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<p>A diazotization–coupling route was used to synthesize the para (<b>4)</b> and ortho (<b>5)</b> azobenzaldehyde isomers, which were fully characterized by FT-IR, ¹H/¹³C NMR and MS techniques. Global reactivity descriptors were computed at the M06-2X-D3/6-311G(d, p) level. The para form has a much stronger NBO stabilization energy (≈ 4771 vs. 3187&#xa0;kcal·mol⁻¹), thus it is more delocalized and polarizable, while the ortho remains a slightly harder and more electronegative. Molecular docking on the target 2IOK, validated by redocking of the co–crystallized ligand (RMSD = 1.553 Å), reveals nearly identical binding affinities for both isomers (para − 8.45; ortho − 8.44&#xa0;kcal·mol<sup>− 1</sup>) and a common hydrophobic anchoring pattern involving PHE, LEU and MET residues, augmented by polar contacts with HIS524 and ARG394; however, the para isomer establishes a somewhat richer polar interaction network. The docked pose is confirmed by molecular dynamics simulations at 100 ns for both apo 2IOK and the 2IOK–para complex, characterized by stable backbone RMSD values and local backbone RMSF damping centered on the binding site, consistent with local ligand-induced rigidification without global structural disruption. PASS predictions indicate a high likelihood of mitochondrial/redox-related activities (Pa ≳ 0.90) for the para isomer and strong agonism of apoptosis (Pa ≈ 0.8), as well as an increased likelihood of modulation of TP53 expression (Pa ≈ 0.54). Collectively, the two isomers represent a pair of closely related chemotypes; the para derivative exhibits marginally enhanced electronic softness and interactability, making these scaffolds compelling leads for redox- and apoptosis-directed pharmacological development.</p>

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Experimental and computational investigation of ortho/para azobenzaldehyde isomers: synthesis, DFT, molecular docking, and molecular dynamics insights

  • 期刊论文

  • 发表日期：

    2026年4月18日

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  • Myasar Kh. Ibrahim,
  • Shireen R. Mohammed,
  • Haydar Mohammad-Salim,
  • Saeed S. Samman,
  • Munirah M. Al-Rooqi,
  • Abdellah Zeroual,
  • Abdulaziz M. Almohyawi,
  • Abdulrahman A. Alsimaree,
  • Saleh A. Ahmed

摘要

A diazotization–coupling route was used to synthesize the para (4) and ortho (5) azobenzaldehyde isomers, which were fully characterized by FT-IR, ¹H/¹³C NMR and MS techniques. Global reactivity descriptors were computed at the M06-2X-D3/6-311G(d, p) level. The para form has a much stronger NBO stabilization energy (≈ 4771 vs. 3187 kcal·mol⁻¹), thus it is more delocalized and polarizable, while the ortho remains a slightly harder and more electronegative. Molecular docking on the target 2IOK, validated by redocking of the co–crystallized ligand (RMSD = 1.553 Å), reveals nearly identical binding affinities for both isomers (para − 8.45; ortho − 8.44 kcal·mol− 1) and a common hydrophobic anchoring pattern involving PHE, LEU and MET residues, augmented by polar contacts with HIS524 and ARG394; however, the para isomer establishes a somewhat richer polar interaction network. The docked pose is confirmed by molecular dynamics simulations at 100 ns for both apo 2IOK and the 2IOK–para complex, characterized by stable backbone RMSD values and local backbone RMSF damping centered on the binding site, consistent with local ligand-induced rigidification without global structural disruption. PASS predictions indicate a high likelihood of mitochondrial/redox-related activities (Pa ≳ 0.90) for the para isomer and strong agonism of apoptosis (Pa ≈ 0.8), as well as an increased likelihood of modulation of TP53 expression (Pa ≈ 0.54). Collectively, the two isomers represent a pair of closely related chemotypes; the para derivative exhibits marginally enhanced electronic softness and interactability, making these scaffolds compelling leads for redox- and apoptosis-directed pharmacological development.