Secondary/tertiary benzenesulfonamides with inhibitory action against the cytosolic human carbonic anhydrase isoforms I and II

Abstract

Carbonic anhydrase inhibitors of primary sulfonamide type, RSO(2)NH(2), have clinical applications as diuretics, antiglaucoma, antiepileptic, antiobesity and antitumor drugs. Here we investigated inhibition of two human cytosolic isozymes, hCA I and II, with a series of secondary/tertiary sulfonamides, incorporating tosyl moieties (CH(3)C(6)H(4)SO(2)NR1R2). Most compounds inhibited both isoforms in low micromolar range, with inhibition constants between 0.181-6.01 μM against hCA I, and 0.209-0.779 μM against hCA II, respectively. These findings point out that substituted benzenesulfonamides may be used as leads for generating interesting CAIs probably possessing a distinct mechanism of action compared to primary sulfonamides. Indeed, classical RSO(2)NH(2) inhibitors bind in deprotonated form to the Zn(II) ion from the CA active site and participate in many other favorable interactions with amino acid residues lining the cavity. The secondary/tertiary sulfonamides cannot bind to the zinc due to steric hindrance and probably are accommodated at the entrance of the active site, in coumarin binding-site.

Cloning, expression and biochemical characterization of aβ-carbonic anhydrase from the soil bacteriumEnterobactersp. B13

“…Acetazolamide (AAZ) inhibition data are also provided. B13-CAI, further studies may reveal new classes of inhibitors/ activators of this enzyme [58][59][60] , which may show biomedical or environmental applications.…”

Kinetic andin silicoanalysis of thiazolidin-based inhibitors of α-carbonic anhydrase isoenzymes

“…AZA and ZNA are also medium inhibitors with this assay and substrate against hCA I (K I -s of 14.8 and 36.2 µM, respectively). Kinetic investigations (Lineweaver Burk plots, data not shown) indicate that similarly to phenolic compounds, sulfonamides and inorganic anions 17,[26][27][28][29][30][31][32][33][34][35] , all the investigated compounds act as non-competitive inhibitors with 4-NPA as substrate, i.e. they bind in different regions of the active site cavity as compared to the substrate.…”

“…The best hCA II inhibitor in this series of derivatives was the bulky 6b (Figure 4), which with a K I of 0.81 µM, is similar inhibitor ZNA and AZA, a clinically used sulfonamide. It must be stressed that K I -s measured with the esterase method are most of the time in the micromolar range because hCA I and II are weak esterases [26][27][28][29][30][31][32][33][34] .…”

A magnificent enzyme superfamily: carbonic anhydrases, their purification and characterization

“…Apart from the classical applications of the CA inhibitors (CAIs) as diuretics, antiglaucoma and antiepileptic agents [83][84][85][86][87][88][89][90][91] of pharmaceuticals that suppress the activity of carbonic anhydrase, ultimately many such agents were shown to be effective as antiobesity and anticancer agents [91][92][93] . Moreover, the inhibition of CAs from pathogenic organisms (such as bacteria, fungi and protozoa) started to be considered as an interesting approach for designing anti-infective agents with a new mechanism of action [1][2][3]94 .…”