Molecular Design and Synthesis of New 3,4-Dihydropyrimidin-2(1H)-Ones as Potential Anticancer Agents with VEGFR-2 Inhibiting Activity

Amany S Mostafa; Waleed A Bayoumi; Mohamed El-Mesery; Abdelaziz Elgaml

doi:10.2174/1871520618666180717125906

Molecular Design and Synthesis of New 3,4-Dihydropyrimidin-2(1H)-Ones as Potential Anticancer Agents with VEGFR-2 Inhibiting Activity

Anticancer Agents Med Chem. 2019;19(3):310-322. doi: 10.2174/1871520618666180717125906.

Authors

Amany S Mostafa¹, Waleed A Bayoumi^{1

2}, Mohamed El-Mesery³, Abdelaziz Elgaml⁴

Affiliations

¹ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamassa, Egypt.
³ Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
⁴ Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

PMID: 30019649
DOI: 10.2174/1871520618666180717125906

Abstract

Background: Two series of 3,4-dihydropyrimidin-2(1H)-one derivatives were designed based on the main structural features characterizing reported anticancer compounds with potent VEGFR-2 inhibiting activity.

Methods: All the target compounds were synthesized and investigated for their in vitro anticancer activity using MTT assay and NCI protocol. The most active compounds were further investigated for the VEGFR-2 inhibiting activity using enzyme inhibition assay.

Result: Of these derivatives, compound 8b possessed significant activity against Caco-2 (IC50 of 24.9 µM) and MCF7 (IC50 of 29.4 µM), compound 10 showed excellent potency against HCT-116 (IC50 of 32.6 µM), HEPG2 (IC50 of 16.4 µM) and MCF7 (IC50 of 32.8 µM), while compound 11b exhibited moderate anticancer activity towards MCF7 (IC50 of 41.7µM). Both 8b and 10 exhibited good potency regarding the inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2), with an IC50 of 14.00 and 21.62 nM, respectively.

Conclusion: The activity was rationalized based on molecular docking study that supported their VEGFR-2 inhibitory activity; as indicated by their favorable binding with the active site.

Keywords: Anticancer; MTT assay; VEGFR-2 inhibitors; dihydropyrimidin-2(1H)-ones; docking; synthesis..

MeSH terms

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

Substances

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