scholarly journals Carbonic Anhydrase Inhibition with Sulfonamides Incorporating Pyrazole- and Pyridazinecarboxamide Moieties Provides Examples of Isoform-Selective Inhibitors

Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 7023
Author(s):  
Andrea Angeli ◽  
Victor Kartsev ◽  
Anthi Petrou ◽  
Mariana Pinteala ◽  
Volodymyr Brovarets ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Drug Design ◽  
Carbonic Anhydrase ◽  
Computational Approach ◽  
Selective Inhibitors ◽  
Carbonic Anhydrase Inhibition ◽  
Human Carbonic Anhydrase ◽  
Cytosolic Enzymes

A series of benzenesulfonamides incorporating pyrazole- and pyridazinecarboxamides decorated with several bulky moieties has been obtained by original procedures. The new derivatives were investigated for the inhibition of four physiologically crucial human carbonic anhydrase (hCA, EC 4.2.2.1.1) isoforms, hCA I and II (cytosolic enzymes) as well as hCA IX and XII (transmembrane, tumor-associated isoforms). Examples of isoform-selective inhibitors were obtained for all four enzymes investigated here, and a computational approach was employed for explaining the observed selectivity, which may be useful in drug design approaches for obtaining inhibitors with pharmacological applications useful as antiglaucoma, diuretic, antitumor or anti-cerebral ischemia drugs.

Kinetically Selective Inhibitors of Human Carbonic Anhydrase Isozymes I, II, VII, IX, XII, and XIII

2016 ◽  
Vol 59 (5) ◽  
pp. 2083-2093 ◽  
Author(s):  
Vladimir O. Talibov ◽  
Vaida Linkuvienė ◽  
Daumantas Matulis ◽  
U. Helena Danielson
Keyword(s):  
Carbonic Anhydrase ◽  
Selective Inhibitors ◽  
Human Carbonic Anhydrase

scholarly journals Carbonic anhydrase inhibition for the management of cerebral ischemia: in vivo evaluation of sulfonamide and coumarin inhibitors

2015 ◽  
Vol 31 (6) ◽  
pp. 894-899 ◽  
Author(s):  
Lorenzo Di Cesare Mannelli ◽  
Laura Micheli ◽  
Fabrizio Carta ◽  
Andrea Cozzi ◽  
Carla Ghelardini ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Carbonic Anhydrase ◽  
In Vivo Evaluation ◽  
Carbonic Anhydrase Inhibition

scholarly journals Hydrophobic Substituents of the Phenylmethylsulfamide Moiety Can Be Used for the Development of New Selective Carbonic Anhydrase Inhibitors

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Giuseppina De Simone ◽  
Ginta Pizika ◽  
Simona Maria Monti ◽  
Anna Di Fiore ◽  
Jekaterina Ivanova ◽  
...  
Keyword(s):  
Drug Design ◽  
Carbonic Anhydrase ◽  
Van Der Waals ◽  
Van Der Waals Interactions ◽  
Zinc Binding ◽  
Binding Mechanism ◽  
Carbonic Anhydrase Inhibitors ◽  
X Ray ◽  
Human Carbonic Anhydrase ◽  
Hydrophobic Cleft

A new series of compounds containing a sulfamide moiety as zinc-binding group (ZBG) has been synthesized and tested for determining inhibitory properties against four human carbonic anhydrase (hCA) isoforms, namely, CAs I, II, IX, and XII. The X-ray structure of the cytosolic dominant isoform hCA II in complex with the best inhibitor of the series has also been determined providing further insights into sulfamide binding mechanism and confirming that such zinc-binding group, if opportunely derivatized, can be usefully exploited for obtaining new potent and selective CAIs. The analysis of the structure also suggests that for drug design purposes the but-2-yn-1-yloxy moiety tail emerges as a very interesting substituent of the phenylmethylsulfamide moiety due to its capability to establish strong van der Waals interactions with a hydrophobic cleft on the hCA II surface, delimited by residues Phe131, Val135, Pro202, and Leu204. Indeed, the complementarity of this tail with the cleft suggests that different substituents could be used to discriminate between isoforms having clefts with different sizes.

scholarly journals Localization of ligands within human carbonic anhydrase II using 19F pseudocontact shift analysis

2019 ◽  
Vol 10 (19) ◽  
pp. 5064-5072 ◽  
Author(s):  
Kaspar Zimmermann ◽  
Daniel Joss ◽  
Thomas Müntener ◽  
Elisa S. Nogueira ◽  
Marc Schäfer ◽  
...  
Keyword(s):  
Drug Design ◽  
Carbonic Anhydrase ◽  
Rational Drug Design ◽  
Carbonic Anhydrase Ii ◽  
Pseudocontact Shift ◽  
Native Structure ◽  
Shift Analysis ◽  
Rational Drug ◽  
Human Carbonic Anhydrase

Unraveling the native structure of protein–ligand complexes in solution enables rational drug design.

scholarly journals Indole-Based Hydrazones Containing A Sulfonamide Moiety as Selective Inhibitors of Tumor-Associated Human Carbonic Anhydrase Isoforms IX and XII

2019 ◽  
Vol 20 (9) ◽  
pp. 2354 ◽  
Author(s):  
Kübra Demir-Yazıcı ◽  
Silvia Bua ◽  
Nurgül Mutlu Akgüneş ◽  
Atilla Akdemir ◽  
Claudiu T. Supuran ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Carbonic Anhydrase ◽  
Enzyme Inhibition ◽  
Active Sites ◽  
Selective Inhibitors ◽  
Binding Interactions ◽  
Modeling Studies ◽  
Molecular Modeling Studies ◽  
Human Carbonic Anhydrase

Novel sulfonamidoindole-based hydrazones with a 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide scaffold were synthesized and tested in enzyme inhibition assays against the tumor-associated carbonic anhydrase isoforms, hCA IX and XII, and the off-targets, hCA I and II. The compounds showed selectivity against hCA IX and XII over hCA I and II. Six compounds showed KI values lower than 10 nM against hCA IX or XII. Molecular modeling studies were performed to suggest binding interactions between the ligand and the hCA active sites.

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