Design, Synthesis, Computational Studies, and Evaluation of Triazole Acetamide Linked with Phenyl Piperazine Derivatives as Anticancer Agents Against Breast Cancer

A new series of triazole acetamide linked with phenyl piperazine derivatives 8a–r were synthesized by click chemistry approach and evaluated the anti-cancer activity against breast cancer. Most of the compounds were found active against breast cancer cell line MCF-7 (8.93 ± 3.08 to 65.06 ± 0.90% inhibition at 20 µM). Compound 8h was found to be the most active compound (IC₅₀ value: 18.62 ± 1.41 µM) followed by the compound 8g (IC₅₀ value: 50.19 ± 2.28 µM) and the morphology of cells treated with these compounds became smaller, lost their typical shape, and ability to adhere to the culture plate. It has been also observed that compound 8h exhibited a better therapeutic response than doxorubicin at ≥20 µM concentration. The study was also accessed with human normal kidney cell line HEK-293. Compounds 8h and 8g also showed better binding potentials toward the active site of hERα-LBD (ΔG: −9 and −8.6 kcal/mol, respectively) proteins than their native ligand (ΔG: −8.4 kcal/mol). Furthermore, molecular dynamics simulation parameters confirm the complex stability of compound 8h with the protein hERα-LBD. Hence, compound 8h possesses better anticancer properties among all the synthesized compounds which could be further evaluated by in-vitro and in-vivo studies.