Design and Synthesis of Hydrazone-Bearing Benzenesulfonamides as Carbonic Anhydrase VB Inhibitors

The alpha-amino acid derivatives are constituents of many bioactive compounds and display a wide variety of biological activities. We have synthesized a series of new benzenesulfonamide derivatives bearing alpha-amino acid moiety at para-position and evaluated their binding affinity to human carbonic anhydrase isozymes by fluorescent thermal shift assay. The dichloro- and monobromo-substitutions on the benzenesulfonamide ring have been introduced to determine the halogenation effect on the binding affinity. Chloro substituents at 3,5-positions of benzenesulfonamide derivatives increased the affinity for all carbonic anhydrases as compared to non-chlorinated compounds. The hydrazone-bearing 3,5-dichlorobenzenesulfonamides 9 a, 9 d, and 12 exhibited a low nanomolar affinity for CA VB (K-d in the range of 6.6-8.1 nM), an isozyme implicated in diseases of the central nervous system and obesity.