Synthesis of benzhydrol analogues based on 1´-acetoxychavicol acetate (ACA), as a stable and potent antiproliferative agent on breast cancer cell lines, ADMET analysis and molecular docking study

Six benzhydrol analogues were successfully synthesised and evaluated for their antiproliferative effect on breast cancer cells. These compounds were designed based on the structure of 1´-acetoxychavicol acetate (ACA) and 1´-acetoxyeugenol acetate (AEA), which known for their anticancer properties. Among them, compounds 3b, 3e, and 3f demonstrated significant activity against MCF-7 and MDA-MB-231 breast cancer cell lines (between 5.5-6.0 µM and 1.1-7.0 µM, respectively), outperforming tamoxifen as the standard control. Molecular docking studies revealed that compounds 3b, 3e, and 3f shows good binding energies ranging from ˗5.13 to ˗7.27 kcal/mol with Nuclear Factor-KappaB Kinase alpha (IκBα) protein (PDB ID: 1NFI), compared to ˗5.27 kcal/mol for tamoxifen (control). 3b and 3finteract with IκBα at several residues including APE77, VAL93, and VAL97. The SwissADME and toxicity prediction analysis indicates that three compounds (3b, 3e, and 3f) adhere to the principles of drug-likeness. These findings suggest that the benzhydrol analogues, particularly 3b, 3e, and 3f, could be promising lead for further development as anticancer agents.