Balancing Efficacy and Safety: Discovery and Biological Activity Evaluation of Novel Nitrogen-Containing Fused Heterocyclic Cyclooxygenase Inhibitors

Nonsteroidal anti-inflammatory drugs (NSAIDs) target cyclooxygenase (COX) Enzymes to relieve pain and inflammation, but their use is often limited by significant gastrointestinal and cardiovascular side effects. Herein, we report the discovery of a novel chemotype of nitrogen-containing fused heterocycles that act as potent dual COX-1/2 inhibitors. Combining virtual screening and structure-based design, we identified compounds 19, 39, 70, and 73 as the most promising analogues, surpassing celecoxib in both COX-2 (IC₅₀ 17.4-31.1 nM; vs celecoxib: 59 nM) and COX-1 inhibition (IC₅₀ 26.4-43.8 nM; vs celecoxib: 1455 nM). In vivo studies further validated their therapeutic potential. These compounds showed robust antinociceptive activity and antiedema efficacy in vivo. Notably, compound 73 exhibited an oral bioavailability of 12.4% in rats and showed no overt toxicity in acute or chronic studies. These findings provide promising preclinical candidates for a new generation of NSAIDs and introduce a novel molecular scaffold for future COX Inhibitor design.