Ferrocenyl Acetylaniline Derivatives as Potential Modulators of Thyroid Receptors: Synthesis, Char￾acterisation and Computational Insights

Abstract

This thesis reports the synthesis, physicochemical characterisation and comprehensive in silico evaluation of a series of ferrocenyl acetylaniline derivatives (FcMe2Ac, FcMe3Ac and FcMe4Ac), with the aim of elucidating the relationship between molecular structure, electronic properties and interaction behaviour towards thyroid-related molecular targets. The target compounds were successfully synthesised via a nucleophilic substitution strategy and isolated in moderate to good yields ranging from 48% to 80%. Structural elucidation was achieved using complementary spectroscopic techniques, including FT-IR, UV–Visible spectros￾copy and nuclear magnetic resonance (¹H, ¹³C and 2D NMR). FT-IR spectra exhibited character￾istic absorption bands corresponding to N–H stretching (~3290–3445 cm⁻¹) and carbonyl groups (~1647–1651 cm⁻¹), while UV–Visible analysis revealed absorption maxima in the range of 259– 432 nm, associated with π→π* and d–d transitions. NMR data confirmed the expected structural features, including signals assigned to the ferrocenyl moiety (~4.1–4.3 ppm) and aromatic protons (~6.6–7.8 ppm). Electrochemical studies using cyclic voltammetry revealed a quasi-reversible Fe (II)/Fe (III) redox system, with formal potentials of 43.9, 51.0 and 57.5 mV for FcMe2Ac, FcMe3Ac and FcMe4Ac, respectively. Peak-to-peak separations (ΔEp = 87.8–115 mV) and current ratios close to unity confirmed quasi-reversible behaviour. Diffusion coefficients ranged from 1.11 × 10⁻⁷ to 5.74 × 10⁻⁷ cm²·s⁻¹, while heterogeneous electron-transfer rate constants (kₛ) varied between 0.14 × 10⁻³ and 0.62 × 10⁻³ cm·s⁻¹, reflecting the influence of substitution on electron-transfer kinetics. Density functional theory calculations indicated HOMO energies between −5.83 and −5.68 eV and HOMO–LUMO gaps ranging from 3.99 to 4.29 eV, suggesting moderate chemical stability combined with controlled reactivity. Global reactivity descriptors revealed hardness values be￾tween 1.995 and 2.143 eV and electrophilicity indices up to 3.519 eV, while dipole moments increased from 3.82 to 5.12 D, indicating enhanced molecular polarity across the series. Molecular docking studies against thyroid-related targets, including the thyroid hormone recep