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Claudiu T Supuran - One of the best experts on this subject based on the ideXlab platform.
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the synthesis of novel Sulfamides derived from β benzylphenethylamines as acetylcholinesterase butyrylcholinesterase and carbonic anhydrase enzymes inhibitors
Bioorganic Chemistry, 2017Co-Authors: Claudiu T Supuran, Hulya Akincioglu, Akin Akincioglu, Ilhami Gulcin, Serdar Durdagi, Ebutalib Kocaman, Ramin Ekhteiari Salmas, Suleyman GoksuAbstract:Abstract In this study, a series of novel β-benzylphenethylamines and their sulfamide derivatives were synthesized starting from (Z)-2,3-diphenylacrylonitriles. Pd-C catalysed hydrogenation of diphenylacrylonitriles, reduction of propanenitriles with LiAlH 4 in the presence of AlCl 3 followed by addition of conc. HCl afforded β-benzylphenethylamine hydrochloride salts. The reactions of these amine hydrochloride salts with chlorosulfonyl isocyanate (CSI) in the presence of tert -BuOH and excess Et 3 N gave sulfamoylcarbamates. Removing of Boc group from the synthesized sulfamoylcarbamates with trifluoroacetic acid (TFA) yielded novel Sulfamides in good yields. These novel Sulfamides derived from β-benzylphenethylamines were effective inhibitors of the cytosolic carbonic anhydrase I and II isoenzymes (hCA I and II), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with K i values in the range of 0.278–2.260 nM for hCA I, 0.187–1.478 nM for hCA II, 0.127–2.452 nM for AChE and 0.494–1.790 nM for BChE. The inhibitory effects of the synthesized novel Sulfamides derived from β-benzylphenethylamines were compared to those of acetazolamide and dorzolamide as clinical hCA I and II isoenzymes inhibitors and tacrine as a clinical AChE and BChE enzymes inhibitors. In addition to in vitro tests, molecular modeling approaches are implemented not only for prediction of the binding affinities of the compounds but also to study their inhibition mechanisms in atomic level at the catalytic domains.
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Special Issue: Sulfonamides
MDPI AG, 2017Co-Authors: Claudiu T SupuranAbstract:The sulfonamides and their structurally related derivatives, such as the sulfamates and Sulfamides, possess the general formula A-SO2NHR, in which the functional group is either directly bound to an aromatic, heterocyclic, aliphatic, or sugar scaffold (of type A), or appended to such a scaffold via a heteroatom, most frequently oxygen or nitrogen (leading thus to sulfamates and Sulfamides, respectively) [...
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the anticonvulsant sulfamide jnj 26990990 and its s s dioxide analog strongly inhibit carbonic anhydrases solution and x ray crystallographic studies
Organic and Biomolecular Chemistry, 2016Co-Authors: Anna Di Fiore, Vincenzo Alterio, Vincenzo Riccio, Claudiu T SupuranAbstract:JNJ-26990990 ((benzo[b]thien-3-yl)methyl)sulfamide, a sulfamide derivative structurally related to the antiepileptic drug zonisamide, was reported to be devoid of carbonic anhydrase (CA, EC 4.2.1.1) inhibitory properties. Here we report that JNJ-26990990 and its S,S-dioxide analog significantly inhibit six human (h) isoforms, hCA I, II, VII, IX, XII and XIV, involved in crucial physiological processes. Inhibition and X-ray crystallographic data for the binding of the two compounds to these enzymes show significant similarity with the zonisamide inhibitory pattern. These findings prompted us to reconsider the structural/pharmacological requirements for designing effective antiepileptics possessing zinc-binding groups of the sulfamide, sulfamate or sulfonamide type in their molecules.
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sulfamide derivatives with selective carbonic anhydrase vii inhibitory action
Bioorganic & Medicinal Chemistry, 2016Co-Authors: Maria Villalba, Claudiu T Supuran, Jose Gonzalez L Funes, Pablo Hernan Palestro, Luis Enrique Bruno Blanch, Mariangela Ceruso, Alan Talevi, Luciana GavernetAbstract:Abstract A set of N , N ′-disubstituted Sulfamides and sodium cyclamate have been tested for their inhibitory action against six isoforms of carbonic anhydrase (CA, EC 4.2.1.1) found in the brain, that is, CA I, CA II, CA VII, CA IX, CA XII and CA XIV, some of which are involved in epileptogenesis. The biological data showed interesting results for CA VII inhibition, the isozyme thought to be a novel antiepileptic target. Strong CA VII inhibitors, with K i values in the low nanomolar–subnanomolar range were identified. Some of these derivatives showed selectivity for inhibition of CA VII versus the ubiquitous isoform CA II, for which the K i values were in the micromolar range. Molecular modeling approaches were employed to understand the binding interactions between these compounds and the two CA isoforms, since the mechanism of action of such disubstituted Sulfamides was not yet investigated by means of X-ray crystallography.
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discovery of potent carbonic anhydrase and acetylcholine esterase inhibitors novel sulfamoylcarbamates and Sulfamides derived from acetophenones
Bioorganic & Medicinal Chemistry, 2015Co-Authors: Claudiu T Supuran, Hulya Akincioglu, Akin Akincioglu, Ilhami Gulcin, Serdar Durdagi, Suleyman GoksuAbstract:Abstract In this study, several novel Sulfamides were synthesized and evaluated for their acetylcholine esterase (AChE) and human carbonic anhydrase I, and II isoenzymes (hCA I and II) inhibition profiles. Reductive amination of methoxyacetophenones was used for the synthesis of amines. Amines were converted to sulfamoylcarbamates with chlorosulfonyl isocyanate (CSI) in the presence of BnOH. Pd-C catalyzed hydrogenolysis of sulfamoylcarbamates afforded Sulfamides. These novel compounds were good inhibitors of the cytosolic hCA I, and hCA II with Ki values in the range of 45.9 ± 8.9–687.5 ± 84.3 pM for hCA I, and 48.80 ± 8.2–672.2 ± 71.9 pM for hCA II. The inhibitory effects of the synthesized novel compounds on AChE were also investigated. The Ki values of these compounds were in the range of 4.52 ± 0.61–38.28 ± 6.84 pM for AChE. These results show that hCA I, II, and AChE were effectively inhibited by the novel sulfamoylcarbamates 17–21 and sulfamide derivatives 22–26. All investigated compounds were docked within the active sites of the corresponding enzymes revealing the reasons of the effective inhibitory activity.
Richard C D Brown - One of the best experts on this subject based on the ideXlab platform.
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one pot enyne ring closing metathesis diels alder reactions for the synthesis of polycyclic Sulfamides
ChemInform, 2014Co-Authors: Joseph T Hillcousins, Sofia S Salim, Richard K Bellingham, Youssef M Bakar, Mark E Light, Richard C D BrownAbstract:A one-pot procedure for the formation of polycyclic Sulfamides via an enyne ring-closing metathesis—Diels—Alder sequence is developed, giving rise to the endo-adducts as the sole observed diastereoisomers.
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one pot enyne ring closing metathesis diels alder reactions for the synthesis of polycyclic Sulfamides
Tetrahedron, 2014Co-Authors: Joseph T Hillcousins, Sofia S Salim, Richard K Bellingham, Youssef M Bakar, Mark E Light, Richard C D BrownAbstract:Ring-closing metathesis (RCM) and sequential Yb(OTf)3 promoted Diels–Alder reactions of sulfamide-linked enynes proceeded selectively in one-pot to afford a series of bicyclic and tricyclic Sulfamides. Excellent levels of diastereoselectivity are observed for the cycloaddition step, with only the endo-adducts being isolated. The protocol was further extended to incorporate a one-pot RCM–cross metathesis (CM)–Diels–Alder sequence, permitting rapid access to high levels of molecular complexity from simple and easily accessible precursors.
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one pot ring closing metathesis alkene cross metathesis reactions of sulfamide linked enynes
European Journal of Organic Chemistry, 2004Co-Authors: Sofia S Salim, Richard K Bellingham, Richard C D BrownAbstract:Ring-closing metathesis (RCM) of sulfamide-linked enynes 7, 11 and 12 containing disubstituted alkynes afforded a series of novel 7-membered cyclic Sulfamides 13-15 in good yield. Substrates 5, 9 and 10 containing mono-substituted dlkynes gave either simple RCM products 18a-c or those arising from combinations of enyne RCM and olefin cross metathesis 16/17a-c depending on the reaction conditions. Not-ably, in the presence of two equivalents of styrene or ethyl acrylate, substrates 5, 9 and 10 containing terminal alkynes underwent selective enyne-RCM-olefin-cross metathesis to provide cyclic Sulfamides 17a-c and 19b,c in yields of 54-83%.
Anders Hallberg - One of the best experts on this subject based on the ideXlab platform.
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cyclic sulfamide hiv 1 protease inhibitors with sidechains spanning from p2 p2 to p1 p1
Bioorganic & Medicinal Chemistry, 2005Co-Authors: Wesley Schaal, Bertil Samuelsson, Anders Hallberg, Lotta Vrang, Anders KarlenAbstract:Cyclic sulfamide HIV-1 protease inhibitors, with sidechains spanning from P2/P2' to P1/P1'.
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inhibitors of the c2 symmetric hiv 1 protease nonsymmetric binding of a symmetric cyclic sulfamide with ketoxime groups in the p2 p2 side chains
Journal of Medicinal Chemistry, 1999Co-Authors: Johan Hulten, Hans O Andersson, Wesley Schaal, Helena U Danielson, Bjorn Classon, Ingemar Kvarnstrom, Anders Karlen, Torsten Unge, Bertil Samuelsson, Anders HallbergAbstract:Symmetric cyclic Sulfamides, substituted in the P2/P2' position with functional groups foreseen to bind preferentially to the S2/S2' subsites of HIV-1 protease, have been prepared. Despite efforts to promote a symmetric binding, the Sulfamides seemed prone to bind nonsymmetrically, as deduced from X-ray crystal structure analysis of one of the most potent inhibitors, possessing ketoxime groups in the P2/P2' side chains. Ab initio calculations suggested that the nonsymmetric conformation of the cyclic sulfamide scaffold had lower energy than the corresponding symmetric, cyclic urea-like conformation.
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unexpected binding mode of a cyclic sulfamide hiv 1 protease inhibitor
Journal of Medicinal Chemistry, 1997Co-Authors: Kristina Backbro, Johan Hulten, Wesley Schaal, Anders Karlen, Torsten Unge, Seved Lowgren, Katrin Osterlund, Johnson Atepo, Nicholas M Bonham, Anders HallbergAbstract:Two cyclic, C2-symmetric HIV-1 protease inhibitors, one sulfamide and one urea derivative, both comprising phenyl ether groups in the P1/P1‘ positions, were cocrystallized with HIV-1 protease, and the crystal structures were determined to 2.0 A resolution. The structure of the urea 2 showed a conformation similar to that reported for the related urea 3 by Lam et al., while the sulfamide 1 adopted an unanticipated conformation in which the P1‘ and P2‘ side chains were transposed.
Wesley Schaal - One of the best experts on this subject based on the ideXlab platform.
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cyclic sulfamide hiv 1 protease inhibitors with sidechains spanning from p2 p2 to p1 p1
Bioorganic & Medicinal Chemistry, 2005Co-Authors: Wesley Schaal, Bertil Samuelsson, Anders Hallberg, Lotta Vrang, Anders KarlenAbstract:Cyclic sulfamide HIV-1 protease inhibitors, with sidechains spanning from P2/P2' to P1/P1'.
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synthesis and comparative molecular field analysis comfa of symmetric and nonsymmetric cyclic sulfamide hiv 1 protease inhibitors
Journal of Medicinal Chemistry, 2001Co-Authors: Wesley Schaal, Helena U Danielson, Bjorn Classon, Torsten Unge, Bertil Samuelsson, Anna Karlsson, Goran Ahlsen, Jimmy Lindberg, Hans Andersson, Johan HultenAbstract:We have previously reported on the unexpected flipped conformation in the cyclic sulfamide class of inhibitors. An attempt to induce a symmetric binding conformation by introducing P2/P2' substituents foreseen to bind preferentially in the S2/S2' subsite was unsuccessful. On the basis of the flipped conformation we anticipated that nonsymmetric sulfamide inhibitors, with P2/P2' side chains modified individually for the S1' and S2 subsites, should be more potent than the corresponding symmetric analogues. To test this hypothesis, a set of 18 cyclic sulfamide inhibitors (11 nonsymmetric and 7 symmetric) with different P2/P2' substituents was prepared and evaluated in an enzyme assay. To rationalize the structure-activity relationship (SAR) and enable the alignment of the nonsymmetric inhibitors, i.e., which of the P2/P2' substituents of the nonsymmetric inhibitors interact with which subsite, a CoMFA study was performed. The CoMFA model, constructed from the 18 inhibitors in this study along with seven inhibitors from previous work by our group, has successfully been used to rationalize the SAR of the cyclic sulfamide inhibitors. Furthermore, from the information presented herein, the SAR of the cyclic sulfamide class of inhibitors seems to differ from the SAR of the related cyclic urea inhibitors reported by DuPont and DuPont-Merck.
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inhibitors of the c2 symmetric hiv 1 protease nonsymmetric binding of a symmetric cyclic sulfamide with ketoxime groups in the p2 p2 side chains
Journal of Medicinal Chemistry, 1999Co-Authors: Johan Hulten, Hans O Andersson, Wesley Schaal, Helena U Danielson, Bjorn Classon, Ingemar Kvarnstrom, Anders Karlen, Torsten Unge, Bertil Samuelsson, Anders HallbergAbstract:Symmetric cyclic Sulfamides, substituted in the P2/P2' position with functional groups foreseen to bind preferentially to the S2/S2' subsites of HIV-1 protease, have been prepared. Despite efforts to promote a symmetric binding, the Sulfamides seemed prone to bind nonsymmetrically, as deduced from X-ray crystal structure analysis of one of the most potent inhibitors, possessing ketoxime groups in the P2/P2' side chains. Ab initio calculations suggested that the nonsymmetric conformation of the cyclic sulfamide scaffold had lower energy than the corresponding symmetric, cyclic urea-like conformation.
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unexpected binding mode of a cyclic sulfamide hiv 1 protease inhibitor
Journal of Medicinal Chemistry, 1997Co-Authors: Kristina Backbro, Johan Hulten, Wesley Schaal, Anders Karlen, Torsten Unge, Seved Lowgren, Katrin Osterlund, Johnson Atepo, Nicholas M Bonham, Anders HallbergAbstract:Two cyclic, C2-symmetric HIV-1 protease inhibitors, one sulfamide and one urea derivative, both comprising phenyl ether groups in the P1/P1‘ positions, were cocrystallized with HIV-1 protease, and the crystal structures were determined to 2.0 A resolution. The structure of the urea 2 showed a conformation similar to that reported for the related urea 3 by Lam et al., while the sulfamide 1 adopted an unanticipated conformation in which the P1‘ and P2‘ side chains were transposed.
Anders Karlen - One of the best experts on this subject based on the ideXlab platform.
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cyclic sulfamide hiv 1 protease inhibitors with sidechains spanning from p2 p2 to p1 p1
Bioorganic & Medicinal Chemistry, 2005Co-Authors: Wesley Schaal, Bertil Samuelsson, Anders Hallberg, Lotta Vrang, Anders KarlenAbstract:Cyclic sulfamide HIV-1 protease inhibitors, with sidechains spanning from P2/P2' to P1/P1'.
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inhibitors of the c2 symmetric hiv 1 protease nonsymmetric binding of a symmetric cyclic sulfamide with ketoxime groups in the p2 p2 side chains
Journal of Medicinal Chemistry, 1999Co-Authors: Johan Hulten, Hans O Andersson, Wesley Schaal, Helena U Danielson, Bjorn Classon, Ingemar Kvarnstrom, Anders Karlen, Torsten Unge, Bertil Samuelsson, Anders HallbergAbstract:Symmetric cyclic Sulfamides, substituted in the P2/P2' position with functional groups foreseen to bind preferentially to the S2/S2' subsites of HIV-1 protease, have been prepared. Despite efforts to promote a symmetric binding, the Sulfamides seemed prone to bind nonsymmetrically, as deduced from X-ray crystal structure analysis of one of the most potent inhibitors, possessing ketoxime groups in the P2/P2' side chains. Ab initio calculations suggested that the nonsymmetric conformation of the cyclic sulfamide scaffold had lower energy than the corresponding symmetric, cyclic urea-like conformation.
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unexpected binding mode of a cyclic sulfamide hiv 1 protease inhibitor
Journal of Medicinal Chemistry, 1997Co-Authors: Kristina Backbro, Johan Hulten, Wesley Schaal, Anders Karlen, Torsten Unge, Seved Lowgren, Katrin Osterlund, Johnson Atepo, Nicholas M Bonham, Anders HallbergAbstract:Two cyclic, C2-symmetric HIV-1 protease inhibitors, one sulfamide and one urea derivative, both comprising phenyl ether groups in the P1/P1‘ positions, were cocrystallized with HIV-1 protease, and the crystal structures were determined to 2.0 A resolution. The structure of the urea 2 showed a conformation similar to that reported for the related urea 3 by Lam et al., while the sulfamide 1 adopted an unanticipated conformation in which the P1‘ and P2‘ side chains were transposed.
