Synthesis and Pharmacological Evaluation of Tetrazolobenzimidazoles as Novel Anti-inflammatory Agents.

BACKGROUND: Currently used anti-inflammatory drugs are associated with some severe side effects such as gastric irritation, which may range from simple discomfort to ulcer formation. Therefore, the development of potent anti-inflammatory drugs with fewer side effects is important. Benzimidazole, tetrazole and its various derivatives have been used in the synthesis of numerous heterocyclic compounds. In the past few decades, these compounds received much attention due to their diverse array of biological activities. As these heterocycles are known to possess anti-inflammatory activity individually, we thought it worthwhile to link these heterocycles, synthesize them and evaluate for possible changes in this anti-inflammatory activity.

METHODS: Novel benzimidazole linked tetrazole compound 2-{[2-(1H-tetrazole-5-yl)ethyl] sulfanyl}-1,3-benzimidazole (3) was synthesized by cyclization of 3-(1,3-benzimidazol-2-ylsulfanyl) propanenitrile in presence of sodium azide. A series of tetrazolobenzimidazole derivatives (3a-h) were synthesized by the reaction of compound (3) with acid chlorides. All the synthesized compounds were subjected to structural elucidation by IR, 1H-NMR spectroscopy, Mass spectrometry and elemental analyses. The newly synthesized compounds were screened for anti-inflammatory activity by carrageenan-induced paw oedema method in albino rats.

RESULTS: Compounds (3a, 3c, 3g) which contain acetyl, benzoyl and benzoyl moieties; respectively at N-1of tetrazole exhibited anti-inflammatory activities comparable with standard drug diclofenac. Other compounds exhibited anti-inflammatory activity less than the standard. The differences between control and treatment group were tested using one way ANOVA followed by Dunnett's test. A probability value less than 0.01 was considered to be statistically significant. The GraphPad Instat 3.0 version was used for statistical analysis.

CONCLUSION: Synthesized compounds having anti-inflammatory activity better than standard were found to be 1-{5-[2-(benzimidazol-2-yl-sulfanyl)ethyl]-2H-tetrazol-2yl}methanone (3c) and 1-{5-[5-methoxy-2-(benzimidazol-2-yl-sulfanyl)ethyl]-2H-tetrazol-2yl}methanone (3g) and the compounds (3a, 3e, 3f) were found to exhibit anti-inflammatory activity comparable to that of standard. All the compounds were found to cause less gastric ulceration than the standard drug diclofenac.