Expanding Chemical Space of N-Acyl Sulfonamides with Click Chemistry for Carbonic Anhydrase Inhibitor Discovery

This study presents the generation of synthetically tractable N-acyl sulfonamide chemical space using a two-step parallel synthetic methodology, providing structurally diverse compounds with high efficiency. The key reaction included the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) combined with primary sulfonamide N-acylation, which proved to be highly effective in generating structurally diverse N-acyl sulfonamides with typically good synthesis success rates (up to 85%) and average yields (up to 61%). The approach demonstrated reliability across different substrates, supporting the efficient construction of a 256-member compound library (out of 73,331 possible combinations) with minor synthetic limitations. Biological evaluations of the synthesized library identified promising inhibitors of human carbonic anhydrase isoforms hCA-IX and hCA-II. Differential scanning fluorimetry and enzymatic assay revealed potent and selective compounds, with some derivatives exhibiting low micromolar IC50 values and noticeable selectivity toward hCA-II. Docking and molecular dynamics simulations provided further insights into binding interactions, confirming the stability of ligand-protein complexes. Thus, this work highlights the synthetic efficiency and pharmacological relevance of 1,2,3-triazole-containing N-acyl sulfonamides, expanding the accessible chemical space for drug discovery.