8-氟-2,3-二氢喹啉-4(1H)-酮缩氨基脲类化合物的设计、合成及抗真菌活性研究  

Design,synthesis and antifungal activity of 8-fluoro-2,3-dihydroquinoline-4(1H)-one semicarbazone derivatives

作　　者：原静[1] 骆伟[1] 张欣[1] 田野[1] 王伟[1] 苏昕[1] 郭春[1] 

机构地区：[1]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016

出　　处：《中国药物化学杂志》2012年第1期10-15,共6页Chinese Journal of Medicinal Chemistry

基　　金：国家十一五"重大新药创制"科技重大专项(2009ZX09301-012)

摘　　要：目的合成一系列8-氟-2,3-二氢喹啉-4(1H)-酮缩氨基脲类化合物,测定其体外抗真菌活性。方法以邻氟苯胺为起始原料,经与丙烯酸加成、在多聚磷酸(PPA)中环合制得中间体8-氟-2,3-二氢喹啉-4(1H)-酮;该中间体与各种N4-取代的氨基脲缩合得到目标化合物。采用二倍浓度稀释法测试各目标化合物的体外抗真菌活性,实验选用8种临床上常用的致病真菌为测试菌株,以氟康唑、伊曲康唑为阳性对照药。结果与结论16个8-氟-2,3-二氢喹啉-4(1H)-酮缩氨基脲类化合物均未见文献报道,其结构经1H-NMR、MS谱确证;活性测试结果表明,合成的多个目标化合物对测试真菌表现出较好的体外抑菌活性,尤其是对红色毛藓菌的活性均好于阳性对照药。In recent years, the incidence of fungal infections has reached alarming proportions, and the latest market outlook from data monitor shows that the rate of invasive fungal infection is increasingly rising specially. So it is of great significance to develop more effective and safer antifungal agents with novel mechanism of action. The target compounds were designed based on the bioisosterism and combination principle in drug design,to substitute the sulphur atom of thiochromanones with nitrogen giving the 2,3-dihydroquinolin- 4（1H）-one scaffold and combine this moiety with semicarbazones which is the pharrnacophore of cysteine protease inhibitors to give the scaffold of 2,3-dihydroquinolin-4 （1 H）-one semicarbazone. Totally sixteen 8- fluoro-2,3-dihydroquinoline-4 （1H）-one semicarbazone derivatives were synthesized and their structures were confirmed by MS and m H-NMR. The antifungal assay was carded out in vitro by two-fold dilution method,with fluoconazole and itraconazole as the control drugs. The result showed that all the compounds displayed antifungal activities against the tested fungi, Rh , T. r ,As , M. g, T. v, C. n, R. r, and C. a, in different levels, of which 11, 16, 17, I u, and 114 showed better activity. The preliminary structure activity relationship was summarized.

关 键 词：8-氟-2 3-二氢喹啉-4(1H)-酮缩氨基脲 合成 抗真菌活性 

分 类 号：R914[医药卫生—药物化学]