Synthesis of thiazolidinone-triazole hybrid compounds as anticancer agents and molecular modeling study

• Nine thiazolidinone-triazole hybrid compounds 9, 10 , and 11 were synthesized via utilizing an efficient click reaction protocol. • The DFT calculations of the synthesized hybrids revealed comparable non-planar configurations. • The hybrids FMO’s energies presented close values, wherein the analogue 10c exhibited the lowest energy gap. • Hybrids 9a and 11a exhibited potent antiproliferative effects against MCF-7. • Hybrid 10c showed the lowest IC₅₀ (0.048 μM) for CAIX inhibition. • Molecular docking revealed strong binding affinities for hybrids 10c, 10b , and 9c . Nine thiazolidinone-triazole hybrid compounds 7, 8 , and 9 were produced through applying an effective click reaction procedure. The DFT calculations of the synthesized hybrids revealed comparable twisted configurations as well as HOMO-LUMO shapes and energies. The energy gap data cleared out that the acetate analogue 4 has higher value than acetyl 5 and butanoate 3 , respectively, and so their corresponding triazole conjugates 8a-c > 9a-c > 7a-c . Meanwhile, the in vitro antiproliferative activeness of the manufactured hybrids had been assessed versus diverse cell lines, using the doxorubicin as reference. Hybrids 7a and 9a demonstrated the most potent effectiveness, particularly against MCF-7 (IC₅₀ = 23.36±0.34 and 39.56±0.23 μM) comparable to doxorubicin. Moreover, the inhibitory effect against carbonic anhydrase IX (CAIX) and XII (CAXII) isoforms showed that hybrid 8c was the most eminent towards CAIX (IC₅₀ = 0.048 μM), followed by hybrids 7c and 7b , respectively. The molecular docking investigation was conducted to evaluate the binding affinities, interactions, and binding modes of novel hybrid compounds with a target receptor. Notably, hybrids 8c, 8b , and 8c demonstrated the most favorable binding energies, while different hybrids displayed diverse binding interactions, including hydrogen bonding, π-cation interactions, and hydrophobic interactions. Finally, a comprehensive analysis of the prepared hybrids was conducted to assess their pharmacokinetic properties, focusing on SwissADME parameters. The findings suggest that hybrids 8c and 8b offer significant potential for therapeutic applications, although optimization may be required to address bioavailability and ADME-related concerns.