Inhibition of human carbonic anhydrase isozymes I, II, IX and XII with a new series of sulfonamides incorporating aroylhydrazone-, [1,2,4]triazolo[3,4-b][1,3,4]thiadiazinyl- or 2-(cyanophenylmethylene)-1,3,4-thiadiazol-3(2H)-yl moieties

Abstract

A series of benzenesulfonamides incorporating aroylhydrazone, piperidinyl, sulfone, [1,2,4]triazolo[3,4-b][1,3,4]thiadiazinyl- or 2-(cyanophenyl-methylene)-1,3,4-thiadiazol-3(2H)-yl moieties was investigated as inhibitors of four α-carbonic anhydrases (CAs, EC 4.2.1.1), the human (h) isoforms hCA I, II (cytosolic, offtarget enzymes) and hCA IX and XII (transmembrane, tumor-associated isoforms). Low nanomolar activity was observed against hCA II (K_Is of 0.56–17.1 nM) with these sulfonamides, whereas the slow cytosolic isoform hCA I was less inhibited by these compounds (K_Is of 86.4 nM–32.8 µM). Most of these sulfonamides significantly inhibited CA IX, with K_Is in the range of 4.5–47.0 nM, although some of the derivatives incorporating bulkier bicyclic moieties, as well as 2-thienyl fragments, showed a weaker activity against this isoform (K_Is in the range 50.1–553 nM). All the investigated compounds also inhibited CA XII with K_Is in the range 0.85–376 nM. The best inhibitors were those incorporating bulky [1,2,4]triazolo[3,4-b][1,3,4]thiadiazinyl moieties and 1,3,4-thiadiazol-3(2H)-yl groups.

• Cancer-associated isoform
• carbonic anhydrase
• enzyme inhibitor
• sulfonamide

Declaration of interest

This research was financed by a 7th FP EU grant, METOXIA (to C.T.S.) and by the National Plan of Science, Technology and Innovation (Grant No. 10-MED1188-02), King Saud University, Riyadh and by the Graduate Studies and Scientific Research Agency, Salman bin Abdulaziz University, Grant No. 2.H.33, Alkharj, Saudi Arabia (to A.M.A).