Design and synthesis of bioisosteric tetrasubstituted thiophenes as novel anti-inflammatory agents: Part-I

Abstract

Fourteen novel tetrasubstituted thiophene esters (VIIIa-VIIIg) and the corresponding acid derivatives (IXa- IXg) were designed, synthesized, characterized and evaluated for their anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at doses of 10, 20 and 40 mg/kg body weight. The designed compounds have the pharmacophoric features of COX-1 (acid/ester, as in mefenamic acid), 5-LOX and the p38 MAP kinase inhibitors. In the present study we report the optimization of electron withdrawing groups in the bioisosteric tetrasubstituted thiophenes at the para position in anilino moiety (R3) and in benzoyl moiety (R2) falling in +σ , ±π quadrant of the Craig plot and the effect on their anti-inflammatory activity. The reaction was brought about by reacting equimolar amount of the enamine (II) with arylisothiocyanates to yield the addition products (III), which on reaction with substituted phenacyl bromides (V) gave tetrasubstituted thiophene esters (VIIIa-VIIIg). The corresponding acids (IXa-IXg) of the tetrasubstituted thiophene esters (VIIIa-VIIIg) were prepared by hydrolyzing the methyl ester in methanol with one equivalent of potassium hydroxide solution at room temperature. All the synthesized compounds were evaluated for their anti-inflammatory activity. Compounds VIIIe (30%), VIIIf (55%), VIIIg (54%), IXc (37%), IXf (70%) and IXg (46%) showed moderate to good activity at a dose of 20 mg/kg when compared with the activity of ibuprofen (33%). The most active compound among the whole series was IXf, a bioisosteric analogue of mefenamic acid which showed 63% protection at 10 mg/kg, 70% at 20 mg/kg, and 60% at 40 mg/kg to inflamed paw. These results indicate that the presence of 2,4-Cl2 substitution at R2 position in tetrasubstituted thiophenes is one of the requirements for eliciting comparable antiinflammatory activity in both the ester and acid series. VIIIf, VIIIg, IXf and IXg were also tested for their analgesic activity in acetic acid-induced writhing response in albino mice at a dose of 10 mg/kg and showed 15%, 35%, 10% and 32% inhibition, respectively. Keywords : tetrasubstituted thiophenes, COX- inhibitors, p38 MAP kinase inhibitors, anti-inflammatory activity, analgesic activity Ethiopian Pharmaceutical Journal Vol. 24, 2006: 1-12