Design, Synthesis and Biological Evaluation of Novel – 1,2,3 Triazole Hybrids as Selective Her2 Kinase Inhibitors for Breast Cancer Therapy

A virtual library of fifteen novel 1,2,3-triazole hybrid compounds (HT-01–HT-15) was rationally designed as selective HER2 kinase inhibitors, based on three heterocyclic scaffolds: 4-anilinoquinoline–triazoles (Series A), N-arylphthalazin-1(2H)-one–triazoles (Series B), and 1-arylquinoxalin-2(1H)-one–triazoles (Series C). Molecular docking against the HER2 kinase domain (PDB ID: 3RCD) using AutoDock Vina (v1.2.7) predicted binding free energies of −8.634 to −11.294 kcal mol⁻¹, with eleven compounds outperforming the reference inhibitor lapatinib. Based on docking scores, binding interactions, drug-likeness, and structural diversity, one representative compound from each series—HT-05 (ΔG = −10.372 kcal mol⁻¹), HT-08 (ΔG = −11.294 kcal mol⁻¹), and HT-14 (ΔG = −11.132 kcal mol⁻¹)—was selected for synthesis. These compounds were prepared via multistep routes employing copper(I)-catalysed azide–alkyne cycloaddition (CuAAC) click chemistry, in overall yields of 34–42%, and characterized by FTIR, ¹H NMR, and HRMS. Biochemical evaluation using the ADP-Glo™ HER2 kinase assay showed HT-14 exhibited the highest inhibitory activity (IC₅₀ = 14 ± 1 nM), followed by HT-08 (18 ± 2 nM) and HT-05 (81 ± 5 nM). A 500 ns molecular dynamics simulation of the HT-14–HER2 complex, performed using GROMACS (v2023.3) with the CHARMM36m force field, revealed stable ligand–protein interactions, supported by favorable RMSD, RMSF, hydrogen-bond occupancy, and free-energy landscape analyses. Collectively, these computational and biochemical findings identify HT-14 as the most promising lead compound and support quinoxalinone–triazole hybrids as a promising scaffold for developing selective HER2 kinase inhibitors.