Design, synthesis, anticancer evaluation and molecular docking studies of chalcone linked pyrido[4,3-b]pyrazin-5(6H)-one derivatives

Abstract

A series of novel chalcone derivatives pyrido[4,3-b]pyrazin-5(6H)-one (10a-j) were designed, synthesized and their structures were confirmed by 1H NMR, 13C NMR and mass spectral data. Further, all derivatives were tested for their anticancer activities against five human cancer cell lines such as MCF-7 (breast cancer), A-549 (lung cancer), Colo-205 (colon cancer), A2780 (ovarian cancer) and DU-145 (prostate cancer) by employing MTT assay. The clinically used drug etoposide was used as standard reference and the anticancer activity was expressed as the IC50 in µM. Among the ten compounds examined compounds, 10b, 10c, 10d, 10h, and 10i possessed more promising anticancer activity. A molecular docking study implying ATR kinase was carried out to observe the binding mode of chalcone derivatives pyrido[4,3-b]pyrazin-5(6H)-one (10a-j) on the active site of ATR kinase. The most promising compound, 10h showed π−π stacking interaction of trimethoxy phenyl and pyridone moiety with the residue Trp850, while the carbonyl (α,β-unsaturated carbonyl) and methoxy functions showed H-bond interaction with the residue Ser773 and Thr856 respectively.