Towards discovery of novel scaffold with potent antiangiogenic activity; design, synthesis of pyridazine based compounds, impact of hinge interaction, and accessibility of their bioactive conformation on VEGFR-2 activities

Maiy Y Jaballah; Rabah A T Serya; Nasser Saad; Sohair M Khojah; Marawan Ahmed; Khaled Barakat; Khaled A M Abouzid

doi:10.1080/14756366.2019.1651723

Towards discovery of novel scaffold with potent antiangiogenic activity; design, synthesis of pyridazine based compounds, impact of hinge interaction, and accessibility of their bioactive conformation on VEGFR-2 activities

J Enzyme Inhib Med Chem. 2019 Dec;34(1):1573-1589. doi: 10.1080/14756366.2019.1651723.

Authors

Maiy Y Jaballah¹, Rabah A T Serya¹, Nasser Saad², Sohair M Khojah³, Marawan Ahmed⁴, Khaled Barakat^{4

5

6}, Khaled A M Abouzid^{1

7}

Affiliations

¹ Faculty of Pharmacy, Pharmaceutical Chemistry Department, Ain Shams University, Abbassia, Cairo, Egypt.
² Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Pharmaceutical Chemistry Department, Future University in Egypt, Cairo, Egypt.
³ Faculty of Science, Biochemistry Department, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
⁴ Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
⁵ Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada.
⁶ Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, AB, Canada.
⁷ Faculty of Pharmacy, Department of Organic and Medicinal Chemistry, University of Sadat City, Menoufia, Egypt.

Abstract

Pyridazine scaffolds are considered privileged structures pertaining to its novelty, chemical stability, and synthetic feasibility. In our quest towards the development of novel scaffolds for effective vascular endothelial growth 2 (VEGFR-2) inhibition with antiangiogenic activity, four novel series of pyridazines were designed and synthesised. Five of the synthesised compounds; namely (8c, 8f, 15, 18b, and 18c) exhibited potent VEGFR-2 inhibitory potency (>80%); with IC₅₀ values ranging from low micromolar to nanomolar range; namely compounds 8c, 8f, 15, 18c with (1.8 µM, 1.3 µM, 1.4 µM, 107 nM), respectively. Moreover, 3-[4-{(6-oxo-1,6-dihydropyridazin-3-yl)oxy}phenyl]urea derivative (18b) exhibited nanomolar potency towards VEGFR-2 (60.7 nM). In cellular assay, the above compounds showed excellent inhibition of VEGF-stimulated proliferation of human umbilical vein endothelial cells at 10 μM concentration. Finally, an extensive molecular simulation study was performed to investigate the probable interaction with VEGFR-2.

Keywords: HUVEC; Pyridazine derivatives; VEGFR-2 inhibitors; antiangiogenic agents; antitumor agents; hinge interaction.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Density Functional Theory
Drug Discovery*
Drug Screening Assays, Antitumor
Human Umbilical Vein Endothelial Cells / drug effects
Humans
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyridazines / chemical synthesis
Pyridazines / chemistry
Pyridazines / pharmacology*
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

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

Grants and funding

This work was funded by STDF (project no. 5251).