Rational Design and Multiscale Investigation of Ferrocenyl Acetylaniline Derivatives Targeting Topoisomerase IIα: From Synthesis to Molecular Dynamics and ADMET Profiling

Abstract

This thesis investigates the design, synthesis, physicochemical characterization, and in silico evaluation of ferrocenyl acetylaniline derivatives (FcMe2Ac, FcMe3Ac, and FcMe4Ac), with emphasis on their electronic properties and interactions with Topoisomerase IIα, a key anticancer target. The compounds were synthesized via nucleophilic substitution, yielding regioisomers with moderate to high yields (48–80%). Structural elucidation was confirmed using FT-IR, UV–Visible, and NMR spectroscopy, revealing characteristic signals of ferrocenyl and aromatic moieties. Electrochemical analysis by cyclic voltammetry indicated quasi-reversible Fe(II)/Fe(III) redox behavior, with potentials ranging from 43.9 to 57.5 mV. Diffusion coefficients and electron transfer rates suggested that substitution patterns significantly influence electrochemical properties. Density Functional Theory (DFT) calculations showed HOMO energies between −5.83 and −5.68 eV and energy gaps of 3.99–4.29 eV, indicating moderate stability and reactivity. Increased dipole moments confirmed enhanced molecular polarity. Molecular docking against Topoisomerase IIα demonstrated favorable binding affinities (−6.95 to −8.72 kcal/mol), with FcMe4Ac showing the strongest interaction. Molecular dynamics simulations (100 ns) confirmed complex stability, with low RMSD values. ADMET predictions revealed favorable pharmacokinetic profiles, including high gastrointestinal absorption, balanced lipophilicity, and absence of toxicity risks. Overall, structural modification significantly affects electronic and biological behavior. FcMe4Ac emerged as the most promising candidate, combining strong binding, stability, and favorable drug-like properties, suggesting its potential as a lead compound for anticancer drug development. This study successfully establishes the therapeutic potential of novel ferrocenyl acetylaniline derivatives, highlighting FcMe4Ac as a premier lead compound. By seamlessly bridging experimental synthesis and electrochemistry with advanced computational modeling, these findings pave the way for designing next-generation, organometallic-based Topoisomerase IIα inhibitors with optimized anticancer efficacy and safety profiles.