非对称双杂环取代均三唑并噻二唑哌嗪衍生物的合成及抗菌活性  

Synthesis and Bioactivity of Asymmetrical Bis-heterocyclic Substituted s-Triazolothiadiazole Piperazine Derivatives

作　　者：胡国强[1] 侯莉莉[1] 谢松强[1] 杜钢军[1] 黄文龙[2] 张惠斌[2] 

机构地区：[1]河南大学药物研究所,开封475001 [2]中国药科大学新药中心,南京

出　　处：《应用化学》2009年第1期63-66,共4页Chinese Journal of Applied Chemistry

基　　金：国家自然科学基金(20872028);河南大学重点科研基金(04ZDZR009)资助项目

摘　　要：采用4-氨基-3-吡啶-3-基-5-巯基-均三唑(2)在复合催化剂DMAP和TBAB催化剂下,与氯代吡唑羧酸1a～1c经环缩合反应以高收率得中间体6-(5-氯-3-甲基-1-取代苯基-1H-吡唑-4-基)-3-吡啶-3-基-均三唑并[3,4-b][1,3,4]噻二唑(3a～3c),吡唑环氯原子与取代哌嗪在聚乙二醇(PEG)催化作用下发生亲核取代反应至相应的哌嗪游离碱,与盐酸反应得相应水溶性盐酸盐4a～4o。目标化合物结构经元素分析和光谱数据表征,用二倍试管稀释法研究了新化合物体外对金葡菌(S.aureus)、大肠埃希氏菌(E.coli)和铜绿假单孢菌(P.aeruginosa)的最低抑菌浓度(MICs)。结果表明,引入极性哌嗪基可显著提高稠杂环化合物的抑菌活性。To improve the water solubility of fused heterocyclis so as to find a novel structural lead compound from them for the development of potential antibacterial agents, the intermediates of 6-（5-chloro-3-methyl-1- substituted phenyl-1H-pyrazol-4-yl ） -3-pyrid-3-yl-s-triazolo [ 1,3,4 ] [ 3,4-b ] thiadia-zoles （ 3a - 3c ） were synthesized via cyclocondensation of 4-amino-3-pyrid-3-yl-5-mercapto-s-triazole （2） with chloro-pyrazole carboxylic acids （1a - 1c） catalyzed with a phase transfer catalyst TBAB and an acylating catalyst DMAP in the presence of POCI3 in high yields, respectively. The compounds 3a - 3c were subjected to nucleophilic substitution of the chlorine at the pyrazole ring with substituted piperazine under the catalysis of PEG-600 to give the corresponding free bases 4a - 4o successfully, which were subsequently treated with hydrochloride to afford corresponding chlorides of 4a - 4o. The structures of the title compounds were characterized by elemental analysis and spectral data, and the in vitro inhibitory activities of the title compounds against three microorgranisms, S. aureus, E. coli, and P. aeruginosa, were evaluated v/a the respective MICs values by means of 2-fold agar dilution assay. The results showed that the introduction of a polar piperazine group around the fused heterocyclic core of s-tria-zolo[ 1,3,4 ] [ 3,4-b ] thiadiazole could result in a significant enhancement of bioactivity of the corresponding parent compounds.

关 键 词：均三唑 吡唑 均三唑并噻二唑 哌嗪 抗菌活性 

分 类 号：O621[理学—有机化学]