Discovery of 4-sulfamoyl-phenyl-?-lactams as a new class of potent carbonic anhydrase isoforms I, II, IV and VII inhibitors: The first example of subnanomolar CA IV inhibitors

A series of benzenesulfonamides incorporating 1,3,4-trisubstituted-?-lactam moieties was prepared from sulfanilamide Schiff bases and in situ obtained ketenes, by using the Staudinger cycloaddition reaction. The new compounds were assayed as inhibitors of four human isoforms of the metalloenzyme carbonic anhydrase (hCA, EC 4.2.1.1) involved in various physiological/pathological conditions, hCA I, II, IV and VII. Excellent inhibitory activity was observed against all these isoforms, as follows: hCA I, involved in some eye diseases was inhibited with Ks in the range of 7.3-917 nM; hCA II, an antiglaucoma drug target, with Ks in the range of 0.76-163 nM. hCA IV, an isoform involved in several pathological conditions such as glaucoma, retinitis pigmentosa and edema was potently inhibited by the lactam-sulfonamides, with Ks in the range of 0.53-51.0 nM, whereas hCA VII, a recently validated anti-neuropathic pain target was the most inhibited isoform by these derivatives, with Ks in the range of 0.68-9.1 nM. The structure-activity relationship for inhibiting these CAs with the new lactam-sulfonamides is discussed in detail.