Carbonic Anhydrase Inhibitors:  The First On-Resin Screening of a 4-Sulfamoylphenylthiourea Library

Abstract

Sulfonamide carbonic anhydrase (CA) inhibitors are widely employed in the diagnosis and treatment of diverse diseases such as glaucoma and different neuromuscular disorders. Moreover, an emerging area is represented by their use in the prevention and treatment of tumors. In this paper we propose an optimized synthesis of on-resin CA inhibitor libraries to be used for a high-throughput biological screening. A library of 4-sulfamoylphenylthioureas, previously described to be attractive candidates as novel antiglaucoma drugs, has been synthesized by a solid-phase approach, avoiding the formation of thiohydantoin side products. The on-resin screening assay has been developed for the inhibition tests of different CA isozymes with the on-resin supported sulfonamides, allowing the direct identification of the biologically active lead compounds. These results allow the development of new designed libraries in the solid phase of sulfonamide CA inhibitors characterized by a set of prefixed parameters to be used as possible drug candidates.

Sulfapyridine-like benzenesulfonamide derivatives as inhibitors of carbonic anhydrase isoenzymes I, II and VI

“…Carbonic anhydrase inhibitors or activators have several medical applications, such as in the treatment of glaucoma, as diuretics, in the management of several neurological disorders, including epilepsy, possibly in the treatment of Alzheimer's disease, whereas several agents are in clinical evaluations as antiobesity or antitumor drugs/diagnostic tools [3][4][5][6][7] . A class of derivatives which showed very promising applications among the various CAIs reported by Supuran's group in the last years, were the thioureas obtained from isothiocyanato sulfonamides (such as e.g., 4-isothiocyanatobenzenesulfonamide) and amines, hydrazines or amino acids [22][23][24] . Such compounds generally showed potent inhibitory activity against the cytosolic isozyme hCA II as well as the transmembrane, tumor-associated isozyme hCA IX, being thus interesting candidates for developing anti-glaucoma/anti-tumor therapies based on them [22][23][24] .…”

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] .…”

Design, synthesis and biological evaluation ofN-(5-methyl-isoxazol-3-yl/1,3,4-thiadiazol-2-yl)-4-(3-substitutedphenylureido) benzenesulfonamides as human carbonic anhydrase isoenzymes I, II, VII and XII inhibitors

“…The inhibition constants were obtained by non-linear least-squares methods using the ChengPrusoff equation, and represent the mean from at least three different determinations. The human isoforms hCA I, II, VII and XII were recombinant enzymes produced as described earlier in our laboratory [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] .…”

“…All the synthesized compounds (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) were studied for the inhibition of four CA isozymes of human origin, i.e. hCA I, hCA II, hCA VII and hCA XII ( Table 1).…”