Pyridinium derivatives of 3-aminobenzenesulfonamide are nanomolar-potent inhibitors of tumor-expressed carbonic anhydrase isozymes CA IX and CA XII

Building on the conclusions of previous inhibition studies with pyridinium-benzenesulfonamides from our team and on the X-ray crystal structure of the lead compound identified, a series of 24 pyridinium derivatives of 3-aminobenzenesulfonamide was synthesized and investigated for carbonic anhydrase inhibition. The new pyridinium-sulfonamides were evaluated as inhibitors of four human carbonic anhydrase (CA, EC 4.2.1.1) isoforms, namely CA I, CA II (cytosolic), CA IX and XII (transmembrane, tumor-associated forms). Excellent inhibitory activity in the nanomolar range was observed against CA IX with most of these sulfonamides, and against CA XII (nanomolar/sub-nanomolar) with some of the new compounds. These sulfonamides were generally potent inhibitors of CA II and CA I too. Docking studies revealed a preference of these compounds to bind the P1 hydrophobic site of CAs, supporting the observed inhibition profile. The salt-like nature of these positively charged sulfonamides can further focus the inhibitory ability on membrane-bound CA IX and CA XII and could efficiently decrease the viability of three human carcinomas under hypoxic conditions where these isozymes are overexpressed, thus recommending the new compounds as potential diagnostic tools or therapeutic agents.