N′-([1,1′-Biphenyl]-4-ylmethylene)-4-methylbenzenesulfonohydrazide as a potential EGFR inhibitor: ADMET, docking, dynamics, and DFT studies

The Epidermal Growth Factor Receptor (EGFR) is a transmembrane tyrosine kinase receptor that regulates key cellular processes such as proliferation, differentiation, and survival. Aberrant activation or overexpression of EGFR has been extensively associated with the onset and progression of various malignancies, including lung, breast, and colorectal cancers. Consequently, EGFR has emerged as a validated molecular target for the design of novel anticancer therapeutics. Sulfonyl hydrazone derivatives constitute a versatile class of organic compounds exhibiting a wide spectrum of biological activities, such as antimicrobial, anti-inflammatory, and anticancer effects. Their structural flexibility, presence of electron-donating and withdrawing substituents, and ability to form stable interactions with biological macromolecules make them promising scaffolds for the development of potent EGFR inhibitors with improved pharmacological profiles. To synthesize and comprehensively evaluate the structural, electronic, optical, and biological properties of a novel sulfonyl hydrazone derivative, N′-([1,1′-biphenyl]-4-ylmethylene)-4-methylbenzenesulfonohydrazide (BMBSH), as a potential EGFR inhibitor. BMBSH was synthesized via condensation of 4-methylbenzenesulfonohydrazide with [1,1′-biphenyl]-4-carbaldehyde using H₂SO₄ as a catalyst. The compound was characterized using FT-IR, ¹H NMR, and ¹ ³C NMR. Computational studies included DFT optimization, MEP and Mulliken analyses, molecular docking, 100 ns molecular dynamics (MD) simulation, and ADMET profiling. Spectroscopic data confirmed the formation of the hydrazone linkage and the imine (C N) bond. DFT results (HOMO–LUMO gap 4.215 eV) indicated strong electronic stability and close agreement with experimental data. BMBSH showed high nonlinear optical activity (β₀ = 2.939 × 10⁻³⁰ esu). Docking and MD studies demonstrated stable EGFR binding through hydrogen bonds and π–π interactions, with better stability than doxorubicin. ADMET analysis showed excellent intestinal absorption (92.86 %), blood–brain barrier penetration, and favorable bioavailability (0.55). BMBSH is a structurally stable, electronically robust, and pharmacologically promising EGFR inhibitor with strong binding affinity, superior stability, and good drug-like properties. These results highlight its potential as a lead compound for future anticancer drug design integrating synthetic and computational approaches. • Synthesis of novel hydrazone derivatives confirmed by FT-IR and NMR spectral techniques. • Investigation of electronic properties through DFT-based analysis. • Molecular docking and Dynamics simulation analysis to evaluate the inhibitory potential of the synthesized compound. • ADMET analysis was examined.