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

ABSTRACT

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 1 g (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 1 g 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.