Targeting carbonic anhydrases II/IX/XII with novel series of coumarin-based compounds: Synthesis, biological activity and molecular dynamics analysis

In the current study, unique series of coumarin sulfonate and sulfamate derivatives were synthesized. Their selectivity and inhibitory activity against glaucoma and cancer-associated CAs (hCA II, IX, and XII) were evaluated compared to standard acetazolamide. In addition, the cytotoxic effects of the synthesized compounds on colorectal carcinoma (HCT116) were examined. Generally, structure-activity relationship (SAR) analysis revealed that potent inhibitors bearing zinc binding group (ZBG) dimethyl sulfamate (4a-c) were shown to lack selectivity against three isoforms owing to the classical inhibitory mode of action. The incorporation of aryl or fluoro aryl sulfone moiety in non-sulfamate coumarin derivatives shifted selectivity toward cancer-related isoforms XII and IX, respectively. Para-fluorine substituted derivative 3c with IC50 value of 0.62 mu M exhibited excellent activity and selectivity against hCA IX, while benzene sulfone possessing derivative 3b demonstrated selectivity toward hCA XII with IC50 value of 0.56 mu M. Moreover, coumarin derivatives with ethyl sulfone (3e, 3i, and 6a) reported excellent selectivity toward CAII. In-silico studies were also conducted over selective, potent compounds. Molecular docking studies have shown that potent compounds could interact with the active site by different modes of action. The molecular dynamic analysis confirmed the stability of the protein in the presence of a potent ligand.