Synthesis, crystal structure, and molecular docking analysis of 1-(3-(2-chlorophenyl)-4,5-dihydroisoxazol-5-yl) pyrrolidin-2-one: insights into biological interactions and drug design

Karadağ Alpaslan M., Rouzi K., Poyraz E. B., Dege N., Bouatia M., Karbane M. E., ...Daha Fazla

Journal of Molecular Structure, cilt.1347, 2025 (SCI-Expanded) identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 1347
  • Basım Tarihi: 2025
  • Doi Numarası: 10.1016/j.molstruc.2025.143354
  • Dergi Adı: Journal of Molecular Structure
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Chemical Abstracts Core, Chimica, Compendex, INSPEC
  • Anahtar Kelimeler: Crystal structure, Cyp1a2 inhibition, Drug discovery, Isoxazoline, Molecular Docking, Pyrrolidin-2-one
  • Ondokuz Mayıs Üniversitesi Adresli: Evet

Özet

A novel compound, 1-(3-(2-chlorophenyl)-4,5-dihydroisoxazol-5-yl)pyrrolidin-2-one (CDPO), was synthesized via 1,3-dipolar cycloaddition with a yield of 40% and melting point of 178–180 °C. The structure was confirmed by NMR, FT-IR, HRMS (m/z = 265.0733), and single-crystal X-ray diffraction. Crystallographic analysis revealed a triclinic system with space group P-1, unit cell volume of 636.33 ų, and key hydrogen bonding and π–π stacking interactions (centroid distance = 3.956 Å). Hirshfeld surface analysis showed H···H (40.5%) and O···H/H···O (20.1%) contacts as dominant contributors to crystal stability. DFT calculations (B3LYP/6-311G(d,p)) confirmed structural agreement (e.g., C=O bond = 1.218 Å) and revealed a HOMO–LUMO gap of 5.086 eV, with an ionization potential of 6.844 eV and electrophilicity index of 3.640 eV. ADMET predictions indicated good gastrointestinal absorption and blood-brain barrier permeability. Molecular docking (AutoDock 4.2) against six protein targets showed the strongest affinities with CYP3A4 (–6.32 kcal/mol, Ki = 23.4 µM) and CYP1A2 (–6.12 kcal/mol, Ki = 32.8 µM). Moderate binding was observed with Muscarinic M2 (–5.36 kcal/mol) and Serotonin 5-HT2B (–5.14 kcal/mol), while weak interaction was noted with Histamine H1 (–3.04 kcal/mol). The docking protocol was validated with a redocking RMSD of 1.835 Å. The data suggest CDPO as a promising scaffold with potential anticancer and neuroactive properties through multi-target modulation. Further in vitro and pharmacokinetic evaluations are warranted to explore therapeutic applications and off-target risks.