Design, Synthesis, and Molecular Docking Studies of 2‐Azetidinone‐Based Combretastatin A‐4 Analogues with Anticancer Activity

Abstract This study develops new combretastatin A‐4 (CA‐4) analogues to enhance anticancer efficacy, selectivity, and address drug resistance. A series of 2‐azetidinones, designed as CA‐4 analogues, feature two substituted phenyl rings bridged by an amidic carbonyl and a β‐lactam ring. Target compounds (7–11, 20–23, and 28–31) were synthesized through two‐step routes and characterized using FT‐IR, 1 H NMR, 13 C NMR, and mass spectrometry. Anti‐proliferative activity against the breast cancer cell line MCF‐7 and the normal cell line WRL 68 revealed compounds 9 and 21 as the most potent, with IC 50 values of 34.27 and 28.86 µM, respectively. Molecular docking studies of these compounds showed high binding affinity to the colchicine site on tubulin (PDB ID: 4O2B). Results suggest that symmetrical aromatic rings in this scaffold may enhance anticancer activity, highlighting compounds 9 and 21 as promising candidates.