Synthesis and biological evaluation of pyridine-linked indanone derivatives: Potential agents for inflammatory bowel disease

• Published in: Bioorganic & medicinal chemistry letters 2018-08, Vol.28 (14), p.2436-2441
• Main Authors: Kadayat, Tara Man, Banskota, Suhrid, Bist, Ganesh, Gurung, Pallavi, Magar, Til Bahadur Thapa, Shrestha, Aarajana, Kim, Jung-Ae, Lee, Eung-Seok
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Antiinflammatory agents; Cell Adhesion - drug effects; Colitis - chemically induced; Colitis - drug therapy; Colitis - pathology; Disease Models, Animal; Dose-Response Relationship, Drug; Epithelial Cells - drug effects; Epithelial Cells - pathology; HT29 Cells; Humans; Indans - administration & dosage; Indans - chemical synthesis; Indans - pharmacology; Inflammatory bowel disease; Inflammatory Bowel Diseases - drug therapy; Inflammatory Bowel Diseases - pathology; Molecular Structure; Monocytes - drug effects; Monocytes - metabolism; Pyridine-linked indanones; Pyridines - administration & dosage; Pyridines - chemistry; Pyridines - pharmacology; Rats; Structure-Activity Relationship; Synthesis; TNF-α; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.06.012

[Display omitted] •Synthesis of pyridine-linked indanone derivatives 2, 5a–l, 8a–c and 11a–c.•Potent anti-inflammatory effect by compounds 2, 5a, 5b, 5d, 5f, and 5h.•Hydroxyl group substitution is favorable but alkoxy groups at indanone ring is less favored.•5b and 5d as potential agents for inflammatory bowel disease. A series of pyridine-linked indanone derivatives were designed and synthesized to discover new small molecules for the treatment of inflammatory bowel disease (IBD). Compounds 5b and 5d exhibited strongest inhibitory activity against TNF-α-induced monocyte adhesion to colon epithelial cells (an in vitro model of colitis). In TNBS (2,4,6-trinitrobenzenesulfonic acid)-induced rat colitis model, oral administration of the compounds 5b and 5d ameliorated colitis with significant recovery in altered expressions of E-cadherin, TNF-α and IL-1β expressions, indicating 5b and 5d as potential agents for therapeutics development against IBD.