Abstract
In order to reduce the ulcerogenic effect of ibuprofen, its carboxylic group has been converted into 5-membered heterocyclic rings. Various 1,3,4-oxadiazoles (3-8, 16-21), 1,2,4-triazoles (22-27), 1,3,4-thiadiazoles (28-30), and 1,2,4-triazine (9) derivatives of ibuprofen were prepared by cyclization of 2-(4-i-butylphenyl) propionic acid hydrazide (2) and N1-[2-(4-i-butylphenyl) propionyl]-N4-alkyl/arylthiosemicarbazides (10-15) under various reaction conditions. The cyclized derivatives were screened for their anti-inflammatory activity by the carrageenan induced rat paw edema method and showed 50 to 86% inhibition, whereas the standard drug ibuprofen showed 92% inhibition at the same oral dose. Five compounds, 7, 16, 18, 22 and 30 that showed more than 80% anti-inflammatory activity were selected to study their analgesic, ulcerogenic and lipid peroxidation activities. All the tested compounds showed a significant reduction in ulcerogenic activity compared to ibuprofen through the severity index 0.5 to 0.8, vs. ibuprofen 1.8. The compounds, that showed less ulcerogenic effect also produced less malondialdehyde content in gastric mucosa, which is one of the end products of lipid peroxidation. The results of biological studies showed that oxadiazole derivative 16 as the lead molecule with maximum anti-inflammatory, analgesic and minimum ulcerogenic and lipid peroxidation activities.