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

Mohammed S Taghour; Hazem A Mahdy; Maher H Gomaa; Ahmed Aglan; Mahmoud Gomaa Eldeib; Alaa Elwan; Mohammed A Dahab; Eslam B Elkaeed; Aisha A Alsfouk; Mohamed M Khalifa; Ibrahim H Eissa; Hazem Elkady

doi:10.1080/14756366.2022.2103552

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

J Enzyme Inhib Med Chem. 2022 Dec;37(1):2063-2077. doi: 10.1080/14756366.2022.2103552.

Affiliations

¹ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
² Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
³ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
⁴ Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

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; VEGFR-2; apoptosis; benzoxazole; cell cycle.

MeSH terms

Antineoplastic Agents* / chemistry
Apoptosis
Benzoxazoles
Dose-Response Relationship, Drug
Drug Design
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2*

Substances

Antineoplastic Agents
Benzoxazoles
Protein Kinase Inhibitors
Vascular Endothelial Growth Factor Receptor-2

Grants and funding

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