Rational design of carbonic anhydrase VII inhibitors. Synthesis of new candidates with the sulfamide scaffold

Catalytically active carbonic anhydrases (CAs) control the rate of the reversible hydration of CO₂ to HCO₃^- and H⁺¹. In particular, the isoform VII (CA VII) appears to be involved in seizure generation and represents a promising molecular target for the design of anticonvulsant drugs. By means of an experimentally validated docking protocol, a series of N,N'-disubstituted sulfamides derivatives were selected as potential new CA VII inhibitors. They present the general structure R-NH-SO₂-NH-(CH₂)₃-COOCH₃, since they share the gamma-aminobutyl (GABA) methyl ester scaffold.
The synthesis starts with the preparation of catechol sulfate using sulfuryl chloride and catechol. Then, this cyclic sulfate reacts with the amino group of the GABA methyl ester to give the corresponding sulfamate. Finally, the sulfamide is generated by the substitution reaction between catechol and the amine with the second substituent (R), releasing the catechol in equimolar quantities.
The synthesized compounds will be evaluated in vitro for their activity on CA VII and then the most promising candidates will be tested in vivo in acute mouse models of seizures.