Design, synthesis, and in silico insights of novel N'-(2-oxoindolin-3-ylidene)piperidine-4-carbohydrazide derivatives as VEGFR-2 inhibitors.

Eldehna, WM; Habib, YA; Mahmoud, AE; Barghash, MF; Elsayed, ZM; Elsawi, AE; Maklad, RM; Rashed, M; Khalil, A; Hammad, SF; Ali, MM; El Kerdawy, AM

Design, synthesis, and in silico insights of novel N'-(2-oxoindolin-3-ylidene)piperidine-4-carbohydrazide derivatives as VEGFR-2 inhibitors.

Eldehna, WM Habib, YA Mahmoud, AE Barghash, MF Elsayed, ZM Elsawi, AE Maklad, RM Rashed, M Khalil, A Hammad, SF Ali, MM El Kerdawy, AM

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Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: Bioorg Chem, 2024, 153, pp. 107829
Issue Date:: 2024-12

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Field	Value	Language
dc.contributor.author	Eldehna, WM
dc.contributor.author	Habib, YA
dc.contributor.author	Mahmoud, AE
dc.contributor.author	Barghash, MF
dc.contributor.author	Elsayed, ZM
dc.contributor.author	Elsawi, AE
dc.contributor.author	Maklad, RM
dc.contributor.author	Rashed, M
dc.contributor.author	Khalil, A
dc.contributor.author	Hammad, SF
dc.contributor.author	Ali, MM
dc.contributor.author	El Kerdawy, AM
dc.date.accessioned	2025-01-31T01:03:13Z
dc.date.available	2024-09-16
dc.date.available	2025-01-31T01:03:13Z
dc.date.issued	2024-12
dc.identifier.citation	Bioorg Chem, 2024, 153, pp. 107829
dc.identifier.issn	0045-2068
dc.identifier.issn	1090-2120
dc.identifier.uri	http://hdl.handle.net/10453/184730
dc.description.abstract	Vascular endothelial growth factor (VEGF) is a crucial key factor in breast tumorigenesis. VEGF plays an important role in angiogenesis, tumor proliferation, and metastasis. Herein, we report the design and synthesis of twenty-one novel piperidine/oxindole derivatives as potential VEGFR-2 inhibitors. The designed compound library aimed to occupy the binding site of VEGFR-2 in a similar binding pattern to that of the reference VEGFR-2 inhibitor Sorafenib. The synthesized compounds were biologically evaluated for their cytotoxic effects against two breast cancer cell lines (MCF-7 and MDA-MB-468). Compounds 12e and 6n were the most potent cytotoxic derivatives against the former and the latter cell lines, showing IC50 values of 8.00 and 0.60 µM, respectively. Furthermore, all the synthesized compounds were evaluated for their inhibitory activities towards VEGFR-2, with compound 12e showing the most potent activity with an IC50 value of 45.9 nM, surpassing the reference standard Sorafenib (IC50 = 48.6 nM). Additionally, compound 6n emerged as the top performer when tested with the other most promising compounds for their cytotoxic effects on HUVEC (IC50 = 28.77 nM). The designed library of compounds was subjected to molecular docking and molecular dynamic simulations, which revealed key binding interactions within the VEGFR-2 active site, including hydrogen bonding with Cys919, Glu885, and Asp1046 residues. Moreover, in silico predictions of physicochemical and pharmacokinetic properties for the target compounds indicated favorable drug-like characteristics.
dc.language	eng
dc.publisher	Elsevier
dc.relation.ispartof	Bioorg Chem
dc.relation.isbasedon	10.1016/j.bioorg.2024.107829
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry
dc.subject.classification	Organic Chemistry
dc.subject.classification	3404 Medicinal and biomolecular chemistry
dc.subject.classification	3405 Organic chemistry
dc.subject.mesh	Humans
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	Dose-Response Relationship, Drug
dc.subject.mesh	Drug Design
dc.subject.mesh	Drug Screening Assays, Antitumor
dc.subject.mesh	Hydrazines
dc.subject.mesh	Molecular Docking Simulation
dc.subject.mesh	Molecular Structure
dc.subject.mesh	Piperidines
dc.subject.mesh	Protein Kinase Inhibitors
dc.subject.mesh	Structure-Activity Relationship
dc.subject.mesh	Vascular Endothelial Growth Factor Receptor-2
dc.subject.mesh	Humans
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	Dose-Response Relationship, Drug
dc.subject.mesh	Drug Design
dc.subject.mesh	Drug Screening Assays, Antitumor
dc.subject.mesh	Hydrazines
dc.subject.mesh	Molecular Docking Simulation
dc.subject.mesh	Molecular Structure
dc.subject.mesh	Piperidines
dc.subject.mesh	Protein Kinase Inhibitors
dc.subject.mesh	Structure-Activity Relationship
dc.subject.mesh	Vascular Endothelial Growth Factor Receptor-2
dc.title	Design, synthesis, and in silico insights of novel N'-(2-oxoindolin-3-ylidene)piperidine-4-carbohydrazide derivatives as VEGFR-2 inhibitors.
dc.type	Journal Article
utslib.citation.volume	153
utslib.location.activity	United States
utslib.for	0304 Medicinal and Biomolecular Chemistry
utslib.for	0305 Organic Chemistry
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
pubs.organisational-group	University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
utslib.copyright.status	closed_access	*
dc.date.updated	2025-01-31T01:03:09Z
pubs.publication-status	Published
pubs.volume	153

Abstract:

Vascular endothelial growth factor (VEGF) is a crucial key factor in breast tumorigenesis. VEGF plays an important role in angiogenesis, tumor proliferation, and metastasis. Herein, we report the design and synthesis of twenty-one novel piperidine/oxindole derivatives as potential VEGFR-2 inhibitors. The designed compound library aimed to occupy the binding site of VEGFR-2 in a similar binding pattern to that of the reference VEGFR-2 inhibitor Sorafenib. The synthesized compounds were biologically evaluated for their cytotoxic effects against two breast cancer cell lines (MCF-7 and MDA-MB-468). Compounds 12e and 6n were the most potent cytotoxic derivatives against the former and the latter cell lines, showing IC50 values of 8.00 and 0.60 µM, respectively. Furthermore, all the synthesized compounds were evaluated for their inhibitory activities towards VEGFR-2, with compound 12e showing the most potent activity with an IC50 value of 45.9 nM, surpassing the reference standard Sorafenib (IC50 = 48.6 nM). Additionally, compound 6n emerged as the top performer when tested with the other most promising compounds for their cytotoxic effects on HUVEC (IC50 = 28.77 nM). The designed library of compounds was subjected to molecular docking and molecular dynamic simulations, which revealed key binding interactions within the VEGFR-2 active site, including hydrogen bonding with Cys919, Glu885, and Asp1046 residues. Moreover, in silico predictions of physicochemical and pharmacokinetic properties for the target compounds indicated favorable drug-like characteristics.

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http://hdl.handle.net/10453/184730