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In this study a series of pyrazole-3,4-dicarboxamide (3–10) derivatives bearing sulfonamide moiety were synthesized starting from 1-(3-nitrophenyl)-5-phenyl-1H-pyrazole-3,4-dicarboxylic acid (1). The structures of synthesized molecules were characterized by FT-IR, 1H NMR, 13C NMR, and elemental analysis methods. Human carbonic anhydrase isoenzymes (hCA I and hCA II) were purified separately from erythrocyte cells by the Sepharose-4B-L-tyrosine-sulfanilamide affinity column chromatography and inhibitory effects of newly synthesized sulfonamides on esterase activities of these isoenzymes have been studied as in vitro. The Ki values of compounds were found in the range of 0.056–110.400 μM for hCA I and 0.057–533.400 μM for hCA II. Compound 4 has the highest inhibitory effect for hCA I and hCA II while compound 5 showed lowest inhibition. The structure–activity relationships for the inhibition of these isoforms with the pyrazole-sulfonamides reported here were also elucidated. Keywords: Pyrazole, Pyrazole-3,4-dicarboxamide, Synthesis, Reduction, Carbonic anhydrase, Enzyme inhibition

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. © 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group., This work was supported by Scientific and Technological Research Council of Turkey (TUB€ İTAK) with Grant No. TBAG-104T406.

WOS: 000387978400008, PubMed: 27454619, A series of 1-(3-substituted-phenyl)-5-phenyl-N-3,N-4-bis(5-sulfamoyl-1,3,4-thiadiazol-2-yl)-1H-pyrazole-3,4- dicarboxamides (4-15) were synthesized. The structures of these pyrazole-sulfonamides were confirmed by FT-IR, H-1 NMR, C-13 NMR and elemental analysis methods. Human cytosolic carbonic anhydrase (CA, EC 4.2.1.1) isozymes (hCA I and II) were purified from erythrocyte cells by affinity chromatography. The inhibitory effects of newly synthesized derivatives (4-15) were investigated in vitro on esterase activities of these isozymes. The K-i values were determined as 0.119-3.999 mu M for hCA I and 0.084-0.878 mu Mfor hCA II. The results showed that the compound 6 for hCA I and the compound 11 for hCA II had the highest inhibitory effect. Beside that, the compound 8 had the lowest inhibition effect on both isozymes. (C) 2016 Elsevier Inc. All rights reserved., Dumlupinar University Research FundDumlupinar University [2010/14], This work was supported by the Dumlupinar University Research Fund (Project Number: 2010/14). Also the authors are grateful to the Ataturk University Faculty of Sciences Department of Chemistry for providing the usage of spectroanalytic laboratory facilities and Dumlupinar University Faculty of Arts and Sciences Department of Physics for FT-IR measurements.

In the current study, a series of pyrazole-sulfonamide derivatives (2-14) were synthesized, characterized, and the inhibition effects of the derivatives on human carbonic anhydrases (hCA I and hCA II) were investigated as in vitro. Structures of these sulfonamides were confirmed by FT-IR, 1H NMR, 13C NMR and LC-MS analysis. 1H NMR and 13C NMR revealed the tautomeric structures. hCA I and hCA II isozymes were purified from human erythrocytes and inhibitory effects of newly synthesized sulfonamides on esterase activities of these isoenzymes have been studied. The Ki values of compounds were 0.062-1.278 µM for hCA I and 0.012-0.379 µM for hCA II. The inhibition effects of 7 for hCA I and 4 for hCA II isozymes were almost in nanomolar concentration range. © 2012 Elsevier Ltd. All rights reserved., California Department of Fish and Game: STE 1127/15-1 National Council for Scientific Research King Fahd University of Petroleum and Minerals 106T180 King Fahd University of Petroleum and Minerals, The authors are very grateful to The Scientific and Research Council of Turkey (TUBITAK) for providing financial support for this project (Grant No. 106T180). The facility of King Fahd University of Petroleum and Minerals (KFUPM) is used, and KFUPM is gratefully acknowledged for the support of this project. The authors are thankful Stefan Walter and Kerstin Ruecker at Chemistry/Biology Branch of Osnabrück University for LC/MS and TGA measurements, respectively. S.O. is also grateful to German Science Foundation (DFG) for the support of summer research stay at Osnabrück University/Germany with Grant number STE 1127/15-1.

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 (IC50 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 IC50 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 (Ki) 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.

In this study, some novel inhibitors were synthesised from the further stage reactions of 4-benzoyl-1-(4-nitrophenyl)-5-phenyl-1H-pyrazole-3-carbonyl chloride with 5-amino-1,3,4-thiadiazole-2-sulphonamide 1 (inhibitor 1). They were characterised by elemental and spectral (1H NMR, 13C NMR, IR) analyses. Human carbonic anhydrase isoenzymes (hCA-I and hCA-II) were purified from erythrocyte cells by affinity chromatography. The inhibitory effects of inhibitor 1, acetazolamide (2) and the 11 newly synthesised amides (8-18) on the hydratase and esterase activities of these isoenzymes (hCA-I and hCA-II) were studied in vitro. In relation to these activities, the inhibition equilibrium constants (Ki) were determined. The Ki values for the new compounds (8-18) were observed to be well below that of the parent compound inhibitor 1 and were also compared to 2 under the same experimental conditions. The comparison of the newly synthesised amides to inhibitor 1 and to 2 indicated that the new derivatives preferentially inhibited hCA-II and were more potent inhibitors of hCA-II than the parent inhibitor 1 and 2. © 2011 Informa UK, Ltd., 106T180, This research was funded by TUBITAK (The Foundation of Scientific and Technological Research of Turkey, 106T180) (Ankara, Turkey).