Design and biological evaluation of 3-substituted quinazoline-2,4(1H,3H)-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(1H,3H)-dione derivatives as dual c-Met/VEGFR-2 TK inhibitors. We introduced new synthetic methods for reported derivatives of 3-substituted quinazoline-2,4(1H,3H)-dione 2a–g, in addition to the preparation of some new derivatives namely, 3 and 4a–j. Three compounds namely, 2c, 4b, and 4e showed substantial amount of inhibition for both c-Met and VEGFR-2 TK (IC(50) range 0.052–0.084 µM). Both compounds 4b, 4e showed HB with highly conserved residue Asp1222 in the HB region of c-Met TK. For VEGFR-2 TK, compound 4b showed HB with a highly conserved residue Asp1046 in the HB region. Compound 4e showed HB with Glu885 and Asp1046. Moreover, in silico prediction of pharmacokinetic and physicochemical parameters of target compounds was carried out using SwissADME website. The quinazoline-2,4(1H,3H)-dione derivatives are promising antiproliferative candidates that require further optimisation. HIGHLIGHTS: New 3-substituted quinazoline-2,4(1H,3H)-dione derivatives were synthesised and characterised. Compounds 4b and 4e showed higher cytotoxic activity than cabozantinib against HCT-116 colorectal cell lines. Both compounds 4b and 4e showed less toxicity to WI38 normal cell line compared to HCT 116 colon cancer cell line. Compound 4b was superior to cabozantinib in VEGFR-2 inhibition while compound 2c was equipotent to cabozantinib. Compounds 4b and 4e showed remarkable c-Met inhibitory activity. Compounds 4b and 4e arrested cell cycle and induced significant levels of apoptosis. In silico 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.