Design of [(2-pyrimidinylthio)acetyl]benzenesulfonamides as inhibitors of human carbonic anhydrases

A series of [(2-pyrimidinylthio)acetyl]benzenesulfonamides were designed and synthesized. Their binding affinities as inhibitors of several recombinant human carbonic anhydrase (CA) isozymes were determined by isothermal titration calorimetry (ITC) and thermal shift assay (TSA). A group of compounds containing a chlorine atom in the benzenesulfonamide ring were found to exhibit higher selectivity but lower binding affinity toward tested CAs. The crystal structures of selected compounds in complex with CA II were determined to atomic resolution. Docking studies were performed to compare the binding modes of experimentally determined crystallographic structures with computational prediction of the pyrimidine derivative binding to CA II. Several compounds bound to select CAs with single-digit nanomolar affinities and could be used as leads for inhibitor development toward a select CA isozyme.

Graphical AbstractFigure optionsDownload as PowerPoint slideHighlights
► [(2-pyrimidinylthio)acetyl]benzenesulfonamides are efficient CA binders.
► Compound affinities were ranked by titration calorimetry and thermal shift assay.
► Crystal structures and docking provide insight for novel inhibitor design.
► Affinities of up to 10–20 nM were reached by selected compounds.
► Selectivities of up to 50 times toward selected CA isozymes were achieved.