Synthesis and Biological Evaluation of 5,6-Dimethylthieno[2,3-d]Pyrimidin-4(3H)-One Derivatives as Selective Cyclooxygenase 2 Inhibitors

Abstract:

Background: NSAIDs are well-established for treating pain, fever, and inflammation mainly by inhibiting inducible Cyclooxygenase 2 (COX-2) isoenzyme. However, most of the marketed NSAIDs non-selectively inhibit physiological COX-1 and exhibit adverse side effects like GI ulcers, renal toxicity, and platelet disorder. Moreover, cardiac side effects also led to the market withdrawal of some of the potential selective COX-2 inhibitors. Thus, several investigations are underway by researchers from academia and industry in search of safer and more effective COX-2 selective inhibitors devoid of existing side effects. Materials and Methods: In this work, four 2-substituted-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one derivatives (5,6,7,8 and 9) have been synthesized, purified, and characterized based on their physical and spectral data. These compounds were evaluated (in vitro) for their affinity and selectivity for human COX-2 enzyme against COX-1 isoenzyme using indomethacin as a positive control. Results and Discussion: Compound 5 with para fluorophenyl substituent was found to be the most potent, exhibiting better inhibition and selectivity towards COX-2 isoenzyme (IC₅₀=42.19 M, SI=4.81) against COX-1 isoenzyme (IC₅₀=202.96 M, SI=4.81) as compared to the other derivatives (6-8). Conclusion: The activity of compound 5 is promising compared to the non-selective drug indomethacin (IC₅₀ COX-1=0.68 M, COX-2=18.3 M, SI=0.04). Therefore, compound 8 can be considered a lead molecule for further optimization to develop novel selective COX-2 inhibitors at nanomolar potency.

Keywords: Thieno[2,3-d]pyrimidines, Cyclooxygenase 2 (COX-2) inhibitors, Inflammation.