Structural insight into π-stacking interactions of non-aromatic oxazolo[5,4-d]pyrimidine derivatives and their neuroactivity in a Galleria mellonella model.

Abstract

In this study, the physicochemical characteristics, quantum-chemical properties, and neurobiological activity of 6-N-benzyloxazolo[5,4-d]pyrimidin-7(6H)-imine derivatives 1-9 were investigated. Solid-state structural analysis using single-crystal X-ray diffraction (XRD) revealed intermolecular π-stacking interactions involving the formally non-aromatic oxazolo[5,4-d]pyrimidine scaffold. Energy decomposition analysis (EDA) showed that the tested crystallographic dimers are energetically stabilizing, with dispersion representing the largest attractive contribution throughout the series. Complementary non-covalent interaction (NCI) analysis demonstrated spatially extended regions of weak non-covalent interactions between the stacked molecular fragments. Density functional theory (DFT) calculations showed that the HOMO-LUMO gaps and related global reactivity descriptors varied only within a narrow range across derivatives 1-9. Combined crystallographic and thermal analyses indicated that the nature and position of substituents on the N-6-benzyl group are associated with differences in crystal packing, melting behavior, and thermal stability. The neurobiological effects of the tested compounds were assessed in vivo using the Galleria mellonella model. Following an initial screening of oxazolo[5,4-d]pyrimidine derivatives 1-9, compounds 5 and 6 were selected for more detailed locomotor analysis and showed the most pronounced changes in larval behavior. Overall, the combined crystallographic, EDA, and NCI results provide complementary structural, energetic, and real-space evidence supporting dispersion-dominated stacking interactions in the solid state, whereas their possible relationship with the observed neurobiological effects remains to be established.