Benzoxazole derivatives as new VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, in silico studies, and antiproliferative evaluation

Abstract

In this study, a set of novel benzoxazole derivatives were designed, synthesised, and biologically evaluated as potential VEGFR-2 inhibitors. Five compounds (12d, 12f, 12i, 12l, and 13a) displayed high growth inhibitory activities against HepG2 and MCF-7 cell lines and were further investigated for their VEGFR-2 inhibitory activities. The most potent anti-proliferative member 12 l (IC₅₀ = 10.50 μM and 15.21 μM against HepG2 and MCF-7, respectively) had the most promising VEGFR-2 inhibitory activity (IC₅₀ = 97.38 nM). A further biological evaluation revealed that compound 12l could arrest the HepG2 cell growth mainly at the Pre-G1 and G1 phases. Furthermore, compound 12l could induce apoptosis in HepG2 cells by 35.13%. likely, compound 12l exhibited a significant elevation in caspase-3 level (2.98-fold) and BAX (3.40-fold), and a significant reduction in Bcl-2 level (2.12-fold). Finally, docking studies indicated that 12l exhibited interactions with the key amino acids in a similar way to sorafenib.

Keywords:

• Anticancer
• cell cycle
• apoptosis
• benzoxazole
• VEGFR-2

Acknowledgements

The authors would like to acknowledge the technical assistance made by Dr. Mohamed R. Elnagar, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research was funded by Princess Nourah bint Abdulrahman University Researchers Supporting Project number [PNURSP2022R116], Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.