What question did this study set out to answer?

The study aims to explore the structural characteristics and biological activity of a novel benzimidazolium salt against various cancer cell lines.

March 16, 2026Open Access

Integrated Experimental and Computational Study of a Novel Benzimidazolium Salt: Crystal Structure, Antiproliferative Activity on Human Cancer Cell Lines, DFT Analysis, VEGFR2 Molecular Docking and VEGFR2‐Targeted Molecular Dynamics Simulations

Key Points

The study aims to explore the structural characteristics and biological activity of a novel benzimidazolium salt against various cancer cell lines.
Synthesis and characterization of the benzimidazolium salt using NMR, FT-IR, LC-MS/MS, and X-ray diffraction.
Evaluation of cytotoxicity against various human cancer cell lines.
Analyses using density functional theory (DFT) and molecular docking to assess binding with VEGFR2.
Molecular dynamics simulations to evaluate the stability of binding conformations.
The benzimidazolium salt demonstrated varying cytotoxic effects, with IC50 values between 24.55 µM and 64.25 µM.
Molecular docking revealed a favorable VEGFR2 binding score of −8.5 kcal/mol.
Molecular dynamics simulations indicated stable binding with minimal fluctuation compared to sorafenib.
The binding interactions were primarily driven by hydrophobic and van der Waals forces.

Abstract

ABSTRACT 3‐(3‐Methoxybenzyl)‐1‐(3‐methylbenzyl)‐1 H ‐benzo d imidazol‐3‐ium chloride ( 4 ) was synthesized and characterized by 1 H NMR, 13 C NMR, FT‐IR, LC‐MS/MS, and single‐crystal X‐ray diffraction. The single‐crystal X‐ray diffraction analysis revealed that compound 4 crystallizes in the triclinic P ‐1 space group, forming a planar benzimidazole core stabilized by hydrogen‐bonding and π–π stacking interactions. Its cytotoxic activity was evaluated against breast (MCF‐7), liver (HepG2), colon (DLD‐1), lung (A549), and prostate (PC3) carcinoma cell lines, showing IC 50 values ranging from 24.55 µM (MCF‐7) to 64.25 µM (DLD‐1). Density functional theory (DFT) and potential energy surface (PES) analyses identified four stable conformers, one being the most thermodynamically favorable. Molecular docking indicated favorable VEGFR2 binding (docking score: −8.5 kcal/mol), albeit lower than sorafenib (−12.0 kcal/mol). Frontier molecular orbital analysis revealed the highest occupied molecular orbital (HOMO) localization on the benzimidazole core, supporting nucleophilic potential, while the lowest unoccupied molecular orbital (LUMO) is mainly localized over the aromatic substituents, suggesting potential π–π stacking interactions. Molecular dynamics simulations showed that compound 4 maintains a stable binding conformation with limited fluctuations. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) binding free energy calculations indicated energetically favorable complexes, with stabilization mainly driven by hydrophobic/van der Waals interactions, whereas sorafenib benefits more from electrostatic contributions.

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