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Synthesis, activity and mechanism of alkoxy-, carbamato-, sulfonamido-, thioureido-, and ureido-derivatives of 2,4,5-trimethylpyridin-3-ol against inflammatory bowel disease.
Journal of Enzyme inhibition and Medicinal Chemistry ( IF 5.6 ) Pub Date : 2019-10-16 , DOI: 10.1080/14756366.2019.1677637
Chhabi Lal Chaudhary 1 , Pallavi Gurung 1 , Seoul Jang 2 , Suhrid Banskota 1 , Tae-Gyu Nam 2 , Jung-Ae Kim 1 , Byeong-Seon Jeong 1
Affiliation  

Inflammatory bowel disease (IBD) is a chronic immuno-inflammation in gastrointestinal tract. We have evaluated the activity of the compounds to inhibit the adhesion of monocytes to colon epithelial cells is triggered by a pro-inflammatory cytokine, tumour necrosis factor (TNF)-α. The in vitro activity of the compounds, 13b (an ureido-derivative), 14c, 14j, 14k, 14n (thioureido-), 18c and 18d (sulfonamido-), was in correlation with in vivo anti-colitis activity revealed as significant recovery in body- and colon-weights and colon myeloperoxidase level, a biochemical marker of inflammation reflecting neutrophil infiltration. In vivo, TNBS-induced changes in the expression of inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-10, and TGF-β), NLRP3 inflammasome components (NLRP-3, Caspase-1, and IL-18), and epithelial junction molecules (E-cadherin, claudin2/3, and ZO-1) were blocked and recovered by oral administration of the compounds (1 mg/kg). Compound 14n which showed the best efficacy can be a promising lead for orally available therapeutics for pathology of IBD.

中文翻译:

2,4,5-三甲基吡啶-3-醇的烷氧基,氨基甲酸酯,磺酰胺基,硫脲基和脲基衍生物的合成,活性及其机制,可抗炎性肠病。

炎症性肠病(IBD)是胃肠道中的一种慢性免疫炎症。我们已经评估了该化合物抑制单核细胞粘附到结肠上皮细胞的活性是由促炎性细胞因子,肿瘤坏死因子(TNF)-α触发的。化合物13b(脲基衍生物),14c,14j,14k,14n(硫脲基-),18c和18d(磺酰胺基)的体外活性与体内抗结肠炎活性相关,显示出显着的恢复体重和结肠重量以及结肠髓过氧化物酶水平,这是反映中性粒细胞浸润的炎症的生化指标。在体内,TNBS诱导炎性细胞因子(TNF-α,IL-6,IL-1β,IL-10和TGF-β),NLRP3炎性体成分(NLRP-3,Caspase-1和IL)表达的变化-18)和上皮连接分子(E-cadherin,通过口服给予化合物(1 mg / kg),可阻断并恢复claudin2 / 3和ZO-1)。表现出最佳疗效的化合物14n可能是可用于IBD病理学的口服治疗的有前途的先导。
更新日期:2020-04-20
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