Design, synthesis, and anti-proliferative evaluation of new quinazolin-4(3H)-ones as potential VEGFR-2 inhibitors

Khaled El-Adl; Abdel-Ghany A El-Helby; Rezk R Ayyad; Hazem A Mahdy; Mohamed M Khalifa; Hamdy A Elnagar; Ahmed B M Mehany; Ahmed M Metwaly; Mostafa A Elhendawy; Mohamed M Radwan; Mahmoud A ElSohly; Ibrahim H Eissa

doi:10.1016/j.bmc.2020.115872

Design, synthesis, and anti-proliferative evaluation of new quinazolin-4(3H)-ones as potential VEGFR-2 inhibitors

Bioorg Med Chem. 2021 Jan 1:29:115872. doi: 10.1016/j.bmc.2020.115872. Epub 2020 Nov 12.

Affiliations

¹ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt. Electronic address: eladlkhaled74@yahoo.com.
² Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
³ Zoology Department, Faculty of Science, Al-Azhar University, Cairo 11884, Egypt.
⁴ Pharmacognosy Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
⁵ Department of Agriculture Chemistry, Faculty of Agriculture, Damietta University, Damietta, Egypt; National Center for Natural Products Research, University of Mississippi, MS 38677, USA.
⁶ National Center for Natural Products Research, University of Mississippi, MS 38677, USA; Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
⁷ National Center for Natural Products Research, University of Mississippi, MS 38677, USA; Department of Pharmaceutics and Drug Delivery, University of Mississippi, University, MS 38677, USA.
⁸ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address: Ibrahimeissa@azhar.edu.eg.

PMID: 33214036
DOI: 10.1016/j.bmc.2020.115872

Abstract

Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. Thus, nineteen new quinazoline-4(3H)-one derivatives were designed and synthesized. Preliminary cytotoxicity studies of the synthesized compounds were evaluated against three human cancer cell lines (HepG-2, MCF-7 and HCT-116) using MTT assay method. Doxorubicin and sorafenib were used as positive controls. Five compounds were found to have promising cytotoxic activities against all cell lines. Compound 16_f, containing a 2-chloro-5-nitrophenyl group, has emerged as the most active member. It was approximately 4.39-, 5.73- and 1.96-fold more active than doxorubicin and 3.88-, 5.59- and 1.84-fold more active than sorafenib against HepG2, HCT-116 and MCF-7 cells, respectively. The most active cytotoxic agents were further evaluated in vitro for their VEGFR-2 inhibitory activities. The results of in vitro VEGFR-2 inhibition were consistent with that of the cytotoxicity data. Molecular docking of these compounds into the kinase domain, moreover, supported the results.

Keywords: Anticancer; Molecular docking; Quinazolin-4(3H)-one; VEGFR-2.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Quinazolinones / chemical synthesis
Quinazolinones / chemistry
Quinazolinones / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Quinazolinones
KDR protein, human
Vascular Endothelial Growth Factor Receptor-2