DIPEAc promoted one-pot synthesis of dihydropyrido[2,3-d:6,5-d′]dipyrimidinetetraone and pyrimido[4,5-d]pyrimidine derivatives as potent tyrosinase inhibitors and anticancer agents: in vitro screening, molecular docking and ADMET predictions

Abstract

The present method provides a wide scope and quick access to dihydropyrido[2,3-d:6,5-d′]dipyrimidinetetraone and pyrimido[4,5-d]pyrimidine derivatives in good to excellent isolated yields from a one-pot three-component reaction of aldehydes, barbituric acid and ammonium acetate/urea in DIPEAc at room temperature. Major advantages of the present methodology are: use of green solvent, short reaction time, catalyst free, compatibility with a wide range of substrates, ease of recovery, reusability of the reaction medium, and DIPEAc as an alternative solvent and catalyst. All the synthesized compounds (3a–k) and (4a–g) were evaluated for their in vitro anticancer and tyrosinase inhibitory activity. In vitro anticancer screening of the synthesized compounds was performed against MCF-7, HeLa and A-549 cancer cell lines and 3f, 3h and 3i showed good activity. The compounds 3a, 3c, 3f and 3i showed good in vitro anticancer activity against SK-MEL-2. The synthesized compounds were also tested on non-tumorigenic MCF-10A cell lines and were found to be selective towards their cancer cell lines. At the IC₅₀ concentration of compound 3f there were typical morphological changes such as cell wall deformation, cell detachment, cell shrinkage and a reduced number of viable cells in MCF-7 cancer cell lines in comparison to control cells. Among the series, compounds 3f, 3h and 3i excellently inhibited the tyrosinase enzyme. A molecular docking study of the compounds was also performed and compounds showed overall very effective binding modes and good agglomeration in the active site by forming various interactions with active site residues. The in silico ADMET properties of the synthesized compounds showed that they possess worthy oral drug like properties.