Design, synthesis and biochemical evaluation of novel carbonic anhydrase inhibitors triggered by structural knowledge on hCA VII

To tackle the challenge of isoform selectivity, we explored the entrance of the cavity for selected druggable human Carbonic Anhydrases (hCAs). Based on X-ray crystallographic studies on the 4-(4-(2-chlorobenzoyl) piperazine-1-carbonyl)benzenesulfonamide in complex with the brain expressed hCA VII (PDB code: 7NC4), a series of 4-(4(hetero)aroylpiperazine-1-carbonyl)benzene-1-sulfonamides has been developed. To evaluate their capability to fit the hCA VII catalytic cavity, the newer benzenesulfonamides were preliminary investigated by means of docking simulations. Then, this series of thirteen benzenesulfonamides was synthesized and tested against selected druggable hCAs. Among them, the 4-(4-(furan-2-carbonyl)piperazine-1-carbonyl)benzenesulfonamide showed remarkable affinity towards hCA VII (K-i: 4.3 nM) and good selectivity over the physiologically widespread hCA I when compared to Topiramate (TPM).

Automated summary

To address the challenge of isoform selectivity, the entrance of the cavity for certain druggable human Carbonic Anhydrases (hCAs) was explored. Using X-ray crystallographic studies, a series of 4-(4(hetero)aroylpiperazine-1-carbonyl)benzene-1-sulfonamides was developed based on complex with hCA VII. Through docking simulations, the capability of newer benzenesulfonamides to fit the hCA VII catalytic cavity was evaluated. Subsequently, a series of thirteen benzenesulfonamides was synthesized and tested, with the 4-(4-(furan-2-carbonyl)piperazine-1-carbonyl)benzenesulfonamide showing significant affinity towards hCA VII and good selectivity over hCA I when compared to Topiramate (TPM).