吡唑并[3,4-b]吡啶酮羧酸类化合物的合成及抗菌活性研究  

Synthesis of Pyrazolo[3,4-b]pyridinone Carboxylic Acids and Investigation on Their Antibacterial Activities

作　　者：李珂 蔡永萍 崔红艳 黄文龙[3] 胡国强 LI Ke;CAI Yongping;CUI Hongyan;HUANG Wenlong;HU Guoqiang(Henan Engineering Technology Research Center of Water Environment and Health,Zhengzhou University of Industrial Technology,Zhengzhou 451150,China;School of Clinical Medicine,Henan University,Kaifeng 475001,China;Center of Drug Discovery,China Pharmaceutical University,Nanjing 210009,China)

机构地区：[1]郑州工业应用技术学院,河南省水环境与健康工程技术研究中心,郑州451150 [2]河南大学临床医学院,河南开封475001 [3]中国药科大学新药研究中心,南京210009

出　　处：《中国药学杂志》2023年第24期2246-2251,共6页Chinese Pharmaceutical Journal

基　　金：国家自然科学基金项目资助(20872028,21072045);河南省科技发展计划项目资助(162102310392)。

摘　　要：目的探索新骨架抗菌化合物的构建策略。方法基于生物电子等排药物设计原理,用五元吡唑杂环作为4-喹诺酮骨架中六元芳香环的生物等排体,进而构建了以4-吡唑并吡啶酮羧为结构特征的目标化合物,1-对甲氧苯基-3-甲基-7-取代-1H-吡唑并[3,4-b]吡啶-4(7H)-酮-5-羧酸(10a~10p),其结构经用元素分析和光谱数据确证。用微量二倍浓度稀释方法测定了目标化合物对金黄色葡萄球菌、枯草芽孢杆菌、大肠埃希氏菌、铜绿假单胞菌体外抑菌活性。结果16个新合成的目标化合物对4种实验菌株显示出不同程度的抑制活性,其中7-乙基(10k)和7-环丙基(10l)化合物的活性强于其他取代基的活性,其对金黄色葡萄球菌和大肠埃希氏菌的MIC值与对照诺氟沙星和环丙沙星相当。结论新骨架吡唑并吡啶酮羧酸类目标化合物具有潜在的抗菌活性,预示可能成为有待进一步发展新型结构的抗菌苗头化合物。OBJECTIVE To explore an effective strategy for constructing new molecular scaffold of antibacterial compounds.METHODS Based on the principle of bioisosterism in drug design,novel target compounds,1-(4-methoxylphenyl)-3-methyl-7-substituted-1H-pyrazolo[3,4-b]pyridin-4(7H)-one-5-carboxylic acids(10a-10p)bearing a 4-pyrazolopyridinone scaffold,were designed and synthesized via a bioisoisteric replacement of six-membered aromatic ring in the 4-quinolone scaffold with a five-membered pyrazole ring.The structures of the target compounds were characterized by spectral data and elemental analysis,and the in vitro antibacterial activities against Staphylococcus aureus,Bacillus subtilis,Escherichia coli and pseudomonas aeruginosa were determined by MIC test.RESULTS Sixteen new target compounds were constructed and exhibited different degrees of inhibitory activity against the four tested strains.In particular,7-ethyl(10k)or 7-cycloproyl-substituted compound(10l)displayed better activity than other compounds with a comparable MIC value to the control norfloxacin or cirpofloxacin against Staphylococ cus aureus or Escherichia coli,respectively.CONCLUSION Novel pyrazolopyridinone carboxylic acid compounds display potential antibacterial activity,with prospect to be further developed as new structural antimicrobial hits.

关 键 词：吡唑 吡唑并吡啶酮 4-喹诺酮 优势骨架 生物等排 抗菌活性 

分 类 号：R965[医药卫生—药理学] R95[医药卫生—药学]