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    Novel Dibenzoazepine-Substituted Triazole Hybrids as Cholinesterase and Carbonic Anhydrase Inhibitors and Anticancer Agents: Synthesis, Characterization, Biological Evaluation, and In Silico Studies
    (Amer Chemical Soc, 2024) Erdogan, Musa; Onder, Alper; Demir, Yeliz; Comert Onder, Ferah
    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 mu M 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.