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

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

  • Bioorg Chem. 2024 Dec:153:107829. doi: 10.1016/j.bioorg.2024.107829.
Wagdy M Eldehna 1,  Youmna A Habib 2,  Abeer E Mahmoud 3,  Mohamed F Barghash 3,  Zainab M Elsayed 2,  Ahmed E Elsawi 4,  Raed M Maklad 4,  Mahmoud Rashed 5,  Amira Khalil 6,  Sherif F Hammad 7,  Mamdouh M Ali 3,  Ahmed M El Kerdawy 8
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh P.O. Box 33516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, Canal El Mahmoudia St., Alexandria 21648, Egypt. Electronic address: wagdy2000@gmail.com.
  • 2 Scientific Research and Innovation Support Unit, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
  • 3 Biochemistry Department, Biotechnology Research Institute, National Research Centre, Dokki 12622, Giza, Egypt.
  • 4 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh P.O. Box 33516, Egypt.
  • 5 Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt.
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Ain Helwan, Egypt; PharmD Program, Egypt-Japan University of Science and Technology, New Borg El-Arab, Alexandria, Egypt.
  • 8 School of Pharmacy, College of Health and Science, University of Lincoln, Joseph Banks Laboratories, Green Lane, Lincoln, Lincolnshire, United Kingdom; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, P.O. Box 11562 Cairo, Egypt.
PMID: 39317037 DOI: 10.1016/j.bioorg.2024.107829
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.

Keywords

Breast Cancer; Docking; Kinase inhibitor; Oxindole; Piperidine.

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