Design,synthesis and pharmacological evaluation of novel tetrasubstituted thiophene analogues as anti-inflammatory agents |
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Authors: | Khurshid I. Molvi Vasudevan Sudarsanam Madhubhai M. Patel Navedul Haque |
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Affiliation: | 1. School of Pharmacy, Faculty of Medical Sciences, Jimma University, P.O.Box: 378, Jimma, Ethiopiakhurshidmolvi@yahoo.co.in;3. Department of Medicinal Chemistry, B. V. Patel Pharmaceutical Education and Research Development Centre, Ahmedabad Gujarat, India;4. Shree S. K. Patel College of Pharmaceutical Education and Research, Ganpat Vidayanagar, Mehsana Gujarat, India;5. Department of Chemistry, Faculty of Education, Jimma University, P.O. Box No: 378, Jimma, Ethiopia |
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Abstract: | A new series of tetrasubstituted thiophene analogues (4a-4f, 5a-5f and 8a-8i) were designed incorporating the pharmacophoric features of COX-1 (as in fenamates), 5-LOX and the p38 MAP kinase inhibitors. The designed series was synthesized by nucleophilic addition of aryl/aroylisothiocyanate and enamine (2) yielding the addition product l-(α-Carbomethoxy-β-aminothiocrotonoyl)-aryl/aroyl amines (3/7); which on reaction with substituted phenacyl bromides gave the targeted tetrasubstituted thiophene esters (4a-4f / 8a-8i). The tetrasubstituted thiophenes esters (4a-4f ) on hydrolysis with one equivalent of potassium hydroxide solution in methanol at room temperature gave corresponding acids (5a-5f ). All the targeted compounds were evaluated for their anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at the doses of 10, 20 and 40 mg/kg body weight using standard drugs mefanamic acid and ibuprofen. The compounds (4c, 4e, 4f, 5f, 8a- 8i) which gave reasonable protection to the inflamed paw, eliciting good or moderate comparable anti-inflammatory activity were selected for investigating their analgesic activity using acetic acid induced writhing response test in albino mice at 10 mg/kg dose using standard drug ibuprofen and in order to arrive at possible mechanism of their anti-inflammatory activity, in vitro antioxidant nitric oxide radical scavenging assay at the concentrations of 5, 10, 15, 20, 25, 30 and 35 μg/mL were performed using standard drug ascorbic acid. |
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Keywords: | Tetrasubstituted thiophenes COX-inhibitors Anti-inflammatory activity Analgesic activity Antioxidant activity |
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