activity and neuroprotective effects of the synthesized target compounds were evaluated in vitro.The experimental results showed that compounds 17a-17c exhibited potent inhibitory activity and selectivity towards HDAC6.Additionally,compound 17b showed some neuroprotective effects in vitro.

关 键 词：HDAC6抑制剂 吡唑甲酰胺 硫醇 神经保护 合成 

分 类 号：R914[医药卫生—药物化学]