N‑Alkylated 5,5-Diphenylhydantoin Derivatives: Synthesis, X‑ray, Spectroscopic Characterization, Hirshfeld Surface Analysis, DFT, Molecular Docking, Molecular Dynamics Simulations, and Cholesterol Oxidase Binding Affinity Estimation

  • ACS Omega. 2025 Jul 7;10(27):29267-29284. doi: 10.1021/acsomega.5c02215.
Houda Lamssane  1 ,  Amal Haoudi  1 ,  Aravazhi Amalan Thiruvalluvar  2 ,  Tuncer Hökelek  3 ,  Venkatramanan Varadharajan  4 ,  Said Chakroune  1 ,  Youssef Kandri Rodi  1 ,  Ahmed Mazzah  5 ,  Joel T Mague  6 ,  Mohammed M Alanazi  7 ,  Hanae El Monfalouti  8 ,  Nada Kheira Sebbar  9
Affiliations
  • 1. Laboratory of Applied Organic Chemistry, Faculty of Science and Techniques, Sidi Mohamed Ben Abdellah University, B.P. 2202, Routed Imouzzer, Fez 30050, Morocco.
  • 2. Kunthavai Naacchiyaar Government Arts College for Women (Autonomous), Thanjavur, Tamil Nadu 613 007, India.
  • 3. Department of Physics, Hacettepe University, Ankara, Beytepe 06800, Turkey.
  • 4. Department of Biotechnology, PSG College of Technology, Peelamedu, Coimbatore, Tamil Nadu 641004, India.
  • 5. Université de Lille, CNRS, UAR 3290, MSAP, Miniaturization for Synthesis, Analysis and Proteomics, F-59000 Lille, France.
  • 6. Department of Chemistry, Tulane University, New Orleans, Louisiana 70118, United States.
  • 7. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
  • 8. Laboratory of Plant Chemistry, Organic and Bioorganic Synthesis, Faculty of Sciences, Mohammed V University in Rabat, 4 Avenue Ibn Battouta B.P. 1014 RP, Rabat 10500, Morocco.
  • 9. Laboratory of Heterocyclic Organic Chemistry, Drug Science Research Center, Pharmacochemistry Competence Center, Faculty of Sciences, Mohammed V University in Rabat, 4 Avenue Ibn Battouta B.P. 1014 RP, Rabat 10500, Morocco.
PMID: 40686988 DOI: 10.1021/acsomega.5c02215
Abstract

This study presents the synthesis and characterization of nine N-alkylated phenytoin derivatives 4-13. These compounds were synthesized and characterized using spectroscopic techniques including 13C and 1H nuclear magnetic resonance spectroscopy, UV-visible spectroscopy, infrared spectroscopy, and liquid chromatography-mass spectrometry. The structures of 4-6 were confirmed by X-ray crystallography. The geometrical parameters and spectral data were also compared with those of a density functional theory geometry optimization and molecular orbital calculation at the B3LYP/6-311++G-(d,p) level of theory. Hirshfeld surface analysis indicated that hydrogen-hydrogen interactions (56-62%) predominated in the crystal arrangement. Molecular docking studies demonstrated strong binding affinities with Cholesterol oxidase, with compound 4 exhibiting the highest affinity at -10.97 kcal/mol, outperforming compounds 5 (-8.94 kcal/mol) and 6 (-9.66 kcal/mol). The stability of the compound 4-cholesterol oxidase complex, with a protein root-mean-square deviation of 1.24 ± 0.07 Å, was confirmed through an 80 ns molecular dynamics simulation. Moreover, molecular mechanics-generalized Born surface area (MM-GBSA) calculations estimated a total binding free energy of -51.5 ± 10.6 kcal/mol, with significant contributions from van der Waals and electrostatic interactions. These findings suggest that compound 4 is a promising inhibitor of Cholesterol oxidase, providing valuable insights for pharmaceutical development.

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