Synthesis, activity and mechanism of alkoxy-, carbamato-, sulfonamido-, thioureido-, and ureido-derivatives of 2,4,5-trimethylpyridin-3-ol against inflammatory bowel disease

Abstract

2020) Synthesis, activity and mechanism of alkoxy-, carbamato-, sulfonamido-, thioureido-, and ureido-derivatives of 2,4,5-trimethylpyridin-3-ol against inflammatory bowel disease, ABSTRACT 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)-a. 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-a, IL-6, IL-1b, IL-10, and TGF-b), 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. ARTICLE HISTORY

“Urea to Urea” Approach: Access to Unsymmetrical Ureas Bearing Pyridyl Substituents

“…of p-toluidine (2 a) in DMF at 120 °C showed almost good yield (77%) of the desired product 3 a for 20 h (Table 1, entry 1). The formation of the target product -1-(4-methylpyridin-2yl)-3-(p-tolyl)urea (3 a) -was confirmed by 1 H and 13 C NMR spectroscopy, HRMS as well as X-ray diffraction analysis of the product crystals (Figure 2). Encouraged by the first success, we tried to change the N,N'-dialkyl substituent in starting urea from piperidine moiety to the dimethylamino group (Table 1, entry 2).…”

“…N-Heteroaromatic substituted ureas are extensively used compounds for drug design (Figure 1). [1,2] There are numerous examples of their manifestation as therapeutics for treatment of neurodegenerative diseases (especially Alzheimer's disease [3][4][5][6] ), diabetes, [7][8][9][10][11] cardiovascular disorders, [12] and also as anti-inflammatory agents [13] and antibiotics. [14][15][16][17] Moreover, there is a growing body of research shows that substances bearing N-pyridylurea moiety have antitumor activity.…”

G Protein-Coupled Estrogen Receptor-Mediated Anti-Inflammatory and Mucosal Healing Activity of a Trimethylpyridinol Analogue in Inflammatory Bowel Disease

“…Previously, we reported 6-alkylamido-2,4,5-trimethylpyridin-3-ols as dual inhibitors against both TNFα- and IL-6-induced inflammatory activity in in vitro IBD models, employing a phenotype-based drug discovery strategy. , Analogues with phenylethyl ( 6 – 29 ), benzyl, and cyclohexyl side chains attached to the 6-amido functional group showed high activity, possibly owing to some degree of flatness provided by these side chains. In this study, for better dual inhibition, we expanded the scope of the side chains to increase their flatness and attached them directly to the amido functional group.…”

Bifidobacterium infantis regulates the programmed cell death 1 pathway and immune response in mice with inflammatory bowel disease

“…We have previously found that Bifidobacterium infantis ( B. infantis ) can alleviate intestinal epithelial injury and maintain intestinal immune tolerance in a mouse model of IBD and may have therapeutic implications for the immunological injuries observed in IBD . Bifidobacterium infantis notably increased the expression levels of PD-L1 and PD-1 in the intestine and promoted the expression of nuclear transcription factors and of anti-inflammatory factors (IL-10 and TGF-β1) in Tregs[ 22 , 23 ]. Therefore, this study aimed to explore the mechanism of action of B. infantis in the PD-1/PD-L1 signaling pathway and the differentiation and function of Tregs.…”