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.

Automated summary

A series of new benzenesulfonamide derivatives with alpha-amino acid moiety were synthesized and evaluated for their binding affinity to human carbonic anhydrase isozymes. The introduction of chloro substituents at 3,5-positions on the benzenesulfonamide ring increased the affinity for all carbonic anhydrases. Some derivatives showed low nanomolar affinity to CA VB, an isozyme implicated in diseases of the central nervous system and obesity.