Synthesis and activity of N-(5-hydroxy-3,4,6-trimethylpyridin-2-yl) acetamide analogues as anticolitis agents via dual inhibition of TNF-alpha- and IL-6-induced cell adhesions
- Authors
- Karmacharya, Ujjwala; Regmi, Sushil Chandra; Awasthi, Bhuwan Prasad; Chaudhary, Prakash; Kim, Ye Eun; Lee, Iyn-Hyang; Nam, Tae-gyu; Kim, Jung-Ae; Jeong, Byeong-Seon
- Issue Date
- Jul-2021
- Publisher
- PERGAMON-ELSEVIER SCIENCE LTD
- Keywords
- Inflammatory bowel disease; TNF-alpha; IL-6; Amidopyridinol; TNBS-induced colitis
- Citation
- BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, v.43, pp.1 - 6
- Indexed
- SCIE
SCOPUS
- Journal Title
- BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
- Volume
- 43
- Start Page
- 1
- End Page
- 6
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/105724
- DOI
- 10.1016/j.bmcl.2021.128059
- ISSN
- 0960-894X
- Abstract
- Tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) are the critical pro-inflammatory cytokines involved in the pathogenesis of inflammatory bowel disease (IBD). Inhibition of these cytokines and related signaling pathways has been a target for the development of IBD therapeutics. In the current study, 6-acetamido2,4,5-trimethylpyridin-3-ol (1) and various analogues with the amido scaffold were synthesized and examined for their inhibitory activities in in vitro and in vivo IBD models. The parent compound 1 (1 mu M) showed an inhibitory activity against TNF-alpha- and IL-6-induced adhesion of monocytes to colon epithelial cells, which was similar to tofacitinib (1 mu M), a JAK inhibitor, but much better than mesalazine (1,000 mu M). All the analogues showed a positive relationship (R-2 = 0.8943 in a linear regression model) between the inhibitory activities against TNF-alpha-induced and those against IL-6-induced adhesion. Compound 2-19 turned out to be the best analogue and showed much better inhibitory activity against TNF-alpha- and IL-6-induced adhesion of the cells than tofacitinib. In addition, oral administration of compound 1 and 2-19 resulted in a significant suppression of clinical signs of TNBS-induced rat colitis, including weight loss, colon tissue edema, and myeloperoxidase activity, a marker for inflammatory cell infiltration in colon tissues. More importantly, compound 2-19 (1 mg/kg) was more efficacious in ameliorating colitis than compound 1 and sulfasalazine (300 mg/kg), the commonly prescribed oral IBD drug. Taken together, the results suggest that compound 2-19 can be a novel platform for dual-acting IBD drug discovery targeting both TNF-alpha and IL-6 signaling.
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