Click Chemistry-Enabled Parallel Synthesis of N-Acyl Sulfonamides and Their Evaluation as Carbonic Anhydrase Inhibitors

A synthetically accessible library of <i>N</i>-acyl sulfonamides was constructed using a combination of copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) and <i>N</i>-acylation of primary sulfonamides. The proposed two-step reaction sequence had a high experimentally confirmed synthetic success rate (up to 85%) and gave reasonable product yields (up to 61%). As a result of the validation process, a 262-member compound library (out of >70K accessible combinations) was prepared. Biological profiling of the synthesized library by differential scanning fluorimetry and enzymatic assays identified several low micromolar inhibitors of human carbonic anhydrase. The interaction of the discovered hits with the biological target was studied by docking and molecular dynamics.