Design, synthesis and molecular modeling of new quinazolin-4(3H)-one based VEGFR-2 kinase inhibitors for potential anticancer evaluation

Abdallah E Abdallah; Sally I Eissa; Maged Mohammed Saleh Al Ward; Reda R Mabrouk; Ahmed B M Mehany; Mohamed Ayman El-Zahabi

doi:10.1016/j.bioorg.2021.104695

Design, synthesis and molecular modeling of new quinazolin-4(3H)-one based VEGFR-2 kinase inhibitors for potential anticancer evaluation

Bioorg Chem. 2021 Apr:109:104695. doi: 10.1016/j.bioorg.2021.104695. Epub 2021 Feb 8.

Authors

Abdallah E Abdallah¹, Sally I Eissa², Maged Mohammed Saleh Al Ward³, Reda R Mabrouk³, Ahmed B M Mehany⁴, Mohamed Ayman El-Zahabi⁵

Affiliations

¹ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address: Abdulla_emara@azhar.edu.eg.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11884, Egypt; Faculty of Pharmacy Al-Maareffa University for Science and Technology, Riyadh, Saudi Arabia.
³ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
⁴ Zoology Department, Faculty of Science, Al-Azhar University, Cairo 11884, Egypt. Electronic address: Abelal_81@azhar.edu.eg.
⁵ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address: malzahaby@azhar.edu.eg.

PMID: 33647743
DOI: 10.1016/j.bioorg.2021.104695

Abstract

Globally cancer is the second leading cause of death. So that this work is an attempt to develop new effective anti-cancer agents. In line with pharmacophoric features of VEGFR-2 kinase inhibitors, new nineteen quinazolin-4-one derivatives were designed, synthesized and biologically evaluated for their potential anticancer activity. All target compounds were evaluated in vitro for VEGFR-2 tyrosine kinase inhibition. Then, nine compounds of best results were further investigated by in vitro assay against three human cancer cell lines, namely HepG2, PC3 and MCF. N^'-{2-](3-Ethyl-6-nitro-4-oxo-3,4-dihydroquinazoline-2-yl)thio[acetyl}benzohydrazide (36) was found to be the most potent candidate as it showed IC₅₀ = 4.6 ± 0.06 µM against VEGFR-2 kinase. It also exhibited IC₅₀ = 17.23 ± 1.5, 26.10 ± 2.2 and 30.85 ± 2.3 µg/mL against HepG2, PC3 and MCF, respectively. At the same time it showed IC₅₀ = 145.93 ± 1.1 µg/mL against the normal human lung fibroblasts cell line (WI-38), indicating good selectivity index. Further investigation into HepG2 cell cycle showed the ability of compound 36 to induce apoptosis and arrest cell growth at G2/M phase. Moreover, docking studies demonstrated the ability of compound 36 to bind VEGFR-2 in a correct manner making three essential hydrogen bonds with the key residues Glu885, Asp1046 and Cys919. In sum, this work suggests that compound 36 can serve as a lead for development of effective anticancer agents targeting VEGFR-2.

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

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects*
Cell Survival / drug effects*
Cytochrome P-450 CYP2D6 / metabolism
Cytochrome P-450 CYP2D6 Inhibitors / chemistry
Cytochrome P-450 CYP2D6 Inhibitors / pharmacology
Drug Design*
Drug Screening Assays, Antitumor
Gene Expression Regulation, Enzymologic / drug effects
Gene Expression Regulation, Neoplastic / drug effects
Humans
Molecular Docking Simulation
Molecular Structure
Protein Conformation
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*

Substances

Antineoplastic Agents
Cytochrome P-450 CYP2D6 Inhibitors
Cytochrome P-450 CYP2D6
KDR protein, human
Vascular Endothelial Growth Factor Receptor-2