Design and biological evaluation of 3-substituted quinazoline-2,4(1,3)-dione derivatives as dual c-Met/VEGFR-2-TK inhibitors.

The dual c-Met/vascular endothelial growth factor receptor 2 (VEGFR-2) TK inhibition is a good strategy to overcome therapeutic resistance to small molecules VEGFR-2 inhibitors. In this study, we designed 3-substituted quinazoline-2,4(1,3)-dione derivatives as dual c-Met/VEGFR-2 TK inhibitors. We introduced new synthetic methods for reported derivatives of 3-substituted quinazoline-2,4(1,3)-dione -, in addition to the preparation of some new derivatives namely, and -. Three compounds namely, , , and showed substantial amount of inhibition for both c-Met and VEGFR-2 TK (IC range 0.052-0.084 µM). Both compounds , showed HB with highly conserved residue Asp1222 in the HB region of c-Met TK. For VEGFR-2 TK, compound showed HB with a highly conserved residue Asp1046 in the HB region. Compound showed HB with Glu885 and Asp1046. Moreover, prediction of pharmacokinetic and physicochemical parameters of target compounds was carried out using SwissADME website. The quinazoline-2,4(1,3)-dione derivatives are promising antiproliferative candidates that require further optimisation.HighlightsNew 3-substituted quinazoline-2,4(1,3)-dione derivatives were synthesised and characterised.Compounds and showed higher cytotoxic activity than cabozantinib against HCT-116 colorectal cell lines.Both compounds and showed less toxicity to WI38 normal cell line compared to HCT 116 colon cancer cell line.Compound was superior to cabozantinib in VEGFR-2 inhibition while compound was equipotent to cabozantinib.Compounds and showed remarkable c-Met inhibitory activity.Compounds and arrested cell cycle and induced significant levels of apoptosis. ADME prediction revealed high oral bioavailability and enhanced water solubility of target compounds as compared to cabozantinib.Target compounds interacted with both c-Met and VEGFR-2 active site in similar way to cabozantinib.