Novel substituted and fused pyrrolizine derivatives: Synthesis, anti-inflammatory and ulcerogenecity studies

• Published in: European journal of medicinal chemistry Vol. 45; no. 2; pp. 482 - 491
• Main Authors: ABBAS, Safinaz E, AWADALLAH, Fadi M, IBRAHIM, Nashwa A, GOUDA, Ahmed M
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier 01-02-2010
• Subjects: Analgesics; Analgesics - adverse effects; Analgesics - chemistry; Analgesics - pharmacology; Analgesics - therapeutic use; Animals; Anti-Inflammatory Agents - adverse effects; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Edema - drug therapy; Female; Male; Medical sciences; Mice; Neuropharmacology; Pharmacology. Drug treatments; Pyrroles - adverse effects; Pyrroles - chemistry; Pyrroles - pharmacology; Pyrroles - therapeutic use; Rats; Ulcer - chemically induced; Pentacyclic compound; Rat; Angular nitrogen heterocycle; Toxicity; Lactam; Ulcerogenicity; Gastroduodenal; Pyrimidopyrrolizines; Structure activity relation; Carboxylic acid; Bicyclic compound; Ulcer; Chemical synthesis; Rodentia; Antiinflammatory agent; Oral administration; Pyrrolizines; Tricyclic compound; Vertebrata; Mammalia; Analgesic; Mouse; Animal; Carboxamide; Anti-inflammatory activity; Analgesic activity
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2009.10.031

Synthesis of several substituted pyrrolizines 10a-f, 11a-f, 13a-c, pyrimidopyrrolizines 14a-c, 15a-c, and pyrrolizinopyrimidoisoindoles 12a-c was discussed. The starting compounds 6-amino-7-cyano-N-(4-(un)substitutedphenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamides 9a-c were reacted with different aldehydes, acid chlorides, and acid anhydrides to give the target compounds. The structures of the new compounds were characterized by spectral and elemental analyses. All compounds were tested for their anti-inflammatory activity using the carrageenan-induced rat paw oedema model and exhibited weak to good activities compared to ketorolac as the reference drug. Also, analgesic activity of selected compounds, which are the most active in the anti-inflammatory screening, was measured using the acetic acid-induced writhing model; revealing activities comparable to or higher than ketorolac. Ulcer indices for the most active compounds were calculated and some compounds showed no or minimal ulcerogenic effect compared to ketorolac.