Multitargeted Anticancer Activities: Cathepsin B-Carbonic Anhydrase IX/XII Inhibitors Show Enhanced Cytotoxicity...

The multi-target inhibition of two significant cancer drug targets, cathepsin B and human carbonic anhydrase (hCA) isoforms IX and XII has been explored. The exclusive synthesis of single isomeric structure of final compounds despite two possibilities, in vitro biological studies, in silico molecular docking, DFT and ADMET studies of a small library of 28 new benzenesulfonamides incorporating the 1,2,3-triazolylpyrazole motif are reported. The tumor-associated isoforms hCA IX and hCA XII have been remarkably inhibited in the low nanomolar range, while enzymatically important off-target isoforms hCA I and II were weakly inhibited by most of the synthesized sulfonamides. Overall, respectively, three (K_I < 25 nM) and two compounds (K_I < 5.7 nM) showed better inhibition of hCA IX and XII as compared with reference drug acetazolamide. Compound 9f exhibited 35-fold and eightfold better hCA I/IX and hCA I/XII inhibition selectivity, respectively, as compared with SLC-0111. Likewise, all the synthesized compounds were also assayed for their inhibition profile against cathepsin B. Some compounds exhibited better inhibition of cathepsin B as compared with reference compound curcumin. In vitro cytotoxicity studies targeting non-cancerous Vero cells (green monkey kidney cells) and cancerous A549 cells (human lung adenocarcinoma cells) have also been performed, which showed interesting results.