Design and biological evaluation of 3-substituted quinazoline-2,4(1<i>H</i>,3<i>H</i>)-dione derivatives as dual c-Met/VEGFR-2-TK inhibitors
Creators: name: Hassan, Abdelfattah
name: Mubarak, Fawzy A. F.
name: Shehadi, Ihsan A.
name: Mosallam, Ahmed M.
name: Temairk, Hussain
name: Badr, Mohamed
name: Abdelmonsef, Aboubakr H.
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biochemistry
subject: Medicine
subject: Cell Biology
subject: Molecular Biology
subject: Pharmacology
subject: Biotechnology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: 69999 Biological Sciences not elsewhere classified
subject: FOS: Biological sciences
subject: 80699 Information Systems not elsewhere classified
subject: FOS: Computer and information sciences
subject: Cancer
subject: Hematology

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