Synthesis, characterization and in vitro inhibition of metal complexes of pyrazole based sulfonamide on human erythrocyte carbonic anhydrase isozymes I and II.

Sulfonamides represent an important class of biologically active compounds. A sulfonamide possessing carbonic anhydrase (CA) inhibitory properties obtained from a pyrazole based sulfonamide, ethyl 1-(3-nitrophenyl)-5-phenyl-3-((5-sulfamoyl-1,3,4-thiadiazol-2-yl)carbamoyl)-1H-pyrazole-4-carboxylate (1), and its metal complexes with the Ni(II) for (2), Cu(II) for (3) and Zn(II) for (4) have been synthesized. The structures of metal complexes (2-4) were established on the basis of their elemental analysis, 1H NMR, IR, UV-Vis and MS spectral data. The inhibition of two human carbonic anhydrase (hCA, EC 4.2.1.1) isoenzymes I and II, with 1 and synthesized complexes (2-4) and acetazolamide (AAZ) as a control compound was investigated in vitro by using the hydratase and esterase assays. The complexes 2, 3 and 4 showed inhibition constant in the range 0.1460-0.3930 µM for hCA-I and 0.0740-0.0980 µM for hCA-II, and they had effective more inhibitory activity on hCA-I and hCA-II than corresponding free ligand 1 and than AAZ.

Synthesis and characterisation of novel Co(II) complexes of pyrazole carboxylate derivated of sulfonamide as carbonic anhydrase inhibitors.

OBJECTIVES: Two new metal complexes, diaquabis(4-benzoyl-1,5-diphenyl-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)-1H-pyrazole-3-carboxamide)cobalt(II) dihydrate (2) and diaquabis(ethyl-1-(3-nitrophenyl)-5-phenyl-3-(5-sulfamoyl-1,3,4-thiadiazol-2-ylcarbamoyl)-1H-pyrazole-4-carboxylate)cobalt(II) monohydrate (4), containing sulfonamide have been synthesized by the reaction of Co(II) with 4-benzoyl-1,5-diphenyl-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)-1H-pyrazole-3-carboxamide (1) and ethyl-1-(3-nitrophenyl)-5-phenyl-3-(5-sulfamoyl-1,3,4-thiadiazol-2-ylcarbamoyl)-1H-pyrazole-4-carboxylate (3), respectively. METHODS: The structures of Co(II) complexes 2 and 4 have been characterised by spectroscopic methods and elemental analyses. Human carbonic anhydrase isoenzymes (hCA-I and hCA-II) were purified from erythrocyte cells by affinity chromatography. The inhibitory effects of ligands 3 and 4, acetazolamide as a control compound and the newly synthesized complexes on the activity of hydratase and esterase of these isoenzymes have been studied in vitro. KEY FINDINGS: The concentration of compounds 2 and 4 producing a 50% inhibition of hydratase activity (IC(50) values) were 0.473 ± 0.025 and 0.065 ± 0.002 µm for hCA-I and 0.213 ± 0.015 and 0.833 ± 0.021 µm for hCA-II, respectively. The IC(50) values of synthesized compounds 2 and 4 for esterase activity were, 0.058 ± 0.006 and 0.297 ± 0.015 µm for hCA-I and 0.110 ± 0.010 and 0.052 ± 0.002 µm for hCA-II, respectively. In relation to esterase activity, the inhibition equilibrium constants (K(i) ) were determined as 0.039 ± 0.004 and 0.247 ± 0.035 µm on hCA-I and 0.078 ± 0.002 and 0.363 ± 0.015 µm on hCA-II for 2 and 4, respectively. CONCLUSIONS: The synthesized compounds 2 and 4 had effective inhibitory activity (P < 0.0001) on hCA-I and hCA-II than the corresponding free ligands, 1 and 3, and acetazolamide. Compounds 2 and 4 might be considered as potential inhibitors.

Synthesis and characterization of phenolic Mannich bases and effects of these compounds on human carbonic anhydrase isozymes I and II.

Mannich bases 2a-f derived from 3,4-dimethylphenol (1), formaldehyde and different amines are prepared and subjected to spectral (IR, (1)H and (13)C NMR) and elemental analyses. The inhibition of two human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes I and II, with 1 and synthesized Mannich bases 2a-f and acetazolamide (AAZ) as a control compound was investigated in vitro by using the hydratase and esterase assays. In relation to hydratase and esterase activities of the half maximal inhibitory concentration (IC(50)) and the inhibition equilibrium constants (K(i))values were determined. Only two compounds (2a and 2e)exhibit weak hCA II inhibitory effects on esterase activity. IC(50) and Ki values for 2a and 2e with respect to esterase activity of hCA II are0.88 × 10(3) and 6.3-7.6 µM and 0.44 × 10(3) and 19.0-96.4 µM,respectively. On the contrary, compounds 2b and 2d might be used as CA activators due to increasing esterase activity of hCA I and hCA II isozymes.

Synthesis and characterization of metal complexes of heterocyclic sulfonamide as carbonic anhydrase inhibitors.

Three novel metal complexes of N-[5-(aminosulfonyl)-1,3,4-thiadiazol-2-yl]-4-benzoyl-1-(3-nitrophenyl)-5-phenyl-1H-pyrazole-3-carboxamide which possess strong carbonic anhydrase (CA) inhibitory properties have been synthesised. The structure of these compounds has been investigated by elemental analysis, FT-IR, LC/MS, UV-vis spectrophotometric method and magnetic susceptibility. Human carbonic anhydrase isoenzymes hCA-I and hCA-II were purified from erythrocyte cells by the affinity chromatography. The inhibitory effects of newly synthesized complexes and acetazolamide (AAZ) as a control compound on hydratase and esterase activities of these isoenzymes have been studied in vitro by comparing IC(50) and K(i) values and it has been found that the newly synthesised complexes behave as very powerful inhibitors against hCA-I and hCA-II than parent ligand (1) and than AAZ.