Wang resin catalyzed sonochemical synthesis of dihydropyrano[2,3-c]pyrazole derivatives and their interactions with SIRT1

Abstract

The pyrano[2,3-c]pyrazole framework was explored for the design and synthesis of compounds as potential inhibitors of SIRT1. The feasibility of this strategy was reasoned by the unique structural features of this scaffold and the reported cytotoxicity of compounds containing this framework. The sonochemical synthesis of target compounds was accomplished by using the Wang resin (Wang-OSO3H) as a recoverable catalyst under eco-friendly conditions. Thus, the desired 4-substituted 6-amino-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile derivatives were prepared via a 4-component reaction of β-ketoester, hydrazine, aldehyde and malononitrile in pure water in good yields. The recyclability of the catalyst was demonstrated successfully. All the synthesized compounds were initially assessed in silico against the targeted protein i.e. hSIRT1 that indicated compound 5i and 5l along with several other compounds as possible inhibitors. Both of these compounds participated in two vital H-bond interactions with the residue GLN345 and ASN346 in silico that was reflected in their estimated total energy. In vitro assessment of these pyrano[2,3-c]pyrazoles against SIRT1 revealed encouraging inhibitory activities (> 50% inhibition) that was in agreement with the results of docking studies. Indeed, 5i and 5l were identified as the most active compounds in this series. The Structure-Activity-Relationship (SAR) study suggested important role of the C-4 aryl substituent along with the N-1 phenyl ring of the pyrano[2,3-c]pyrazole moiety in the SIRT1 inhibitory activities of this class of compounds. Thus, a OH or Cl group at the p-position of the C-4 benzene ring together with the N-1 phenyl moiety appeared to be beneficial for activity. Overall, the initial design and then sonochemical synthesis followed by in silico as well as in vitro studies allowed identification of pyrano[2,3-c]pyrazole based small molecules as potential inhibitors of SIRT1.