Development and assessment of novel pyrazole-thiadiazol hybrid derivatives as VEGFR-2 inhibitors: design, synthesis, anticancer activity evaluation, molecular docking, and molecular dynamics simulation.
Z Naturforsch C J Biosci
; 2024 Jun 03.
Article
em En
| MEDLINE
| ID: mdl-38818683
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⯵M against HT-29â¯cells and 23.081 ± 0.400⯵M 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Z Naturforsch C J Biosci
Ano de publicação:
2024
Tipo de documento:
Article