Electronic structure–activity relationships of adenine-based istradefylline derivatives investigated by DFT, topological analysis, and exploratory neuronal excitability modeling

AR) antagonists offer a non-dopaminergic therapeutic strategy for neurological disorders, the electronic factors governing their activity and photostability remain insufficiently understood. In this study, the electronic structure-activity relationships of istradefylline and selected adenosine derivatives were systematically investigated using an integrated quantum chemical approach. Frontier molecular orbitals (FMOs), global reactivity descriptors, excitation properties, and electrostatic distributions were analyzed through density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations, supported by Natural Bond Orbital (NBO), Natural Population Analysis (NPA), and wavefunction-based topological analyses (MEP, RDG/NCI, ELF, and LOL). The results indicate that istradefylline exhibits a balanced electronic profile (ΔE = 3.53 eV), characterized by moderate donor-acceptor interactions and extended π-delocalization. Among the derivatives, II-2-4 demonstrates enhanced electronic flexibility and charge-transfer capacity with the lowest energy gap (3.48 eV) and highest softness, whereas II-1-1 shows reduced reactivity associated with higher hardness and localized orbitals. In contrast, II-2-2 displays a reactivity-stability balance comparable to the reference compound. NBO analysis reveals that lone pair → π* and π → π* interactions dominate molecular stabilization, while MEP and NCI results identify carbonyl oxygens and purine nitrogens as key interaction sites. Structural modification of the exocyclic C=C bond into a rigid purine framework may contribute to improved photostability by limiting conformational flexibility, although this hypothesis requires further experimental validation. Furthermore, an exploratory descriptor-based multi-scale modeling approach is proposed to conceptually map global and local electronic properties-chemical softness, polarizability, dipole moment, and electrostatic potential-onto simulated neuronal excitability; this mapping should be interpreted as a conceptual framework rather than a demonstration of biological or pharmacological activity. These findings suggest the potential importance of a balanced interplay between global and local electronic properties in understanding activity-related trends in A2AR antagonists, while acknowledging that the present computational results require further experimental and receptor-level validation.