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. IC 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 IC values comparable to those of the standard drug, and throughout the process, some indole derivatives exhibited good IC values, indicating good activity and low cytotoxic effects. The most active compounds were identified as compound 15 against GST (IC = 2.228 ± 0.407 µM), compounds 1 and 16 against AChE (IC = 3.329 ± 0.975 and 3.349 ± 0.845 µM), compounds 4 and 14 in HepG2 cells (IC = 33.13 and 36.71 µM at 48 h), and compounds 12 and 17 in U-87 cells (IC = 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.