Scouting Different Phosphodiesterase 4 Inhibitor Chemotypes in Silico To Guide the Design of Anti‐inflammatory/Antioxidant Agents

Abstract

AbstractDuring the last years, we developed a large library of new selective phosphodiesterase 4D inhibitors, maintaining the catechol portion of the well‐known PDE4 inhibitor Rolipram, featuring different substitutions in place of the lactam group of this reference compound. Based on the X‐ray analysis of PDE4 inhibitors (PDE4Is) previously synthesized by us and of naphthyridine‐ and naphthyridinone‐containing derivatives exhibiting PDE4 inhibitory ability described in the literature, we designed and synthesized new compounds 1–3. All of them were screened in silico as putative PDE4Is, via molecular docking studies to exploit structural variation at the catechol group to gain further contacts especially with the flat aromatic residues (Phe506 and Phe538) of enzyme. Subsequent in silico prediction of ADMET properties and in vitro biological assays on platelets and endothelial cells are in good agreement with our previous data concerning the antioxidant/anti‐inflammatory activity exhibited by our previous PDE4Is and similarly to other well‐known PDE4Is.