Novel N-Arylmethyl-aniline/chalcone hybrids as potential VEGFR inhibitors: synthesis, biological evaluations, and molecular dynamic simulations

Abstract

Significant advancements have been made in the domain of targeted anticancer therapy for the management of malignancies in recent times. VEGFR-2 is characterised by its pivotal involvement in angiogenesis and subsequent mechanisms that promote tumour cells survival. Herein, novel N-arylmethyl-aniline/chalcone hybrids 5a–5n were designed and synthesised as potential anticancer and VEGFR-2 inhibitors. The anticancer activity was evaluated at the NCI-USA, resulting in the identification of 10 remarkably potent molecules 5a–5j that were further subjected to the five-dose assays. Thereafter, they were explored for their VEGFR-2 inhibitory activity where 5e and 5h emerged as the most potent inhibitors. 5e and 5h induced apoptosis with cell cycle arrest at the SubG₀-G₁ phase within HCT-116 cells. Moreover, their impact on some key apoptotic genes was assessed, suggesting caspase-dependent apoptosis. Furthermore, molecular docking and molecular dynamics simulations were conducted to explore the binding modes and stability of the protein–ligand complexes.

Keywords:

• VEGFR-2
• anticancer agents
• apoptosis induction
• molecular docking

Acknowledgement

The authors are thankful to the Deanship of Scientific Research at King Khalid University for funding this work through Large Group Research Project under grant number (RGP2/321/44). The authors extend their appreciation to Scientific Research Fund - Vice president′s office for Graduate Studies and Research - Helwan University, and to Prof. Sameh Soror for giving them the opportunity to use the facilities/equipment available in HSBR laboratory. Also, authors would like to acknowledge the National Cancer Institute (NCI), developmental therapeutics program (DTP) of the United States for performing the anticancer screening.

Author contributions

Hesham Haffez (biological experiments, project administration, data curation, formal analysis, writing – original draft, review and editing), Nosaiba A. Elsayed (project administration, chemistry experiments, software and writing – original draft), Marwa F. Ahmed (conceptualization and review and editing), Samar S. Fatahala (data curation, formal analysis, writing – original draft), Eman F. Khaleel (funding acquisition, resources and review and editing), Rehab Mustafa Badi (funding acquisition, resources and review and editing), Eslam B. Elkaeed (funding acquisition, resources and review and editing), Mahmoud A. El Hassab (molecular dynamics, software and writing – original draft, review and editing), Sherif F. Hammad (conceptualization and review and editing), Wagdy M. Eldehna (conceptualization, project administration, molecular dynamics, software and review and editing), Nicolas Masurier (conceptualization and writing – original draft, review and editing), and Radwan El-Haggar (chemistry experiments, project administration, data curation, formal analysis, supervision, funding acquisition, writing – original draft, review and editing).

Disclosure statement

The authors report no conflicts of interest.