Click chemistry of phenyl 1,2,3-triazole–2-pyridylpiperazine hybrids: synthesis, targeted anticancer activity, molecular modeling and computational studies

Abstract

A novel series of phenyl 1,2,3-triazole–2-pyridylpiperazine derivatives (13–23) was synthesized via Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) click chemistry. The structures of the obtained compounds were confirmed using standard spectroscopic techniques. Their antiproliferative activities were evaluated against human colorectal (HCT-116), liver (HepG-2), and breast (MCF-7) cancer cell lines, along with normal human lung fibroblasts (WI-38) using the MTT assay. Several derivatives exhibited significant cytotoxic activity, with compounds 15 and 18 showing potent inhibitory effects comparable to doxorubicin. Molecular docking and molecular dynamics simulations suggested stable binding interactions of the most active compound with the EGFR receptor. In silico drug-likeness and ADME analyses indicated acceptable pharmacokinetic properties for most compounds. These findings suggest that phenyl 1,2,3-triazole–2-pyridylpiperazine derivatives, particularly compound 15, may serve as promising lead candidates for the development of new anticancer agents.