Carbonic anhydrase inhibitors:: N-cyanosulfonamides, a new class of high affinity isozyme II and IV inhibitors

A series of N-cyanosulfonamides has been prepared by reaction of alkyl-, arylalkyl- and aryl sulfonyl halides or sulfonic acid anhydrides with cyanamide, or by reaction of cyanogen bromide with sulfamide/sulfamic acid. Other compounds have been obtained from sulfenyl chlorides, acyl chlorides, or tosyl isocyanate and cyanamide. Inhibition of three carbonic anhydrase (CA) isozymes, hCA I, hCA II and bCA IV (h = human; b = bovine) with the prepared compounds has been investigated. Very good inhibitors, as well as compounds with moderate activity against these isozymes were found, depending on the R group at which the metal-coordinating moiety of the inhibitor molecule was attached. Compounds of the types RSNHCN and RCONHCN were much less active in inhibiting all the investigated isozymes as compared to the strong inhibitors possessing the general formula RSO2NHCN. Susceptibility to inhibition with the N-cyanosulfonamides was generally: hCA II > bCA IV much greater than hCA I. Spectroscopic studies on Co(II)-substituted hCA II proved that the new inhibitors directly bind to the metal ion within the enzyme active site, similarly to the classical inhibitors of the unsubstituted sulfonamide type.