A New Pathway for the Preparation of Pyrano[2,3-]pyrazoles and molecular Docking as Inhibitors of p38 MAP Kinase.

We report a new pathway to synthesize pyrano[2,3-]pyrazoles and their binding mode to p38 MAP kinase. Pyrano[2,3-]pyrazole derivatives have been prepared through a four-component reaction of benzyl alcohols, ethyl acetoacetate, phenylhydrazine, and malononitrile in the presence of sulfonated amorphous carbon and eosin Y as catalysts. All products were characterized by melting point, H and C NMR, and HRMS (ESI). The products were screened for their binding activities to both the ATP-binding pocket and the lipid-binding pocket of p38 MAP kinase, using a structure-based flexible docking provided by the engine ADFR. The results showed that eight synthesized compounds had a higher affinity to the lipid pocket than to the other target site, which implied potential applications as allosteric inhibitors. Finally, the most biologically active compound, , had a binding affinity comparable to those of other proven lipid pocket inhibitors, with affinity to the target pocket reaching -10.9932 kcal/mol, and also had the best binding affinity to the ATP-binding pockets in all of our products. Thus, our research provides a novel pathway for synthesizing pyrano[2,3-]pyrazoles and bioinformatic evidence for their biological capability to block p38 MAP kinase pockets, which could be useful for developing cancer or immune drugs.