Synergistic MgSiO3 nanocatalysis for the efficient synthesis of benzo[d]oxazol-2-yl phenylisoxazoles: structural elucidation, drug-likeness profiling, and target-oriented biomolecular interactions.

A new library of 2-(5-phenylisoxazole-3-yl)benzo[d]oxazole derivatives 3(a-f) was synthesized through a magnesium silicate nanocatalyst-assisted condensation of 2-aminophenol with a series of substituted 5-phenylisoxazole-3-carbaldehydes. The identity of the products was confirmed by FT-IR, 1H NMR, 13C NMR, and mass spectrometry. Their interaction with calf thymus DNA (CT-DNA) was systematically examined using absorption spectroscopy, viscosity assays, thermal denaturation experiments, and molecular docking simulations. The compounds exhibited binding constants in the 105-106 M-1 range, with 3d showing the strongest affinity (Kb = 1.13 × 106 M-1), consistent with an intercalative binding mode. Docking studies with human DNA (PDB ID: 1G3X) revealed stabilizing hydrogen bonds, π-π stacking, and hydrophobic contacts that corroborated the experimental findings. Electronic properties were further explored through density functional theory calculations at the B3LYP level, which demonstrated that frontier orbital parameters-particularly highest occupied molecular orbital-lowest unoccupied molecular orbital gaps and electrophilicity indices-correlated well with DNA-binding behavior, offering mechanistic insight into the electronic contributions to molecular recognition. In silico Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiling suggested favorable pharmacokinetic attributes and drug-like properties. All derivatives promoted UV-induced cleavage of supercoiled pBR322 DNA, underscoring their potential as photoactive nuclease mimetics. These results identify benzoxazole-isoxazole hybrids as promising scaffolds for DNA-targeted applications in medicinal chemistry and chemical biology.