1,5-Benzodiazepines as a platform for the design of carbonic anhydrase inhibitors

A series of novel N-triazolo-benzene sulfonamides-1,5-benzodiazepines 9a–d and 10d were designed and prepared through the copper-catalyzed azide alkyne cycloaddition click chemistry procedure, reacting the N1-propargyl-1,5-benzodiazepine 2 and the N1,N5-dipropargyl analog 6 with various benzene sulfonamide azides 8a–d. The synthesized compounds were found to show nanomolar affinity toward relevant isoforms of human carbonic anhydrase such as hCA I, II, IV, VII, IX, and XII. The divalent derivative 10d showed a particularly high inhibitory activity against all hCA isoforms when compared with acetazolamide, and showed potent multivalent effects, better than reported previously for divalent CA inhibitors.