Multitarget Enzyme Inhibition and Anticancer Potential of 3‐Substituted Indole Derivatives Supported by Molecular Docking Studies

The enzymes and anticancer properties of disubstituted indole, indole-imidazole, and indole-pyrazole derivatives were determined. These building blocks are based on a privileged 3-substituted indole scaffold that, in turn, has been used to explore potential effects for the enzymes and cancer cells. Inhibition studies for acetylcholinesterase (AChE), glutathione S-transferase (GST), alpha-amylase (α-Amy), and alpha-glucosidase (α-Gly) were conducted. IC₅₀ values for the 3-substituted indoles were identified as follows: AChE, 3.329 ± 0.975 to 5.544 ± 0.380 µM; GST, 2.228 ± 0.407 to 6.026 ± 1.100 µM; α-Gly, 3.380 ± 0.616 to 5.330 ± 1.024 µM; and α-Amy, 3.397 ± 0.472 to 5.173 ± 0.682 µM. Indole derivatives that exhibited strong enzyme inhibition were investigated for their cytotoxic effects on hepatocellular carcinoma (HepG2) and glioblastoma (U-87) cell lines at 24 and 48 h. Overall, it was found that some indole derivatives showed IC₅₀ values comparable to those of the standard drug, and throughout the process, some indole derivatives exhibited good IC₅₀ values, indicating good activity and low cytotoxic effects. The most active compounds were identified as compound 15 against GST (IC₅₀ = 2.228 ± 0.407 µM), compounds 1 and 16 against AChE (IC₅₀ = 3.329 ± 0.975 and 3.349 ± 0.845 µM), compounds 4 and 14 in HepG2 cells (IC₅₀ = 33.13 and 36.71 µM at 48 h), and compounds 12 and 17 in U-87 cells (IC₅₀ = 38.43 and 47.53 µM at 48 h). These indole-based derivatives are also subjected to a structure-activity relationship (SAR) study by the molecular docking method. Most indole derivatives showed enzyme inhibition results similar to, but below, those of the standard drug.