Inflammation is an important pathological component of many diseases. It has been treated for many years with steroids and non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs non-selectively inhibit cyclooxygenases 1 and 2 (COX-1 and 2), the key enzymes responsible for the synthesis of prostaglandins (PGs). Although these drugs have good activity, they still suffer from many side effects which, in many cases, are not tolerable. The side effects are mainly due to their inhibition of COX-1 enzyme, which has an important physiological role in many tissues. Selective COX-2 inhibitors have been introduced to the US market as safer anti-inflammatory agents with lower side effects than associated with conventional NSAIDs. Unfortunately, two of these selective inhibitors were withdrawn from the market due to clinically reported side effects. Accordingly, there is a need for safer compounds from this class to fill the gap. During our optimization of Suzuki-type coupling reaction for the synthesis of some biologically active compounds, we discovered a novel class of COX-2 inhibitors that is based on the benzothiazole ring system. Similarity search for one of our reaction substrates suggested that our compounds could be selective COX-2 inhibitors. This new class can be synthesized in two synthetic steps from commercially available aromatic carboxylic acids or aldehydes by applying the newly developed reaction in our lab which uses palladacycles to facilitate Suzuki-type coupling. The optimized reaction proceeds in very good yield (75-99%) with wide substrate scope and functional group tolerability. Six compounds showed promising activity and selectivity against COX-2 and one of them has activity comparable to celecoxib in the biochemical assay. The encouraging activities of these new compounds and their rapid accessibility via the optimized coupling reaction make positive contributions in the areas of palladium coupling chemistry and COX-2 selective inhibitors.<br/>

Palladacycle-facilitated ligand-free Suzuki coupling of hindered aryl bromides yields potent and selective COX-2 inhibitors

254th National Meeting (2017)

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