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

Journal of Enzyme Inhibition and Medicinal Chemistry

Nasser Saad¹  Marawan Ahmed²  Khaled Barakat³  Rabah A. T. Serya⁴  Maiy Y. Jaballah⁴  Khaled A. M. Abouzid⁵  Sohair M. Khojah⁶ 

[1] Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Pharmaceutical Chemistry Department, Future University in Egypt, Cairo, Egypt;Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada;Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada;Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada;Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, AB, Canada;Faculty of Pharmacy, Pharmaceutical Chemistry Department, Ain Shams University, Abbassia, Cairo, Egypt;Faculty of Pharmacy, Pharmaceutical Chemistry Department, Ain Shams University, Abbassia, Cairo, Egypt;Faculty of Pharmacy, Department of Organic and Medicinal Chemistry, University of Sadat City, Menoufia, Egyp;Faculty of Science, Biochemistry Department, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia;

关键词: Pyridazine derivatives;    VEGFR-2 inhibitors;    antitumor agents;    HUVEC;    antiangiogenic agents;    hinge interaction;   

DOI  :  10.1080/14756366.2019.1651723

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY