含喹喔啉基咪唑结构的罗丹宁衍生物的合成及其ALK5、抗菌和抗真菌活性研究  

Synthesis,Antibacterial and Antifungal Evaluation of Rhodanine Derivatives Bearing Quinoxalinyl Imidazole Moiety as ALK5 Inhibitors

作　　者：韩立卓 赵丽敏 王慧敏 窦桐 郭芳妍 齐浚答 许文博 朴莲荀 金学军 陈芬儿 朴虎日[2] 郑昌吉[2] 金成华 Han Lizhuo;Zhao Limin;Wang Huimin;Dou Tong;Guo Fangyan;Qi Junda;Xu Wenbo;Piao Lianxun;Jin Xuejun;Chen Fen'er;Piao Huri;Zheng Changji;Jin Chenghua(Molecular Medicine Research Center,College of Pharmacy,Yanbian University,Yanji,Jilin 133002;Key Laboratory of Natural Medicines of the Changbai Mountain,Minstry of Education,Yanbian University,Yanji,Jilin 133002)

机构地区：[1]延边大学药学院,分子药物研究中心,吉林延吉133002 [2]延边大学,长白山天然药物教育部重点实验室,吉林延吉133002

出　　处：《有机化学》2021年第11期4428-4436,共9页Chinese Journal of Organic Chemistry

基　　金：国家自然科学基金(No.8206023)资助项目.

摘　　要：转化生长因子-β(TGF-β)在许多疾病中过表达,是治疗肿瘤的重要靶点.合成了2个系列3-取代-5-((5-(6-甲基吡啶-2-酰基)-4-(喹啉-6-基)-1氢-咪唑-2-基)亚甲基)-2-噁唑烷-4-酮化合物(12、13a~13e和14a~14h),并对其进行了活性受体样激酶5(ALK5)抑制活性评价.其中(Z)-6-(5-((5-(6-甲基吡啶-2-基)-4-(喹喔啉-6-基)-1H-咪唑-2-基)亚甲基)-4-羰基-2-硫代羰基噻唑-3-基)己酸(13e)对ALK5激酶的活性最高(IC_(50)=0.451μmol·L^(-1)),对p38α激酶的选择性指数大于22,比临床候选化合物LY-2157299选择性高5.0倍.在TGF-β抑制剂的研究中发现这些罗丹宁化合物具有良好的抗真菌活性,而且对革兰氏阳性菌和革兰氏阴性菌显示很高的选择性.它们显示与阳性对照化合物氟康唑(MIC=1μg/mL)类似或更高的抗真菌活性(MIC=0.5 or 1μg/mL).Transforming growth factor-β(TGF-β)is overexpressed in many diseases,and is an important target for treating tumors.Two series of 3-substituted-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methylene)-2-thioxothiazolidin-4-ones(12,13a~13e,and 14a~14h)were synthesized and evaluated for their activin receptor-like kinase 5(ALK5)inhibition activity.Among these compounds,(Z)-6-(5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)hexanoic acid(13e)showed the highest activity(IC_(50)=0.451μmol·L^(-1))against ALK5 kinase,which had a good selectivity index of>22 against p38αMAP kinase,with 5.0-fold more selectivity than the clinical candidate of LY-2157299.These rhodanine compounds showed good antifungal activity and high selectivity against both Gram-positive and Gram-negative bacteria.These compounds showed similar or higher antifungal activity(MIC=0.5 or 1μg/mL)to the positive control compound fluconazole(MIC=1μg/mL).

关 键 词：罗丹宁 转化生长因子-Β 喹喔啉基咪唑 ALK5抑制剂 抗菌 抗真菌 

分 类 号：TQ460.1[化学工程—制药化工]