Wang resin catalyzed sonochemical synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines as potential inhibitors of SIRT1

Abstract

The search of new approaches / strategies for the identification of potential anticancer agents prompted us to focus on SIRT1, which is considered as an emerging pharmacological target for cancer. The 2-amino-3,5-dicarbonitrile-6-thio-pyridine was chosen as a framework for the design of new and possible inhibitors of SIRT1. Firstly, the in silico docking of a number of molecules based on this framework not only showed their promising interactions with SIRT1 but also indicated their potential selectivity towards this protein over SIRT2. The study also suggested VAL412, PHE414, ILE347, ALA262, ILE411, HIS363, GLN345, ASN346, ILE270, ILE316, PHE273 and PHE297 as the common interacting residues for these molecules of which VAL412, and PHE414 were mostly involved in the H-bond interactions. A convenient access to these molecules was established via the 3-component reaction (3-CR) of appropriate aliphatic or (hetero)aromatic aldehyde, malononitrile and thiophenol under ultrasound. The reaction was catalyzed by the sulphonic acid-functionalized Wang resin (Wang-OSO3H) and proceeded in aqueous media under open air for 1 h to afford the desired products in 65–86 % yields. The recoverability and recyclability of the catalyst was established and application potential of the methodology was examined. The synthesized 2-amino-3,5-dicarbonitrile-6-thio-pyridines showed encouraging (> 50 %) SIRT1 inhibition in vitro that was in agreement with the findings of docking studies. Indeed, the compound 4n noted as the most encouraging in the in silico docking studies was also found to be the most active hit molecule in the in vitro assay. The Structure-Activity-Relationship (SAR) suggested encouraging activities when the R group at C-4 position was chosen as a t‑butyl group or the 4-NCC6H4 or 3-HOC6H4 or 2-Cl-6-FC6H3 moiety. However, a linear alkyl chain at the C-4 position was found to be unfavorable for SIRT1 inhibition. Collectively, the current research efforts identified the compound 4n as a promising inhibitor of SIRT1 among the current series of 3,5-dicarbonitrile-6-thio-pyridines examined.