Abstract

A series of carveoylphenol derivatives (1–12) was synthesized using a microwave-assisted approach and evaluated through an integrated in vitro and in silico strategy. Cytotoxicity was assessed against PC-3, MCF-7, and HT-29 human cancer lines, using non-tumorigenic CoN CCD841 cells as a reference. Derivatives 1, 2, 5, 6, 7, 8, and 11 exhibited activity (IC50 < 100 µM) against at least one cancer line, with 2 showing the highest potency (IC50 = 23.2 µM). Flow cytometry of compounds 1, 2, and 5 revealed structure-dependent cellular responses, where 2 at 40 µM induced maximum intracellular ROS generation (39.6%), 1 reduced mitochondrial membrane integrity to 42.1% intact cells, and 5 produced peak caspase activation (34.5%). Molecular docking against caspase-3 yielded predicted binding energies for all three molecules, with 5 scoring −6.4 kcal/mol. SwissADME analysis indicated comparable physicochemical profiles, high predicted gastrointestinal absorption, and potential blood–brain barrier permeability for these three derivatives. Overall, carveoylphenols, particularly compound 2, represent promising scaffolds for further structural optimization and mechanistic investigation.