A rapid synthesis of 5-substituted 7-amino-6-cyano-1,5-dihydro-1H-pyrano[2,3-d]pyrimidine-2,4(3H)-diones and their in silico / in vitro evaluation against SIRT1

Abstract

The 5-substituted 7-amino-6-cyano-1,5-dihydro-2H-pyrano[2,3-d]pyrimidine-2,4(3H)-diones were explored for their potential inhibitory properties against SIRT1 (Sirtuin 1). The rapid access to this class of compounds was achieved via a sonochemical approach involving the Wang-OSO3H catalyzed three component reaction of barbituric acid, aromatic aldehyde and malononitrile in water. A range of desired products was prepared by using this methodology in good to acceptable yields. The potential of all the synthesized compounds against SIRT1 was initially assessed in silico when three of them e.g. 4i, 4k and 4m emerged as the possible hits. The compound 4i participated in interactions nearly comparable to that of the native ligand Ex527a that involved three hydrogen bonds (H-bonds) (two via its -N-C = O moiety with ILE347 and ASP348 and one via its CN group with HIS363) and interactions via its 3-bromophenyl moiety with ILE411 and PHE297. Further, the docking of 4i, 4k and 4m into the hSIRT2 in silico revealed their weaker interactions with this protein thereby their probable selectivity towards SIRT1 over SIRT2. A majority of the synthesized compounds including 4i, 4k and 4m showed > 50% inhibition when tested against SIRT1 in vitro. The SAR within the current series of compounds suggested a key role of the group present at the C-5 position of the 7-amino-6-cyano-1,5-dihydro-2H-pyrano[2,3-d]pyrimidine-2,4(3H)‑dione ring. Based on SIRT1 IC50 values the compound 4i was identified as the most potent among all the compounds tested and was several fold more potent than nicotinamide. The compound 4i also showed effects on MCF7 and HEK 293T cell lines and the in silico assessment predicted its favorable pharmacokinetic properties. Thus, 4i emerged as an initial hit for further pharmacological studies.