Design, synthesis, structural diversity, ADMET profiling and DFT calculations of 1,2,4-oxadiazole-1,3-oxazole hybrids

Abstract

To obtain new bioactive nitrogen-containing heterocycles, hybrid molecules incorporating two heterocyclic rings as potential dual binding sites for biomolecules were synthesized in this study. The resulting compounds combine 1,2,4-oxadiazole and 1,3-oxazole fragments within a single molecular framework. The starting materials for the synthesis of these heterocycles were amino-substituted 1,2,4-oxadiazole derivatives prepared from amidoximes and Boc-protected amino acids. Their reaction with enamides led to heterocyclization, affording the target products containing both 1,2,4-oxadiazole and 1,3-oxazole moieties. Using the proposed synthetic approach, 16 new compounds containing two heterocyclic rings linked by either acyclic or cyclic linkers were obtained. The structures of the synthesized compounds were reliably confirmed by elemental analysis and spectroscopic methods, including ¹H and ¹³C NMR spectroscopy, IR spectroscopy, and mass spectrometry. In addition, ADMET studies were performed to predict the drug-likeness of the synthesized compounds, and quantum-chemical calculations were carried out for model molecules. The proposed synthetic approach demonstrates versatility and enables the preparation of a large library of potentially bioactive 1,2,4-oxadiazole–1,3-oxazole hybrid molecules, which is useful for further investigation of diverse biological activities.