苯甲酸衍生物类神经氨酸酶抑制剂的合成及活性评价  

Synthesis and Activity Evaluation of Benzoic Acid Derivatives as Neuraminidase Inhibitors

作　　者：王敬[1] 袁建勇[1] 刘盼和 胡叶敏[1] 李雁武[1] WANG Jing;YUAN Jian-yong;LIU Pan-he;HU Ye-min;LI Yan-wu(Pharmacy College of Chongqing Medical University, Chongqing 400016, China)

机构地区：[1]重庆医科大学药学院

出　　处：《精细化工》2018年第6期1029-1036,1048,共9页Fine Chemicals

摘　　要：以4-氨基-3-碘苯甲酸甲酯（Ⅴ）为原料,经过偶联、酰化、水解等反应得到苯甲酸衍生物类流感病毒神经氨酸酶抑制剂Ⅵ-Ⅸ,化合物Ⅴd[4-乙酰胺基-3-（2-乙基-1-丁烯基）苯甲酸甲酯]经过氧化、还原、水解反应得到化合物Ⅹ-Ⅻ,结构经^1HNMR、^13CNMR、MS确证,并用化学荧光法测定对神经氨酸酶的抑制率,测试选用流感病毒菌株H3N2（California/04）,H1N1（California/99）和B（Shanghai/02）。结果显示：在Ⅵ-Ⅸ中,苯环C3位置侧链越大,化合物的活性越低,其中,化合物Ⅸ[4-乙酰胺基-3-（2-羟基-2-乙基丁烷基）苯甲酸]的活性最强,对H3N2、H1N1、B的半数抑制浓度分别为1.0、2.1、1.6μmol/L;Ⅹ-Ⅻ中,苯环侧链α位碳上的羟基比β位活性增强,在苯环侧链α位的碳上含有单羟基的化合物Ⅻ[4-乙酰胺基-3-（2-乙基-1-羟基丁烷基）苯甲酸]具有对两种A型流感病毒最强的活性,半数抑制浓度分别为0.15和0.20μmol/L。A series of benzoic acid derivatives as influenza neuraminidase inhibitors Ⅵ to Ⅸ were synthesized with 4-amino-3-iodine methyl benzoate（Ⅴ） as raw material through coupling reaction,acylation,hydrolysis,and so on. The reaction of oxidation,reduction and hydrolysis of compound Ⅴd[methyl 4-acetamido-3-（2-ethylbut-1-en-1-yl）benzoate] led to compounds Ⅹ-Ⅻ. These compounds were confirmed by 1 HNMR,13 CNMR and MS. Inhibition rate on neuraminidase was determined by chemical fluorescence,and the test was carried out using the influenza virus strains H3 N2（California/04）,H1 N1（California/99） and B（Shanghai/02）. The results showed that among compounds Ⅵ-Ⅸ,the greater side chain at benzene ring C3 position,the lower activity of the compound,especially,compound Ⅸ[4-acetamido-3-（2-hydroxybutyl）benzoic acid] had the strongest Activity,the median inhibitory concentration on H3 N2 and H1 N1,B were 1.0,2.1,1.6 μmol/L. For compounds Ⅹ-Ⅻ,the hydroxyl groups on the benzene ring side chain α carbon possessed better activity than that on β carbon. Compound Ⅻ [4-acetamino-3-（2-ethyl-1-hydroxybutyl） benzoic acid] containing single hydroxyl at α carbon in side chains of benzene ring exhibited the strongest activity on two types A influenza virus,the corresponding median inhibitory concentration was 0.15 and 0.20 μmol/L,respectively.

关 键 词：神经氨酸酶 流感病毒 苯甲酸衍生物 化学荧光法 

分 类 号：R978.7[医药卫生—药品]