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

This study explores new anti-inflammatory agents by synthesizing pyrazoline-pyridine hybrids with N-butylsulfonated covalent organic framework (COF-SO₃H) 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 IC₅₀ 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.