Novel 3-phenylquinazolin-2,4(1H,3H)-diones as dual VEGFR-2/c-Met-TK inhibitors: design, synthesis, and biological evaluation

  • Sci Rep. 2023 Oct 30;13(1):18567. doi: 10.1038/s41598-023-45687-y.
Abdelfattah Hassan  1 ,  Ahmed M Mosallam  2 ,  Amal O A Ibrahim  2 ,  Mohamed Badr  3 ,  Aboubakr H Abdelmonsef  4
Affiliations
  • 1. Department of Medicinal Chemistry, Faculty of Pharmacy, South Valley University, Qena, Egypt. [email protected].
  • 2. Department of Chemistry, Faculty of Science, South Valley University, Qena, Egypt.
  • 3. Department of Biochemistry, Faculty of Pharmacy, Menoufia University, Menoufia, Egypt.
  • 4. Department of Chemistry, Faculty of Science, South Valley University, Qena, Egypt. [email protected].
PMID: 37903949 DOI: 10.1038/s41598-023-45687-y
Abstract

Multitarget Anticancer drugs are more superior than single target drugs regarding patient compliance, drug adverse effects, drug-drug interactions, drug resistance as well as pharmaceutical industry economics. Dysregulation of both VEGFR-2 and c-Met tyrosine kinases (TKs) could result in development and progression of different human cancers. Herein, we reported a novel series of 3-phenylquinazolin-2,4(1H,3H)-diones with thiourea moiety as dual VEGFR-2/c-Met TKs. Compared to sorafenib, cabozantinib went behind VEGFR-2 inhibition to target c-Met TK. The dual VEGFR-2/c-Met inhibitory activity of cabozantinib is due to a longer HB domain than that of sorafenib. Based on pharmacophore of cabozantinib analogues, we designed new dual VEGFR-2/c-Met TKs. We synthesized the target compounds via a new single pot three-component reaction. The cytotoxic activity of synthesized compounds was conducted against HCT-116 colorectal Cancer cell line. Compounds 3c and 3e exhibited the highest cytotoxic activity against HCT-116 cell line (IC50 1.184 and 3.403 µM, respectively). The in vitro enzyme inhibitory activity was carried out against both VEGFR-2 and c-Met TKs. Compound 3e has the highest inhibitory activity against both VEGFR-2/c-Met (IC50 = 83 and 48 nM, respectively). Docking studies showed that α-oxo moiety in quinazoline ring formed hydrogen bond HB with Met1160 residue in the adenine region of c-Met TK.

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