Synthesis, in vitro anti-inflammatory activity and molecular docking studies of novel 4,5-diarylthiophene-2-carboxamide derivatives

A series of novel 4,5-diarylthiophene-2-carboxamide containing alkyl, cycloalkyl, aryl, aryl alkyl and heterocyclic alkyl moieties were synthesized, characterized and subsequently evaluated for anti-inflammatory property. Among the novel compounds, the inhibition of bovine serum albumin denaturation assay revealed that the aryl and aryl alkyl derivatives of 4,5-diarylthiophene-2-carboxamide showed anti-inflammatory activity comparable to the standard drug diclofenac sodium whereas alkyl and cycloalkyl amide derivatives showed less activity. Docking studies with these compounds against cyclooxygenase-2 receptor (PDB 1D: 1PXX) indicated that they exhibit specific interactions with key residues located in the site of the COX2 structure, which corroborates the hypothesis that these molecules are potential ligands of COX2. The analysis of the docking results, which takes into account the hydrophilic and hydrophobic interactions between the ligands and the target, identified N-(4-bromophenyl)-4,5-bis(4-hydroxyphenyl)thiophene-2-carboxamide (6k) having high binding free energy of -11.67 kcal /mole (comparable with standard diclofenac sodium) and the best docking score, indicating effective binding of the compound 6k at the active site.