摘要/Abstract

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(IC₅₀=0.451 µmol•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=1 µg/mL)类似或更高的抗真菌活性(MIC=0.5 or 1 µg/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
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-thioxo- thiazolidin-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 (IC₅₀=0.451 µmol•L^–1) against ALK5 kinase, which had a good selectivity index of >22 against p38α MAP 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 1 µg/mL) to the positive control compound fluconazole (MIC=1 µg/mL).
Key words: rhodanine, TGF-β, quinoxalinyl imidazole, ALK5 inhibitor, antimicrobial, antifungal


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