Carbonic anhydrase inhibitors: Inhibition of isozymes I, II and IV by sulfamide and sulfamic acid derivatives

Sulfamide and sulfamic acid are the simplest compounds containing the SO2NH 2 moiety, responsible for binding to the Zn(II) ion within carbonic anhydra se (CA, EC 4.2.1.1) active site, and thus acting as inhibitors of the many CA isozymes presently known. Here we describe two novel classes of CA inhib itors obtained by derivatizations of the lead molecules mentioned above. Th e new compounds, possessing the general formula RSO2NH-SO2X (X = OH, NH2), were obtained by reaction of sulfamide or sulfamic acid with alkyl/arylsulf onyl halides or arylsulfonyl isocyanates. A smaller series of derivatives h as been obtained by reaction of aromatic aldehydes with sulfamide, leading to Schiff bases of the type ArCH=NSO2NH2. All the new compounds act as stro ng inhibitors of isozymes :I, II and IV of carbonic anhydrase. Their mechan ism of CA inhibition is also discussed based on electronic spectroscopic me asurements on adducts with the Co(II)-substituted enzyme. These experiments led to the conclusion that the new inhibitors are directly coordinated tin a monodentate manner) to the metal ion within the enzyme active site, simi larly to the classical inhibitors, the aromatic/heterocyclic sulfonamides.