Evaluation of oxadiazole--phenylacetamide conjugates as VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, anti-proliferative assessment, molecular docking, and dynamics studies.
[AIM] A novel series of oxadiazole-based derivatives was designed and synthesized as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors.
APA
Otify II, Ayyad RRA, et al. (2026). Evaluation of oxadiazole--phenylacetamide conjugates as VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, anti-proliferative assessment, molecular docking, and dynamics studies.. Future medicinal chemistry, 18(1), 19-34. https://doi.org/10.1080/17568919.2025.2594968
MLA
Otify II, et al.. "Evaluation of oxadiazole--phenylacetamide conjugates as VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, anti-proliferative assessment, molecular docking, and dynamics studies.." Future medicinal chemistry, vol. 18, no. 1, 2026, pp. 19-34.
PMID
41306087
Abstract
[AIM] A novel series of oxadiazole-based derivatives was designed and synthesized as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors.
[METHOD] The synthesized compounds were evaluated for their cytotoxic and VEGFR-2 inhibition activities.
[RESULTS] Compound was a super cytotoxic member, showing IC of 3.26 and 5.11 µM, twice as active as sorafenib (IC = 8.83 and 6.68 µM) against hepatocellular carcinoma (HepG2) and colon cancer (HCT-116), respectively. Also, the VEGFR-2 inhibitory assay revealed that derivative was the most potent VEGFR-2 inhibitor, showing a strong IC value of 0.56 nM, compared to sorafenib (IC = 0.46 nM). Furthermore, extra mechanistic studies were conducted on the most active candidate . The results indicated that such a compound arrested the cell cycle at both S and G2/M stages, triggering apoptosis in HepG2 cells. Also, compound produced a significant increase in the expression levels of apoptotic suppressors, caspase-3 and BAX, and a significant reduction of apoptosis motivator, Bcl-2 protein. Moreover, docking and molecular dynamics (MD) simulation studies revealed the correct binding mode and the optimum dynamics of compound inside the VEGFR-2 pocket.
[CONCLUSION] This study represents compound incorporating an oxadiazole scaffold as a promising VEGFR-2 inhibitor with potent anticancer activity.
[METHOD] The synthesized compounds were evaluated for their cytotoxic and VEGFR-2 inhibition activities.
[RESULTS] Compound was a super cytotoxic member, showing IC of 3.26 and 5.11 µM, twice as active as sorafenib (IC = 8.83 and 6.68 µM) against hepatocellular carcinoma (HepG2) and colon cancer (HCT-116), respectively. Also, the VEGFR-2 inhibitory assay revealed that derivative was the most potent VEGFR-2 inhibitor, showing a strong IC value of 0.56 nM, compared to sorafenib (IC = 0.46 nM). Furthermore, extra mechanistic studies were conducted on the most active candidate . The results indicated that such a compound arrested the cell cycle at both S and G2/M stages, triggering apoptosis in HepG2 cells. Also, compound produced a significant increase in the expression levels of apoptotic suppressors, caspase-3 and BAX, and a significant reduction of apoptosis motivator, Bcl-2 protein. Moreover, docking and molecular dynamics (MD) simulation studies revealed the correct binding mode and the optimum dynamics of compound inside the VEGFR-2 pocket.
[CONCLUSION] This study represents compound incorporating an oxadiazole scaffold as a promising VEGFR-2 inhibitor with potent anticancer activity.
MeSH Terms
Humans; Vascular Endothelial Growth Factor Receptor-2; Apoptosis; Molecular Docking Simulation; Oxadiazoles; Cell Proliferation; Antineoplastic Agents; Drug Design; Structure-Activity Relationship; Drug Screening Assays, Antitumor; Protein Kinase Inhibitors; Molecular Structure; Hep G2 Cells; Acetamides; Dose-Response Relationship, Drug; Molecular Dynamics Simulation; HCT116 Cells