Synthesis of novel bis-allyloxy and hydroxypropoxy derivatives of 4, 5-diaryl thiophene-2-carboxylic acid and their biological evaluation

Abstract

In our earlier studies, we have shown that the introduction of amino moieties at carboxylic acid of 4,5-diarylthiophene-2-carboxylic acid significantly improved the anti-inflammatory activity of the compound against the standard drug diclofenac sodium. In the present study, we have synthesized new derivatives of 4,5-diarylthiophene-2-carboxylic acid by modifying the hydroxyl group of the phenyl ring and carboxylic acid group of the thiophene ring. A series of novel 4,5-diarylthiophene-2-carboxylic acid derivatives containing bis-allyloxy and hydroxypropoxy with methyl or ethyl ester moieties were synthesized, characterized and subsequently evaluated for anti-inflammatory and antioxidant property. Among the novel compounds, the inhibition of bovine serum albumin denaturation assay revealed that the compound 4,5-bis(4-(3-hydroxypropoxy)phenyl)thiophene-2-carboxylic acid (15) and ethyl ester (13) having anti-inflammatory activity better than the standard drug diclofenac sodium. The antioxidant screening showing 4,5-bis(4-(allyloxy)phenyl)thiophene-2-carboxylic acid (10), 4,5-bis(4-(3-hydroxypropoxy)phenyl)thiophene-2-carboxylic acid methyl ester (11) and 4,5-bis(4-(3-hydroxypropoxy)phenyl)thiophene-2-carboxylic acid ethyl ester (13) exhibited a slightly moderate antioxidant activity than standard ascorbic acid. Molecular docking analysis was performed for the synthesized compounds with the cyclooxygenase-2 (COX-2) receptor (PDB 1D: 1PXX). Docking studies revealed that all the synthesised compounds exhibit greater binding affinity than the standard drug. Particularly, the compound ethyl 4,5-bis(4-(allyloxy)phenyl)thiophene-2-carboxylate (8) and allyl 4,5-bis(4-(allyloxy)phenyl)thiophene-2-carboxylate (9) having high free energy binding of −10.40 and −10.48 Kcal/mol, respectively. Synopsis: A new series of bis-allyloxy and hydroxypropoxy substituted 4,5-diarylthiophene-2-carboxylic acid derivatives were synthesized, characterized, evaluated their in vitro anti-inflammatory and anti-oxidant activity, and performed molecular docking study.