Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used therapeutic agents that exhibit frequent and sometimes severe adverse effects, including gastrointestinal ulcerations and cardiovascular disorders. In an effort to obtain safer NSAIDs, we assessed the direct cyclooxygenase (COX) inhibition activity and we investigated the potential COX binding mode of some previously reported 2-(trimethoxyphenyl)-thiazoles. The in vitro COX inhibition assays were performed against ovine COX-1 and human recombinant COX-2. Molecular docking studies were performed to explain the possible interactions between the inhibitors and both COX isoforms binding pockets. Four of the tested compounds proved to be good inhibitors of both COX isoforms, but only compound A3 showed a good COX-2 selectivity index, similar to meloxicam. The plausible binding mode of compound A3 revealed hydrogen bond interactions with binding site key residues including Arg120, Tyr355, Ser530, Met522 and Trp387, whereas hydrophobic contacts were detected with Leu352, Val349, Leu359, Phe518, Gly526, and Ala527. Computationally predicted pharmacokinetic profile revealed A3 as lead candidate. The present data prove that the investigated compounds inhibit COX and thus confirm the previously reported in vivo anti-inflammatory screening results suggesting that A3 is a suitable candidate for further development as a NSAID.
Highlights
Non-steroidal anti-inflammatory drugs (NSAIDs) that act by cyclooxygenase inhibition are a major drug class
We described the preliminary evaluation of the anti-inflammatory potential of the compounds by determining their effects using an induced acute inflammation experimental model [9,18]
Stannous chloride was subsequently added to perform the reduction of COX-derived prostaglandin H2 (PGH2) produced in the reaction of COX leading to prostaglandin F2α (PGF2α)
Summary
Non-steroidal anti-inflammatory drugs (NSAIDs) that act by cyclooxygenase inhibition are a major drug class. Due to their ample therapeutic use that ranges from the treatment of fever and mild pain up to severe chronic inflammatory disorders, NSAIDs are one of the most commonly used medicines. The wide scale, frequent and sometimes long-term use of these drugs has allowed for a very good characterization of their safety profile. It is well established that NSAIDs act by blocking the production of pro-inflammatory prostaglandins through the inhibition of cyclooxygenase (COX). COX-1 is mainly considered a “housekeeping enzyme”.
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