Carbonic anhydrase inhibitors: 2-Substituted-1,3,4-thiadiazole-5-sulfamides act as powerful and selective inhibitors of the mitochondrial isozymes VA and VB over the cytosolic and membrane-associated carbonic anhydrases I, II and IV

A series of 2-substituted-1,3,4-thiadiazole-5-sulfamides was prepared and assayed as inhibitors of several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic CA I and II, the membrane-associated CA IV and the mitochondrial CA VA and VB. The new compounds showed weak inhibitory activity against hCA I (KIs of 102 nM–7.42 μM), hCA II (KIs of 0.54–7.42 μM) and hCA IV (KIs of 4.32–10.05 μM) but were low nanomolar inhibitors of hCA VA and hCA VB, with inhibition constants in the range of 4.2–32 nM and 1.3–74 nM, respectively. Furthermore, the selectivity ratios for inhibiting the mitochondrial enzymes over CA II were in the range of 67.5–415, making these sulfamides the first selective CA VA/VB inhibitors.