Computational assessment of the reactivity and anticancer activity of 1,2,3-triazole-thiazolidinones derivatives: An approach combining DFT calculations, molecular dynamics simulations, molecular docking, and ADMET

• A series of natural bioactive (R)-Carvone-based 1,2,3-triazole were synthesized and their anti-cancer potential was tested under both in-silico and in-vitro conditions. • Chemical reactivity and chemical stability parameters were observed via density functional theory calculations (DFT). • Molecular Docking results were supported by molecular dynamic simulations • Through network pharmacology screening identifies potential targets for the treatment of cancer. Cancer is a global health burden with escalating incidence and mortality rates, necessitating the exploration of novel therapeutic strategies. 1,2,3-Triazoles, recognized for their diverse biological activities, have emerged as attractive candidates in drug discovery targeting key proteins associated with various cancers. This study presents the synthesis of a library of 1,2,3-triazole hybrids incorporating thiazolidinone and isoxazoline moieties. The antitumor potential of these compounds was evaluated using both in-silico and in-vitro assays. Structure-activity relationship (SAR) analysis revealed that strategic substitution of the para position of the phenyl ring, particularly with a nitro (NO 2 ) group, is promising to enhance cytotoxic activity. The binding potential of the synthesized compounds with the XIAP BIR2 domain, the specific receptor of caspase-3/7 activators, was explored through molecular docking. The stability of the protein-compound complexes procured from the docking was assessed through molecular dynamics (MD) simulation. The docking study demonstrated that the synthesized compounds had the potential to bind to the target protein. Among the compounds and their stereoisomers, compounds ( R )-6d and ( S )-6e exhibited a better binding potential to the protein. The MD simulation study revealed that the protein -( R )-6d complex was relatively stable.