Discovery and structure-activity relationship studies of 2-benzylidene-2,3-dihydro-1H-inden-1-one and benzofuran-3(2H)-one derivatives as a novel class of potential therapeutics for inflammatory bowel disease
| Autor: | Suhrid Banskota, Til Bahadur Thapa Magar, Ganesh Bist, Pallavi Gurung, Eung-Seok Lee, Jung-Ae Kim, Aarajana Shrestha, Tara Man Kadayat |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Lipopolysaccharide Pharmacology Inflammatory bowel disease Rats Sprague-Dawley Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo Drug Discovery Tumor Cells Cultured medicine Animals Humans Structure–activity relationship Colitis Benzofuran Benzofurans Dose-Response Relationship Drug Molecular Structure U937 cell Tumor Necrosis Factor-alpha Chemistry Organic Chemistry U937 Cells General Medicine Inflammatory Bowel Diseases medicine.disease Rats Transcription Factor AP-1 Disease Models Animal 030104 developmental biology Indenes Trinitrobenzenesulfonic Acid 030220 oncology & carcinogenesis Female Tumor necrosis factor alpha HT29 Cells |
| Zdroj: | European Journal of Medicinal Chemistry. 137:575-597 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2017.06.018 |
| Popis: | To develop effective therapeutics for inflammatory bowel disease (IBD), 2-benzylidene-2,3-dihydro-1H-inden-1-one and benzofuran-3(2H)-one derivatives, were designed and synthesized and their structure-activity relationships (SAR) were investigated. Compounds 7, 25, 26, 32, 39, 41, 52, 54, and 55 showed potent inhibitory effect (>70%) on the TNF-α-induced adhesion of monocytes to colon epithelial cells, which is one of the hallmark events leading to IBD. Such inhibitory activity of the compounds correlated with their suppressive activities against the TNF-α-induced production of ROS; ICAM-1 and MCP-1 expression, critical molecules involved in monocyte-epithelial adhesion; and NF-κB transcriptional activity. In addition, compounds 41 and 55 significantly suppressed the lipopolysaccharide (LPS)-induced expression of the TNF-α gene, with compound 55 showing better efficacy. This inhibition of TNF-α expression by compounds 41 and 55 corresponded to their additional inhibitory activity against AP-1 transcriptional activity, which is another transcription factor required for high level TNF-α expression. The strong inhibitory activity of compound 55 against an in vivo colitis model was confirmed by its dose-dependent inhibitory activity in a rat model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis, demonstrating compound 55 as a new potential candidate for the development of therapeutics against IBD. |
| Databáze: | OpenAIRE |
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