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
Jaballah, Maiy Y; Serya, Rabah; Saad, Nasser; Khojah, Sohair M; Ahmed, Marawan; Barakat, Khaled; Khaled A M Abouzid;
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.
Other data
Title | 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 | Authors | Jaballah, Maiy Y; Serya, Rabah ; Saad, Nasser; Khojah, Sohair M; Ahmed, Marawan; Barakat, Khaled; Khaled A M Abouzid | Keywords | HUVEC;Pyridazine derivatives;VEGFR-2 inhibitors;antiangiogenic agents;antitumor agents;hinge interaction | Issue Date | Dec-2019 | Journal | Journal of Enzyme Inhibition and Medicinal Chemistry | Volume | 34 | Issue | 1 | Start page | 1573 | End page | 1589 | ISSN | 14756366 | DOI | 10.1080/14756366.2019.1651723 | PubMed ID | 31852269 | Scopus ID | 2-s2.0-85071985981 |
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