Novel Taurinamide-Based Compounds as Carbonic Anhydrase Inhibitors

A series of taurinamide-based amides 1-19 were investigated for their effects on human (h) carbonic anhydrase (CA; EC 4.2.1.1) isoforms I, II, VA, VII, IX, and XII, which are all relevant for biomedical applications. According to inhibition data, most of the derivatives displayed affinity and selectivity for the hCA I isoform over the other isoforms tested, and compounds 1, 2, 4, 8, and 9 emerged as potent nanomolar inhibitors of hCA I and hCA IX, exhibiting K I values in the range of 0.65-0.83 and 0.59-0.96 mu M, respectively (asetazolamide K I = 0.25 for CA I and K I = 0.03 M for hCA IX). The X-ray structures of 15 and 18 in complex with hCA II provided detailed insights into the binding mode and molecular determinants. Substitution patterns were found to have a tuning effect on both affinity and selectivity toward specific isoforms, thus providing valuable insights for the design of new CA inhibitors.