Novel Dibenzoazepine-Substituted Triazole Hybrids as Cholinesterase and Carbonic Anhydrase Inhibitors and Anticancer Agents: Synthesis, Characterization, Biological Evaluation, and In Silico Studies

The new dibenzoazepine-substituted triazole hybrids (12–20) were designed by molecular hybridization approach and synthesized utilizing the Cu­(I)-catalyzed click reaction. The hybrid structures (12–20) were obtained in high yields (74–98%) with a simple two-step synthesis strategy and fully characterized. These compounds were assessed for their influence on various metabolic enzymes including human carbonic anhydrase isoenzymes (hCA I and hCA II), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). The Ki values for the compounds concerning hCA I, hCA II, AChE, and BChE enzymes were in the ranges 29.94–121.69, 17.72–89.42, 14.09–44.68, and 1.15–48.82 nM, respectively. Compound 13 was 49.70-fold more active than tacrine (standard drug) for BChE and 5.49-fold for AChE. Compound 14 was 4.16-fold more active than acetazolamide (standard drug) for hCA I and 5.79-fold for hCA II. The cytotoxic effects of the synthesized click products were investigated on human triple-negative breast cancer cell lines. The IC50 values of the most effective compounds were calculated between 12.51 ± 1.92 and 18.07 ± 2.14 μM in MDA-MB-231 and BT-549 cells. Molecular docking and ADME predictions were performed. Then, in vitro effective compounds were analyzed by molecular dynamics (MD) simulation and MM/GBSA calculation. Consequently, click products showed good cytotoxicity and inhibition potential on colony formation in cancer cells.