Synthesis, docking study, and antitumor evaluation of benzamides and oxadiazole derivatives of 3‐phenoxybenzoic acid as VEGFR‐2 inhibitors

• Published in: Drug development research Vol. 85; no. 3; pp. e22186 - n/a
• Main Authors: Heriz, Mohammad H., Mahmood, Ammar A. R., Yasin, Salem R., Saleh, Khaled M., AlSakhen, Mai F., Kanaan, Sana I., Himsawi, Nisreen, Saleh, Abdulrahman M., Tahtamouni, Lubna H.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.05.2024
• Subjects: 1,3,4‐oxadiazole; 3‐phenoxybenzoic acid; Antineoplastic Agents - chemistry; Antineoplastic drugs; Apoptosis; benzamide; Benzamides - pharmacology; Benzoates; Cell cycle; Cell death; Cell Line, Tumor; Cell Proliferation; Chemical synthesis; Chemoresistance; Chemotherapy; Cytotoxicity; Docking; Drug Design; Drug Screening Assays, Antitumor; Flow cytometry; Fourier transforms; Growth factors; Hepatocellular carcinoma; Infrared spectroscopy; Kinases; Mass spectra; Molecular Docking Simulation; Molecular Structure; Necrosis; NMR; Nuclear magnetic resonance; Oxadiazoles; Phenoxybenzoic acid; Physicochemical properties; Protein Kinase Inhibitors - pharmacology; Side effects; Spectrum analysis; Structure-Activity Relationship; Tumor cells; Tyrosine; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A; Vascular endothelial growth factor receptor 2; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vascular endothelial growth factor receptors; VEGFR‐2 inhibitors; benzamide; VEGFR‐2 inhibitors; apoptosis; 1,3,4‐oxadiazole; 3‐phenoxybenzoic acid
• ISSN: 0272-4391; 1098-2299
• DOI: 10.1002/ddr.22186

Current chemotherapeutic agents have several limitations, including lack of selectivity, the development of undesirable side effects, and chemoresistance. As a result, there is an unmet need for the development of novel small molecules with minimal side effects and the ability to specifically target tumor cells. A new series of 3‐phenoxybenzoic acid derivatives, including 1,3,4‐oxadiazole derivatives (4a–d) and benzamides derivatives (5a–e) were synthesized; their chemical structures were confirmed by Fourier‐transform infrared spectroscopy, 1H nuclear magnetic resonance (NMR), 13C NMR, and mass spectra; and various physicochemical properties were determined. The antiproliferative activities of the new derivatives were evaluated by means of the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. Three compounds (4b, 4c, and 4d) exhibited cytotoxicity against two of the three cell lines tested, five compounds (3, 4a, 5a, 5b, and 5e) were toxic to one cell line, while two compounds (5c and 5d) were not cytotoxic to any of the three cell lines tested in the current study. Based on docking scores, MTT assay findings, and vascular endothelial growth factor receptor 2 (VEGFR‐2) kinase activity data, Compound 4d was selected for further biological investigation. Flow cytometry was used to determine the mode of cell death (apoptosis vs. necrosis) and the effect on cell cycle progression. Compound 4d arrested HepG2 hepatocellular carcinoma cells in the G2/M phase and activated both the intrinsic and extrinsic apoptosis pathways. In conclusion, Compound 4d has shown promising results for future research as a potent VEGFR‐2 tyrosine kinase inhibitor.