Carbonic Anhydrase Inhibitors. Schiff Bases of some Aromatic Sulfonamides and Their Metal Complexes: Towards More Selective Inhibitors of Carbonic Anhydrase Isozyme IV

Abstract

Reaction of three aromatic sulfonamides possessing a primary amino group, i.e., sulfanilamide, homosulfanilamide and p-aminoethyl-benzenesulfonamide with heterocyclic and aromatic aldehydes afforded a series of Schiff bases. Metal complexes of some of these Schiff bases with divalent transition ions such as Zn(II), Cu(II), Co(II) and Ni(II) have also been obtained. The new compounds were assayed as inhibitors of three isozymes of carbonic anhydrase (CA). Several of the new compounds showed a modest selectivity for the membrane-bound (bovine) isozyme CA IV (bCA IV) as compared to the cytosolic human isozymes hCA I and II, in contrast to classical inhibitors which generally possess a 17-33 times lower affinity for bCA IV. This greater selectivity toward bCA IV is due mainly to a slightly decreased potency against hCA II relative to classical inhibitors. However, metal complexes of these Schiff bases possessed an increased affinity for hCA II, being less inhibitory against bCA IV. The first type of compounds reported here (i.e., the Schiff bases of aromatic sulfonamides with heterocyclic aldehydes) might thus lead to the development of low molecular weight isozyme specific CA IV inhibitors. The difference in affinity for the three isozymes of the inhibitors reported by us here is tentatively explained on the basis of recent X-ray crystallographic studies of these isozymes and their adducts with substrates/inhibitors.

Carbonic anhydrase inhibitors

“…[73][74][75][76] Such compounds also appreciably inhibited CA II, and to a smaller extent CA I (Table III). [73][74][75][76] G. Isozyme III Although the structure of this isozyme is relatively similar to that of hCA II, CA III has a CO 2 hydration activity of about 0.3% that of hCA II, as it does not possess a His residue in position 64, but a Lys residue, which is much less effective as a proton shuttle. 77 Furthermore, position 198 in CA III is occupied by a Phe, possessing a very bulky side chain, whereas the water bound to Zn(II) has a pK a around 5.5.…”

“…72 Even so, similarly to CA I, the first compounds with some specificity for CA IV, of type 72-76, were again discovered serendipitously, and they all belong to the same class of Schiff bases of aromatic/heterocyclic sulfonamides. [73][74][75][76] Only Schiff bases of aromatic sulfonamides were investigated in some detail, and it was shown that best CA IV inhibition patterns are connected with the presence of heterocyclic moieties (in the original aldehyde used for the preparation of the Schiff base), or aromatic moieties substituted with electron attracting groups, such as the nitro one. [73][74][75][76] Such compounds also appreciably inhibited CA II, and to a smaller extent CA I (Table III).…”

“…[73][74][75][76] Only Schiff bases of aromatic sulfonamides were investigated in some detail, and it was shown that best CA IV inhibition patterns are connected with the presence of heterocyclic moieties (in the original aldehyde used for the preparation of the Schiff base), or aromatic moieties substituted with electron attracting groups, such as the nitro one. [73][74][75][76] Such compounds also appreciably inhibited CA II, and to a smaller extent CA I (Table III). [73][74][75][76] G. Isozyme III Although the structure of this isozyme is relatively similar to that of hCA II, CA III has a CO 2 hydration activity of about 0.3% that of hCA II, as it does not possess a His residue in position 64, but a Lys residue, which is much less effective as a proton shuttle.…”

Inhibition of carbonic anhydrase isoforms I, II, IX and XII with Schiff’s bases incorporating iminoureido moieties

“…Schiff's bases incorporating sulfonamide functionalities attached to aromatic/heterocyclic moieties of the general formula Ar-CH ¼ N-linker-A-SO 2 NH 2 , have been investigated extensively as carbonic anhydrase (CA, EC 4.2.1.1) [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] inhibitors (CAIs starting with the 1990s when the first such compounds were reported by one of these groups [16][17][18][19][20][21][22][23][24][25][26][27] . Some of these derivatives were among the first reported sulfonamides showing good selectivity ratios for the inhibition of some human (h) CA isoforms, such as hCA I, II or IV 16,17 .…”

“…For such reasons, the design of new, potent and isoform-selective inhibitors of various CAs, may lead to clinical applications for treating a multitude of diseases [1][2][3] . The Schiff's base containing sulfonamide inhibitors are in fact just one of the inhibitor classes investigated for such purposes [16][17][18][19][20][21][22][23][24][25][26][27] . In addition to this, a number of Schiff's base derivatives have been reported to exert notable biological activity (antibacterial, antitubercular, antitumor, antileishmanial, DNA-binding activities, etc.)…”