Design, Synthesis, Binding, Crystallography, and Docking of [(2-Pyrimidinylthio)Acetyl]Benzenesulfonamides as Inhibitors of Human Carbonic Anhydrases

Abstract

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 and thermal shift assay yielding intrinsic Gibbs free energies, enthalpies, entropies, and heat capacities of binding. 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 several CAs were determined and the docking studies were performed to compare the binding modes of experimentally determined crystallographic structures with computational prediction of the pyrimidine derivative binding to CAs. Structure-thermodynamics correlations will be discussed. Several compounds bound to select CAs with single-digit nanomolar affinities and could be used as leads for inhibitor development towards anticancer target CA isozymes.