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<p>A series of regioisomeric N-[(ferrocenyl)methyl]acetylaniline derivatives, namely FcMe2Ac, FcMe3Ac and FcMe4Ac, were synthesised via a nucleophilic substitution route and structurally characterised by FT-IR, UV–Vis, ¹H/¹³C NMR (1D and 2D) and cyclic voltammetry. Electrochemical studies revealed a quasi-reversible one-electron Fe(II)/Fe(III) redox process with diffusion-controlled behaviour and formal potentials shifted anodically relative to ferrocene. The anti-inflammatory potential of the compounds was evaluated using inhibition of heat-induced bovine serum albumin (BSA) denaturation and UV–visible binding studies, with diclofenac as reference. All derivatives exhibited concentration-dependent inhibition, with IC₅₀ values ranging from 4.22 to 7.29&#xa0;µg mL⁻¹. Binding constants (10⁶ M⁻¹) and negative Gibbs free energy values indicate favourable interactions with BSA. Density functional theory (DFT) calculations at the B3LYP/6-311 + + G(d, p)/SDD level provided insight into the electronic structure and reactivity. Frontier orbital analysis revealed charge transfer from the ferrocenyl unit to the acetylaniline fragment, while electrostatic analysis identified the carbonyl region as a potential interaction site. Molecular docking against cyclooxygenase-2 (COX-2, PDB ID: 5IKR) showed favourable binding within the catalytic channel, with FcMe4Ac exhibiting the strongest affinity (− 8.36&#xa0;kcal mol⁻¹), exceeding that of diclofenac. The combined experimental and theoretical results demonstrate that structural modification of the acetylaniline substituent significantly influences electronic properties and biological performance. In particular, the para-substituted derivative FcMe4Ac emerged as the most promising candidate, highlighting acetylaniline-functionalised ferrocenes as potential scaffolds for the development of new anti-inflammatory agents.</p>

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Novel acetylaniline-substituted ferrocenes: synthesis, structural characterisation, redox behaviour and anti-inflammatory activity supported by DFT and COX-2 docking

  • 期刊论文

  • 发表日期：

    2026年7月16日

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  • Aicha Adaika,
  • Elhafnaoui Lanez,
  • Ouafa Zouari Ahmed,
  • Dalal Harkati,
  • Yahia Bekkar,
  • Aida Benine,
  • Habiba Haddad,
  • Mohammed Larbi Benamor,
  • Lazhar Bechki,
  • Touhami Lanez

摘要

A series of regioisomeric N-[(ferrocenyl)methyl]acetylaniline derivatives, namely FcMe2Ac, FcMe3Ac and FcMe4Ac, were synthesised via a nucleophilic substitution route and structurally characterised by FT-IR, UV–Vis, ¹H/¹³C NMR (1D and 2D) and cyclic voltammetry. Electrochemical studies revealed a quasi-reversible one-electron Fe(II)/Fe(III) redox process with diffusion-controlled behaviour and formal potentials shifted anodically relative to ferrocene. The anti-inflammatory potential of the compounds was evaluated using inhibition of heat-induced bovine serum albumin (BSA) denaturation and UV–visible binding studies, with diclofenac as reference. All derivatives exhibited concentration-dependent inhibition, with IC₅₀ values ranging from 4.22 to 7.29 µg mL⁻¹. Binding constants (10⁶ M⁻¹) and negative Gibbs free energy values indicate favourable interactions with BSA. Density functional theory (DFT) calculations at the B3LYP/6-311 + + G(d, p)/SDD level provided insight into the electronic structure and reactivity. Frontier orbital analysis revealed charge transfer from the ferrocenyl unit to the acetylaniline fragment, while electrostatic analysis identified the carbonyl region as a potential interaction site. Molecular docking against cyclooxygenase-2 (COX-2, PDB ID: 5IKR) showed favourable binding within the catalytic channel, with FcMe4Ac exhibiting the strongest affinity (− 8.36 kcal mol⁻¹), exceeding that of diclofenac. The combined experimental and theoretical results demonstrate that structural modification of the acetylaniline substituent significantly influences electronic properties and biological performance. In particular, the para-substituted derivative FcMe4Ac emerged as the most promising candidate, highlighting acetylaniline-functionalised ferrocenes as potential scaffolds for the development of new anti-inflammatory agents.