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Development and assessment of novel pyrazole–thiadiazol hybrid derivatives as VEGFR-2 inhibitors: design, synthesis, anticancer activity evaluation, molecular docking, and molecular dynamics simulation

  • Gresa Halimi , Derya Osmaniye ORCID logo EMAIL logo , Yusuf Özkay and Zafer Asım Kaplancıklı
Published/Copyright: June 3, 2024
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Zeitschrift für Naturforschung C
From the journal Zeitschrift für Naturforschung C Volume 79 Issue 9-10

Abstract

Cancer remains a significant health challenge globally, requiring the development of targeted chemotherapeutics capable of specifically inhibiting cancer cell growth. Angiogenesis is one of the key features of tumor growth and metastasis and is, therefore, an important target for the treatment of many tumors. The vascular endothelial growth factor (VEGF) signaling pathway has proven to be a promising lead in anticancer therapy due to the central role it plays in tumor angiogenesis. Vascular endothelial growth factor receptor-2 (VEGFR-2) is a key mediator in the signaling pathway regulating angiogenesis. Targeting VEGFR-2 may disrupt angiogenesis, leading to a reduction in tumor blood supply and tumor progression. The design, synthesis, and assessment of novel VEGFR-2 inhibitor derivatives are the focus of this study, with particular emphasis on incorporating the pyrazole–thiadiazol pharmacophore into the molecular structure. Taking advantage of the pharmacophoric properties of pyrazole and 1,3,4-thiadiazol, compounds with different substituents in the main structure were designed and synthesized. The compounds were also evaluated for antiproliferative activity against cancer cell lines. Compound 4e demonstrated the highest activity among all compounds, with an IC50 of 9.673 ± 0.399 μM against HT-29 cells and 23.081 ± 0.400 μM against NIH3T3 cells. To further support the inhibitory activity of compound 4e, an in silico study was performed. Compound 4e demonstrated strong binding to the active site of VEGFR-2 in molecular docking studies, forming hydrogen bonds with key amino acid residues. The stability of the compound in the enzyme’s active site was demonstrated through molecular dynamics simulations.

Keywords: VEGFR-2; 1,3,4-thiadiazol; pyrazole; molecular docking; molecular dynamics simulations
Corresponding author: Derya Osmaniye, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470, Eskişehir, Türkiye; and Central Analysis Laboratory, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Türkiye, E-mail:

Acknowledgments

As the authors of this study, we thank Anadolu University Faculty of Pharmacy Central Analysis Laboratory for their support and contributions.

  1. Research ethics: Not applicable.

  2. Author contributions: D.O. and Y.O. conceived and designed the experiments; G.H. performed the synthesis; D.O. and G.H. performed the activity tests; D.O. performed the molecular docking and molecular dynamic studies; G.H. and D.O. performed analysis studies; D.O. and G.H. wrote the paper. Y.O. and Z.A.K. edited the paper.

  3. Competing interests: The authors state no conflict of interest.

  4. Research funding: None declared.

  5. Data availability: Not applicable.

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Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/znc-2024-0067).

Received: 2024-03-29
Accepted: 2024-05-05
Published Online: 2024-06-03
Published in Print: 2024-09-25

© 2024 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/znc-2024-0067
Keywords for this article
VEGFR-2; 1,3,4-thiadiazol; pyrazole; molecular docking; molecular dynamics simulations

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. Navigating the landscape of theranostics in nuclear medicine: current practice and future prospects
  4. Research Articles
  5. Insecticidal effect of new synthesized chalcone derivatives on Caribbean fruit fly, Anastrepha suspensa
  6. Cymbopogon proximus phytochemicals induce S-phase arrest in A549 lung cancer cell lines via CDK2/cyclin A2 inhibition: gas chromatography-mass spectrometry and molecular docking analyses
  7. Chemical constituents from the Saposhnikovia divaricata and their antiproliferative activity
  8. Development and assessment of novel pyrazole–thiadiazol hybrid derivatives as VEGFR-2 inhibitors: design, synthesis, anticancer activity evaluation, molecular docking, and molecular dynamics simulation
  9. In vitro antibacterial and antioxidant activity of flavonoids from the roots of Tephrosia vogelii: a combined experimental and computational study
  10. Chemical composition and the anti-inflammatory effect of volatile compounds from Anaxagorea luzonensis A. Gray
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