Non-acidic Biarylcarbaldehydes as Potent COX-2 Inhibitors: Design, Microwave Synthesis, and Multidisciplinary Validation With Improved Gastrointestinal Safety.

This study delineates the rational design, microwave-assisted synthesis, and comprehensive pharmacological evaluation of a novel series of nonacidic biarylcarbaldehydes (1a-l) as selective COX-2 inhibitors. The methodology involved substituting the conventional acidic pharmacophore in NSAIDs with a neutral aldehyde to enhance gastrointestinal safety. The derivatives were synthesized with high yields (90%-99%) through an optimized Suzuki-Miyaura cross-coupling procedure. In silico ADMET analysis demonstrated excellent drug-like characteristics and oral bioavailability throughout the series. Docking studies revealed strong binding affinities to COX-2, particularly for compound 1g (MolDock score: -136.79 kcal/mol), with critical interactions at Tyr385 and Trp387 residues. To assess metabolic stability, the acidic metabolites (2a-l) were modeled, maintaining or improving enzymatic affinity. Molecular dynamics simulations (100 ns) confirmed the structural stability of these complexes. In vivo evaluation utilizing the carrageenan-induced rat paw edema model supported the computational findings, with lead compound 1g achieving complete edema reduction at 4 h, surpassing diclofenac. These results suggest that biarylcarbaldehyde frameworks serve as promising nonacidic alternatives for anti-inflammatory therapy with an improved safety profile.