Design of ortho/meta-substituted selective carbonic anhydrase IX inhibitors

Abstract

In the search for chemical compounds that strongly and selectively bind and inhibit one out of 12 catalytically active CA isozymes, a series of fluorinated substituted benzenesulfonamides was designed and synthesised. Substituents were intended to be stiff and have a limited conformational flexibility. We determined compound affinities using the fluorescence-based thermal shift assay. Afterward, we subtracted the binding-linked protonation reactions and calculated the intrinsic affinities, which were then used to establish the structure–affinity relationships. Compound 5 (2-(cyclohexylamino)-3,5,6-trifluoro-4-(phenylsulfonyl) benzenesulfonamide) exhibited an improved selectivity profile toward CAIX, a cancer-associated isozyme. The analysis of compound functional group contributions and the comparison with previously designed compounds provided insight toward a deeper understanding of the protein–ligand recognition principles for drug design.