Novel isoxazole-containing thiazolidinone: Synthesis, DFT analysis, and pharmacological evaluation

The monoterpene skeleton of (R)-Carvone was selected as a support to access the new heterocyclic isoxazole ring combined with thiazolidinone via the Huisgen cycloaddition reaction. A good yield was achieved for the synthesized product, which was characterized by high-resolution mass spectrometry (HRMS) and NMR ( 1 H & 13 C) analysis. The chemoselectivity of the 1,3-dipolar cycloaddition reaction indicated that the dipolarophilic site is more reactive than the double bond. Density functional theory (DFT) was utilized to determine the peri- and regio-selectivity of the [3+2] cycloaddition reaction of the compounds. The theoretical outcomes closely align with the experimental results. Additionally, the electronic interaction properties of the synthesized compounds were examined through the study of frontier orbitals highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO) and independent gradient model (IGM) analysis. Furthermore, the effect of various solvents on the λmax of the two regioisomers 6 and 6T was investigated. Using network pharmacology, critical genes and pathways associated with breast cancer were identified, highlighting epidermal growth factor receptor (EGFR) and poly (adp-ribose) polymerase 1 (PARP1) as potential therapeutic targets for the designed compounds. Molecular docking studies were then conducted with these top targets, EGFR and PARP1, to assess the binding affinity of the ligands, demonstrating strong interactions between compound 6 and these proteins.