Indole‐Based Curcumin Analogs With Antioxidant and Antitumor Activities: Synthesis, Molecular Docking

ABSTRACT Curcumin, a natural compound with broad pharmacological effects, suffers from low bioavailability due to its unstable β‐diketone structure. To address this, we designed novel indole‐based curcumin analogs via molecular hybridization, replacing the β‐diketone with a monocarbonyl bridge to enhance stability. A series of symmetric ( 1a and 1b ) and asymmetric ( 3a – 3i ) compounds were synthesized. The antioxidant assays (DPPH method) revealed a concentration‐dependent radical scavenging effect, with compound 3e exhibiting 23.1% inhibition at 64 μM. In vitro antitumor screening using the MTT assay across four human cancer cell lines (Eca109, SMMC7721, A549, and MGC803) revealed promising inhibitory effects. Among them, compound 1a displayed the most potent activity against Eca109 cells, with an IC 50 value of 6.84 μM, being markedly lower than those of curcumin (29.5 μM) and cisplatin (10.4 μM), indicating superior cytotoxicity. Molecular docking analysis of 1a predicted strong binding to EGFR (–10.9 kcal/mol) and CDK6 (–11.2 kcal/mol), stabilized by hydrogen bonds and hydrophobic interactions. These results validate the novelty of indole modification and correlate in vitro activity with in silico mechanisms.