Unveiling the Anticancer Properties of New Synthesized Alkoxy‐ and Methyl Thio‐Chalcone Derivatives

ABSTRACT Breast and cervical cancers are a serious problem and the leading cause of death in women in this decade. Chalcone is a promising compound with great potential for anticancer use. In this work, we synthesized six chalcone derivatives with alkoxy‐ and methylthio‐substituents through Claisen–Schmidt condensation at room temperature. The study aimed to design, investigate, synthesize, and evaluate the anticancer activity of these six chalcone derivatives against T47D, MCF‐7, and HeLa human cancer cell lines. First, all candidates were synthesized using Microwave Assisted Organic Synthesis (MAOS) as a green synthesis method with high yields (87%–90%). Products were characterized by IR, NMR, GC‐MS, and HRMS. We used the MTT assay to assess cell viability and measure cytotoxicity. In addition, an in silico method was used to explore the mechanism behind the anticancer activity. All chalcones were optimized by B3LYP functional and tested for anticancer activity by molecular docking to various receptors: Histon deacetylase SIRT1 inhibitor PDB: 4I5I (T47D cell), estrogen receptor alpha ligand binding domain Y5375 Mutant PDB: 6CBZ (MCF‐7 cell), and HeLa cell line protein Caspase 3 V266A PDB: 5I9B (HeLa cell). Chalcone 2 (17.85 ± 0.84 µg/mL) and chalcone 6 (29.09 ± 0.37 µg/mL) were strong for T47D cells. Chalcone 4 (15.89 ± 0.79 µg/mL) was strong for MCF7, and chalcone 1 (28.47 ± 0.41 µg/mL) for HeLa. These results are in line with in silico investigations, which showed all chalcone derivatives had good binding affinity to all receptors (below −5). The cytotoxicity assay also showed low toxicity of chalcone derivatives toward normal human cells, which is remarkable. Therefore, we concluded that the synthesized chalcones (chalcone 1, 2, 4, and 6) have potential as novel anticancer agents in real applications. In addition, MAOS shortens reaction time and gives high yields, supporting green chemistry principles.