Design, Synthesis, and Biological Evaluation of Methoxy-Substituted Chalcones and Gypsogenin-Based Hybrids as Anticancer and Antimicrobial Agents

Chalcones and natural product-based hybrids represent important scaffolds in the development of biologically active small molecules. In this study, a series of methoxy-substituted chalcone derivatives (1a–1i) and acetyl gypsogenin-based hybrid compounds (4a–4i) were synthesized and fully characterized by spectroscopic methods. The cytotoxic activities of all compounds were evaluated against five human cancer cell lines (PANC-1, MDA-MB-231, HeLa, A549, and SH-SY5Y) and the normal HEK293 cell line using the MTT assay. Several chalcone derivatives exhibited pronounced antiproliferative activity, whereas the corresponding gypsogenin-based hybrids generally showed reduced cytotoxic effects. Tumor selectivity was further assessed by calculating the selectivity index values. Antimicrobial activity was determined using minimum inhibitory concentration assays against selected bacterial and fungal strains, revealing moderate inhibitory effects for some compounds. In addition, molecular docking studies of the most active chalcones (1g and 1h) were performed to explore potential interactions with key cancer-related targets. Overall, the results highlight the chalcone scaffold as the main contributor to biological activity in this series and demonstrate that hybridization with gypsogenin did not enhance the cytotoxic potency. © 2026 The Authors. Published by American Chemical Society.