Synthesis, in vitro, in silico and DFT studies of indole curcumin derivatives as potential anticancer agents

The curcumin derivatives were synthesized for the first time using simple starting materials through a three-component reaction, yielding high purity compounds. The synthesized indole curcumin derivatives were characterized by FT-IR, ¹H NMR, ¹³C NMR and HRMS spectral techniques. The anticancer property of curcumin derivatives was evaluated against three cell lines such as, Hep-2, A549 and HeLa. Interestingly, it was found that methoxy substituted indole curcumin was showed the promising anticancer activity with IC₅₀ values of 12 µM (Hep-2), 15 µM (A549) and 4 µM (HeLa) cancer cells lines and equated with standard drugs, doxorubicin and paclitaxel. Moreover, the indole curcumin derivatives were exhibited significant anti-oxidant activity with the reduced levels of 73.41%, 81.95%, and 90.50%, respectively at 50 µg concentration. The methoxy substituted indole curcumin molecule displayed the maximum antioxidant activity, confirming that the indole curcumin has dual action capabilities. The structural characteristics of these potential compounds were explored using DFT studies. The Keto and Enol isomers of indole curcumin derivatives were compared, and energy analysis suggested that the enol isomers were more stable than the keto isomer. Molecular docking results displayed that the keto form of indole curcumin molecules were efficiently binding with GSK-3β, EGFR, and Bcr-Abl proteins, implying that they possess significant anti-cancer activity.