哌嗪取代嘧啶衍生物的合成及其抗菌活性  

Synthesis and antibacterial activity of piperazine-substituted pyrimidine derivatives

作　　者：贾学敏 程铖 刘丽娅 聂久伟 付恒建 汤磊 杨元勇 JIA Xuemin;CHENG Cheng;LIU Liya;NIE Jiuwei;FU Hengjian;TANG Lei;YANG Yuanyong(School of Pharmacology,Guizhou Medical University,Guiyang 550004,Guizhou,China;Guizhou Provincial Engineering TechnologyRresearch Center for Chemical Drug R&D,Guiyang 550004,Guizhou,China)

机构地区：[1]贵州医科大学药学院,贵州贵阳550004 [2]贵州省化学合成药物研发利用工程技术研究中心,贵州贵阳550004

出　　处：《贵州医科大学学报》2022年第7期745-751,共7页Journal of Guizhou Medical University

基　　金：国家自然科学基金(81660348);贵州省科技厅防控新型冠状病毒技术攻关及集成应用(〔2020〕4Y208);贵州省教育厅重点领域项目(〔2021〕047);贵州大学生创新创业训练计划项目(S202010660048)。

摘　　要：目的探讨哌嗪取代嘧啶衍生物的合成方法及其抗菌活性。方法以2-氨基-4,6-二氯嘧啶为原料,在N,N-二异丙基乙胺的催化下与取代酰氯发生取代反应得到相应的中间体,然后再与哌嗪类底物在三乙胺的催化下得到目标化合物4a~4j;在5×10^(8)CFU/L的菌液终浓度下,苯唑西林作为阳性对照组,目标化合物4a~4j作为实验组,以256.00 mg/L为起始浓度,采用二倍稀释法评估目标化合物4a~4j对金黄色葡萄球菌(S.aureus)、表皮葡萄球菌(S.epidermidis)、耐甲氧西林S.aureus(MRSA)、大肠埃希菌(E.coli)及铜绿假单胞菌(Ps.aeruginosa)的最低抑菌浓度(MIC)。结果设计合成了4a~4j共10个哌嗪取代的嘧啶类化合物;目标化合物4a~4j在256.00 mg/L的起始浓度下,化合物4a对S.aureus ATCC 433000、S.epidermidis 102555及MRSA 20151026025的MIC分别为16.00 mg/L、8.00 mg/L及128.00 mg/L;化合物4d和4e对S.aureus ATCC 433000、S.epidermidis 102555及MRSA 20151026025的MIC均为2.00 mg/L,其余化合物于256 mg/L浓度时没有明显抑菌活性,其中化合物4d和4e对MRSA 20151026025的MIC明显优于阳性对照组;目标化合物4a~4j对革兰阴性菌E.coli Dh5a、Ps.aeruginosa ATCCC 9027并于初始浓度未显示出抑菌活性。结论设计合成的哌嗪取代的嘧啶类化合物4d和4e对S.aureus ATCC 433000、S.epidermidis 102555及MRSA 20151026025有较好的抑制作用,尤其是对MRSA 20151026025的抑菌活性明显优于阳性对照。Objective To investigate the synthesis and antibacterial activity of piperazine-substituted pyrimidine derivatives.Methods 2-amino-4,6-dichloropyrimidine was used as the raw material.Catalysed by N,N-diisopropylethylamine,the corresponding intermediates were obtained by the substitution reaction with the substituted acyl chloride.The target compounds 4a to 4j were obtained from piperazine under the catalysis of triethylamine.At the final concentration of 5×10^(8)CFU/L,the initial concentration was 256.00 mg/L,oxacillin was used as the positive control group,and the target compounds 4a to 4j were used as the experimental group.The minimum inhibitory concentrations(MICs)of the target compounds 4 a to 4 j against Staphylococcus aureus(S.aureus),Staphylococcus epidermidis(S.epidermidis),methicillin-resistant S.aureus(MRSA),Escherichia coli(E.coli)and Pseudomonas aeruginosa(Ps.aeruginosa)were evaluated by the two-fold dilution method.Results A total of 10 piperazine-substituted pyrimidines 4a to 4j were designed and synthesized.At the initial concentration of 256.00 mg/L for target compounds 4a to 4j,the MICs of compound 4a against S.aureus ATCC 433000,S.epidermidis 102555 and MRSA 20151026025 were 16.00 mg/L,8.00 mg/L and 128.00 mg/L,respectively.The MICs of compounds 4d and 4e against S.aureus ATCC 433000,S.epidermidis 102555 and MRSA 20151026025 were both 2.00 mg/L.The other compounds had no obvious antibacterial activity at the concentration of 256 mg/L.Among them,the MIC of compounds 4d and 4e against MRSA 20151026025 were significantly better than those of the positive control group.The target compounds 4 a to 4j showed no antibacterial activity against Gram-negative bacteria E.coli Dh5a and Ps.aeruginosa ATCCC 9027.Conclusion The designed and synthesized piperazine-substituted pyrimidine compounds 4d and 4e have good inhibitory effects on S.aureus ATCC 433000,S.epidermidis 102555 and MRSA 20151026025.In particular,their antibacterial activity against MRSA 20151026025 is significantly better than that of the po

关 键 词：哌嗪类 嘧啶类 金黄色葡萄球菌 表皮葡萄球菌 耐甲氧西林金黄色葡萄球菌 最低抑菌浓度 

分 类 号：R914.5[医药卫生—药物化学]