Theoretical Insights into ESIPT and GSIPT in Schiff Base Cu(II)-BSSMO Complexes: Substituent Effects Explored via DFT, Molecular Docking, and Dynamics Simulations for Optoelectronic and Biomedical Applications

Excited-state intramolecular proton transfer (ESIPT) is a key photophysical mechanism with broad implications for the development of advanced materials for optoelectronics, sensing, and biomedical applications. In this study, the effects of electron-donating (EDG) groups (-NH₂, -OCH₃, and -CH₃) and electron-withdrawing (EWG) groups (-Cl, -Br, -COOH, -CF₃, -CN, and -NO₂) on ESIPT and ground-state intramolecular proton transfer (GSIPT) were systematically explored in 10 BSSMO derivatives using a combination of density functional theory (DFT), time-dependent DFT (TD-DFT), transition state analysis, and molecular simulations. The results show that EDGs enhance ESIPT efficiency by increasing electron density around proton donor/acceptor sites, promoting charge delocalization, and lowering proton transfer barriers, as evidenced by bathochromic shifts in absorption and emission spectra. On the other hand, EWGs strengthen hydrogen bonding in the ground state and cause shifts to shorter wavelengths, which make the molecules stiffer and reduces ESIPT. Frontier molecular orbital (FMO) analysis indicates that EDG substitution reduces <i>E</i> _g, improving reactivity and facilitating photoinduced transitions. Further insights from QTAIM and MESP analyses reveal distinct substituent-dependent electronic and bonding characteristics. Biological assessments through molecular docking show that keto tautomers, especially with EDGs, possess stronger binding affinities toward the human histo-aspartic protease (HAP) protein, consistent with improved pharmacokinetic properties predicted via ADMET analysis. Molecular dynamics (MD) simulations further highlight the specific roles of -NH₂ and -NO₂ in mediating protein-ligand interactions. Overall, correlation analysis shows that electron-withdrawing substituents (positive σ) enhance electronic stability by increasing the energy gap, ionization potential (IP), and electron affinity (EA), while electron-donating substituents (negative σ) promote charge delocalization and transport. This study further establishes a clear structure-property relationship, highlighting that strategic substitution can precisely tune ESIPT/GSIPT behavior, optoelectronic properties, and biological activity, making Cu-BSSMO derivatives promising multifunctional candidates for advanced applications.