Synthesis, characterization, DFT, and in-Silico analysis of isoxazole-thiazolidinone hybrids: Reactivity and anticancer potential assessed through pharmacological network, molecular dynamics, molecular docking, and ADMET analysis

This study presents the design, synthesis and computational evaluation of novel isoxazoline-thiazolidinone hybrids derived from (R)-Carvone, targeting key oncogenic proteins in breast cancer. The synthesis involves 1,3-dipolar cycloaddition to obtain isoxazolines, followed by the formation of thiosemicarbazones and thiazolidinones via green chemistry. Structural confirmation by NMR and HRMS verified the successful formation of hybrids 12a (R&S) and 12b (R&S). Density functional theory (DFT) calculations at the B3LYP/6–311+G(d,p) level revealed optimized geometries, boundary molecular orbitals and charge distributions, highlighting the influence of stereochemistry on electronic behavior. Molecular anchoring studies showed that compound 12a (R) exhibited the highest binding affinity for HSP90AA1 (-9.8 kcal/mol), while compound 12b (S) showed a strong interaction with HIF1A (-9.1 kcal/mol). These interactions were stabilized by critical hydrogen bonds and hydrophobic contacts, suggesting strong molecular recognition by the target proteins. Molecular dynamics simulations at 100 ns confirmed the stability of the ligand-protein complexes, with RMSD values stabilizing below 2.0 Å. MM-PBSA free energy calculations also confirmed the existence of favorable binding interactions. In addition, ADMET analysis predicted optimal pharmacokinetic properties, including high gastrointestinal absorption and low toxicity. These results make the synthesized hybrids 12a (R&S) and 12b (R&S) promising candidates for targeted breast cancer therapy.