Design, synthesis, structural characterization, anticancer evaluation, and computational studies of novel...

A novel series of eleven phenyl-substituted quinoline 1,2,3-triazole glycoconjugates 6(a-k) was synthesized via the copper(i)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between 2-phenyl-substituted quinoline-4-carboxylic acid propargyl ester (4a-4e) and various sugar azides (5a, 5b, and 5c). The obtained compounds were comprehensively characterized by FT-IR, ¹H NMR, ¹³C NMR, and mass spectrometry. The chemical structures of compounds 6a, 6b, and 6e were further established by single-crystal X-ray diffraction analysis. Their crystal packing was stabilized through a network of intermolecular hydrogen bonds involving C-H⋯N, N-H⋯N, and C-H⋯O (sp², sp³) interactions, which were qualitatively analyzed using Hirshfeld surface analysis. In vitro anticancer evaluation against the MCF-7 breast cancer cell line revealed that most of the compounds of the series were inactive, while compounds 6c, 6d, and 6f exhibited only weakly cytotoxic activity (IC₅₀ values of 108.59-135.95 µM). Molecular docking with estrogen receptor alpha (ERα, PDB ID: 3ERT) revealed good binding affinities (up to -9.1 kcal mol^-1), comparable to the reference ligand (-9.7 kcal mol^-1). Furthermore, DFT calculations were performed to evaluate key electronic parameters (HOMO-LUMO energies, reactivity, stability, and charge distribution), offering insight into the compounds' chemical behaviour and electronic properties.