Research Information System
Journal of Molecular Structure, vol.1365, 2026 (SCI-Expanded, Scopus)
A novel amino–fluoro substituted isocoumarin derivative, 3-amino-4-((2-fluorophenyl)amino)-1H-isochromen-1-one (4), was rationally designed and synthesized to investigate the impact of targeted fluorine incorporation on the structural, electronic, and biological interaction properties of the isocoumarin scaffold. The compound was prepared via a three-component reaction and fully characterized by FTIR, NMR, and single-crystal X-ray diffraction analyses. XRD results confirmed a triclinic P -1 crystal system with strong intermolecular hydrogen bonding (N–H···O, N–H···F, N–H···N) and π···π stacking interactions stabilizing the packing. Hirshfeld surface and void analyses beside the packing energies supported the presence of significant H···H and H···C contacts and compact molecular packing. DFT calculations determined a significant HOMO–LUMO gap (ΔE = 4.06 eV), indicating balanced chemical reactivity and stability, while molecular electrostatic potential mapping identified distinct electron-rich and electron-deficient regions relevant to potential biological interactions. Molecular docking studies against the LRIG1 receptor demonstrated a strong binding affinity (–7.2 kcal/mol), exceeding that of Erlotinib (–6.2 kcal/mol) and comparable to Afatinib (–7.9 kcal/mol), standard EGFR inhibitors. In silico ADMET predictions indicated favorable oral bioavailability and acceptable pharmacokinetic behavior, with low predicted toxicity except for a positive Ames test, highlighting the need for further optimization. Notably, this work represents the first comprehensive study integrating single-crystal structural analysis, Hirshfeld surface investigation, DFT calculations, LRIG1-targeted molecular docking, and ADMET profiling for an amino–fluoro substituted isocoumarin derivative. Together, these integrated experimental and computational findings suggest that compound (4) may serve as a promising lead scaffold for further experimental exploration targeting the LRIG1–EGFR regulatory pathway.