(E)-N′-芳基亚甲基-4-(4-苯基嘧啶-2-基氨基)苯甲酰肼衍生物作为CDK9抑制剂的设计合成及抗HIV-1活性研究  

Design,Synthesis and Anti-HIV-1 Activity of(E)-N′-Arylmethylene-4-(4-Phenylpyrimidin-2-ylamino)benzohydrazide Derivatives as CDK9 Inhibitors

作　　者：祝科宇 赵胜贤 何凤明 郑筱翔 阳学文 章昭琳 胡鸿雨[1] ZHU Ke-yu;ZHAO Sheng-xian;HE Feng-ming;ZHENG Xiao-xiang;YANG Xue-wen;ZHANG Zhao-lin;HU Hong-yu(Xingzhi College,Zhejiang Normal University,Lanxi 321100,China;Zhejiang Apeloa Tospo Pharmaceutical Co.,Ltd.,Dongyang 322118,China;School of Pharmaceutical Sciences,Xiamen University,Xiamen 361102,China;College of Chemistry and Life Sciences,Zhejiang Normal University,Jinhua 321004,China)

机构地区：[1]浙江师范大学行知学院,浙江兰溪321100 [2]浙江普洛得邦制药有限公司,浙江东阳322118 [3]厦门大学药学院,福建厦门361102 [4]浙江师范大学化学与生命科学学院,浙江金华321004

出　　处：《中国药学杂志》2022年第19期1601-1610,共10页Chinese Pharmaceutical Journal

基　　金：浙江省自然基金项目资助(LGF22H300015);金华市公益性技术应用研究项目资助(2022-4-031);国家级大学生创新创业训练计划项目资助(202113276001,202113276009)。

摘　　要：目的设计合成(E)-N′-芳基亚甲基-4-(4-苯基嘧啶-2-基氨基)苯甲酰肼衍生物,并对其抗HIV-1的活性进行研究。方法4-氨基苯甲酸乙酯为起始原料,通过5步反应合成了目标化合物,采用荧光素酶(luciferase)报告基因检测了合成化合物对于HIV-1转录抑制活性。结果目标化合物对于HIV-1的转录具有一定的抑制活性。其中化合物7p活性最优,在2μmol·L^(-1)浓度下HIV-1转录抑制率为(73±0.05)%,在20μmol·L^(-1)浓度下HIV-1转录活性为(90±0.01)%。进一步研究表明,化合物7p以浓度依赖性在NH1和NH2细胞中抑制HIV-1的转录活性以及下调RNA聚合酶ⅡCTD二号位丝氨酸磷酸化。最后,分子对接表明化合物7p与CDK9有很强的结合作用。结论该系列化合物具有较好的抗HIV-1的活性,具有进一步研究的意义。OBJECTIVE To design and synthesize(E)-N′-arylmethylene-4-(4-phenylpyrimidin-2-ylamino)benzohydrazide derivatives and investigate their anti-HIV-1 activities.METHODS The target compound was synthesized by five step reactions using ethyl aminobenzoate as starting material.The transcriptional inhibitory activities of the synthetic compounds against HIV-1 were detected by luciferase reporter gene.RESULTS The target compounds showed certain inhibitory activities on HIV-1 transcription,among which compound 7 P had the best inhibitory activity,with inhibitory rate of(73±0.05)%at 2μmol·L^(-1)and(90±0.01)%at 20μmol·L^(-1),respectively.Further study showed that compound 7 P inhibited HIV-1 transcriptional activity and down-regulated RNA polymeraseⅡCTD serine 2 phosphorylation in a concentration-dependent manner in NH1 and NH2 cells.Finally,molecular docking showed that compound 7 P had a strong binding effect with CDK9.CONCLUSION This series of compounds have good anti-HIV-1 activities,which has significant research value for further study.

关 键 词：苯甲酰肼衍生物 CDK9抑制剂 抗HIV活性 

分 类 号：R914[医药卫生—药物化学]