Single step synthesis of new fused pyrimidine derivatives and their evaluation as potent Aurora-A kinase inhibitors

A simple, facile, efficient and one pot three-component procedure for the synthesis of pyrazolo[1,5-a]pyrimidines, triazolo[1,5-a]pyrimidines and pyrimido[1,2-a]benzimidazoles ring systems incorporating phenylsulfonyl moiety was developed via the reaction of 1-aryl-2-(phenylsulfonyl)ethanone derivatives 1a–d with the appropriate heterocyclic amine and triethyl orthoformate and evaluated as Aurora-A kinase inhibitors. The cytotoxic activity of the newly synthesized compounds against HST116 colon tumor cell line was investigated. 2,7-Diphenyl-6-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidine (4b) and its p-methoxy analogue 4c were found to be equipotent to Doxorubicin as a reference drug. Molecular modeling study was carried out in order to rationalize the in vitro anti-tumor results.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► We utilize β-keto-β-sulfonylenamines precursors for synthesis fused-heterocycles. ► Aurora-A kinase inhibition assay and anti-colon tumor evaluation. ► Docking study for rationalization of biological activity. ► Two compounds found to be equipotent to Doxorubicin as a reference drug.