COF‐SO3H‐Catalyzed Synthesis of Pyrazoline‐Pyridine Hybrids with Dual Antioxidant and Anti‐Inflammatory Activity Targeting PDE4B

Abstract This study explores new anti‐inflammatory agents by synthesizing pyrazoline‐pyridine hybrids with N‐butylsulfonated covalent organic framework (COF‐SO 3 H) as a recyclable catalyst, achieving excellent yields in just one minute. The protocol was successfully scaled up to a multi‐gram scale, highlighting its robustness and efficiency, and it operates without the need for column chromatography. Among the synthesized hybrids, compound 5d , a pyrazoline‐pyridine hybrid bearing an indole moiety, emerged as a potent anti‐inflammatory and antioxidant agent. It effectively inhibited PDE4B activation with an IC 50 value of 99.38 nM, without adversely affecting HEK cells. Compound 5d demonstrated its dual activity by significantly reducing ROS production and restoring mitochondrial health in LPS‐stimulated A549 and HEK cells, while also downregulating IL‐1β and NF‐ĸB/p65 expression in LPS‐stimulated A549 cells. In silico studies confirmed compound 5d ’s strong binding to PDE4B, with stable RMSD and RMSF values, indicating its potential as a stable and effective PDE4B inhibitor. The compound exhibited favorable physicochemical properties, met drug‐likeness criteria, and showed low toxicity as predicted in silico. These findings suggest that compound 5d has significant potential as a therapeutic agent for inflammatory diseases due to its dual anti‐inflammatory and antioxidant activities.