scholarly journals Discovery of novel isatin-based sulfonamides with potent and selective inhibition of the tumor-associated carbonic anhydrase isoforms IX and XII

2015 ◽  
Vol 13 (23) ◽  
pp. 6493-6499 ◽  
Author(s):  
Özlen Güzel-Akdemir ◽  
Atilla Akdemir ◽  
Nilgün Karalı ◽  
Claudiu T. Supuran
Keyword(s):  
Carbonic Anhydrase ◽  
Inhibitory Activity ◽  
Selective Inhibition ◽  
Carbonic Anhydrases

A series of 2/3/4-[(2-oxo-1,2-dihydro-3H-indol-3-ylidene)amino]benzenesulfonamides, obtained from substituted isatins and 2-, 3- or 4-aminobenzenesulfonamide, showed low nanomolar inhibitory activity against the tumor associated carbonic anhydrases IX and XII.

scholarly journals Aryl-4,5-dihydro-1H-pyrazole-1-carboxamide Derivatives Bearing a Sulfonamide Moiety Show Single-digit Nanomolar-to-Subnanomolar Inhibition Constants against the Tumor-associated Human Carbonic Anhydrases IX and XII

2020 ◽  
Vol 21 (7) ◽  
pp. 2621
Author(s):  
Priya Hargunani ◽  
Nikhil Tadge ◽  
Mariangela Ceruso ◽  
Janis Leitans ◽  
Andris Kazaks ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Inhibitory Activity ◽  
Phenyl Ring ◽  
Drug Targets ◽  
Binding Mode ◽  
Docking Studies ◽  
Carbonic Anhydrases ◽  
Single Digit ◽  
Ca Ix ◽  
Shed Light

A series of new 3-phenyl-5-aryl-N-(4-sulfamoylphenyl)-4,5-dihydro-1H-pyrazole-1-carboxamide derivatives was designed here, synthesized, and studied for carbonic anhydrase (CAs, EC 4.2.1.1) inhibitory activity against the human (h) isozymes I, II, and VII (cytosolic, off-target isoforms), and IX and XII (anticancer drug targets). Generally, CA I was not effectively inhibited, whereas effective inhibitors were identified against both CAs II (KIs in the range of 5.2–233 nM) and VII (KIs in the range of 2.3–350 nM). Nonetheless, CAs IX and XII were the most susceptible isoforms to this class of inhibitors. In particular, compounds bearing an unsubstituted phenyl ring at the pyrazoline 3 position showed 1.3–1.5 nM KIs against CA IX. In contrast, a subset of derivatives having a 4-halo-phenyl at the same position of the aromatic scaffold even reached subnanomolar KIs against CA XII (0.62–0.99 nM). Docking studies with CA IX and XII were used to shed light on the derivative binding mode driving the preferential inhibition of the tumor-associated CAs. The identified potent and selective CA IX/XII inhibitors are of interest as leads for the development of new anticancer strategies.

scholarly journals Chromene-Containing Aromatic Sulfonamides with Carbonic Anhydrase Inhibitory Properties

2021 ◽  
Vol 22 (10) ◽  
pp. 5082
Author(s):  
Andrea Angeli ◽  
Victor Kartsev ◽  
Anthi Petrou ◽  
Mariana Pinteala ◽  
Volodymyr Brovarets ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Active Site ◽  
Inhibitory Activity ◽  
Binding Mode ◽  
Carbonic Anhydrases ◽  
Inhibition Activity ◽  
Physiological Conditions ◽  
Computational Procedures ◽  
Living Organisms ◽  
Human Isoforms

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. Their inhibitory activity was assessed against the cytosolic human isoforms hCA I, hCA II and the transmembrane hCA IX and XII. Several of the investigated derivatives showed interesting inhibition activity towards the tumor associate isoforms hCA IX and hCA XII. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds, within the active site of hCA IX.

Are Carbonic Anhydrases Suitable Targets to Fight Protozoan Parasitic Diseases?

2019 ◽  
Vol 25 (39) ◽  
pp. 5266-5278 ◽  
Author(s):  
Katia D'Ambrosio ◽  
Claudiu T. Supuran ◽  
Giuseppina De Simone
Keyword(s):  
Drug Resistance ◽  
Animal Models ◽  
Carbonic Anhydrase ◽  
Drug Target ◽  
Treatment Options ◽  
Parasitic Diseases ◽  
Carbonic Anhydrases ◽  
Extensive Drug Resistance ◽  
Protozoan Infections

Protozoans belonging to Plasmodium, Leishmania and Trypanosoma genera provoke widespread parasitic diseases with few treatment options and many of the clinically used drugs experiencing an extensive drug resistance phenomenon. In the last several years, the metalloenzyme Carbonic Anhydrase (CA, EC 4.2.1.1) was cloned and characterized in the genome of these protozoa, with the aim to search for a new drug target for fighting malaria, leishmaniasis and Chagas disease. P. falciparum encodes for a CA (PfCA) belonging to a novel genetic family, the η-CA class, L. donovani chagasi for a β-CA (LdcCA), whereas T. cruzi genome contains an α-CA (TcCA). These three enzymes were characterized in detail and a number of in vitro potent and selective inhibitors belonging to the sulfonamide, thiol, dithiocarbamate and hydroxamate classes were discovered. Some of these inhibitors were also effective in cell cultures and animal models of protozoan infections, making them of considerable interest for the development of new antiprotozoan drugs with a novel mechanism of action.

scholarly journals Effect of Sulfonamides and Their Structurally Related Derivatives on the Activity of ι-Carbonic Anhydrase from Burkholderia territorii

2021 ◽  
Vol 22 (2) ◽  
pp. 571
Author(s):  
Viviana De Luca ◽  
Andrea Petreni ◽  
Alessio Nocentini ◽  
Andrea Scaloni ◽  
Claudiu T. Supuran ◽  
...  
Keyword(s):  
Carbon Dioxide ◽  
Antibiotic Resistance ◽  
Pathogenic Bacteria ◽  
Selective Inhibition ◽  
Extensive Study ◽  
Protein Isoforms ◽  
Carbonic Anhydrases ◽  
Physiological Processes ◽  
Microbial Survival ◽  
Reversible Hydration

Carbonic anhydrases (CAs) are essential metalloenzymes in nature, catalyzing the carbon dioxide reversible hydration into bicarbonate and proton. In humans, breathing and many other critical physiological processes depend on this enzymatic activity. The CA superfamily function and inhibition in pathogenic bacteria has recently been the object of significant advances, being demonstrated to affect microbial survival/virulence. Targeting bacterial CAs may thus be a valid alternative to expand the pharmacological arsenal against the emergence of widespread antibiotic resistance. Here, we report an extensive study on the inhibition profile of the recently discovered ι-CA class present in some bacteria, including Burkholderia territorii, namely BteCAι, using substituted benzene-sulfonamides and clinically licensed sulfonamide-, sulfamate- and sulfamide-type drugs. The BteCAι inhibition profile showed: (i) several benzene-sulfonamides with an inhibition constant lower than 100 nM; (ii) a different behavior with respect to other α, β and γ-CAs; (iii) clinically used drugs having a micromolar affinity. This prototype study contributes to the initial recognition of compounds which efficiently and selectively inhibit a bacterial member of the ι-CA class, for which such a selective inhibition with respect to other protein isoforms present in the host is highly desired and may contribute to the development of novel antimicrobials.

scholarly journals Synthesis, Molecular Docking Analysis and Biological Evaluations of Saccharide-Modified Thiadiazole Sulfonamide Derivatives

2021 ◽  
Vol 22 (11) ◽  
pp. 5482
Author(s):  
Zuo-Peng Zhang ◽  
Ye Zhong ◽  
Zhen-Bin Han ◽  
Lin Zhou ◽  
Hua-Sheng Su ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Human Cancer ◽  
Carbonic Anhydrases ◽  
Inhibitory Effects ◽  
Docking Analysis ◽  
Human Cancer Cell Lines ◽  
Hypoxic Conditions ◽  
Ca Ix ◽  
Topological Polar Surface Area ◽  
Ht 29

A series of saccharide-modified thiadiazole sulfonamide derivatives has been designed and synthesized by the “tail approach” and evaluated for inhibitory activity against carbonic anhydrases II, IX, and XII. Most of the compounds showed high topological polar surface area (TPSA) values and excellent enzyme inhibitory activity. The impacts of some compounds on the viability of HT-29, MDA-MB-231, and MG-63 human cancer cell lines were examined under both normoxic and hypoxic conditions, and they showed certain inhibitory effects on cell viability. Moreover, it was found that the series of compounds had the ability to raise the pH of the tumor cell microenvironment. All the results proved that saccharide-modified thiadiazole sulfonamides have important research prospects for the development of CA IX inhibitors.

scholarly journals Prediction of activity and selectivity profiles of human Carbonic Anhydrase inhibitors using machine learning classification models

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Annachiara Tinivella ◽  
Luca Pinzi ◽  
Giulio Rastelli
Keyword(s):  
Machine Learning ◽  
Carbonic Anhydrase ◽  
A Priori ◽  
Selective Inhibition ◽  
Great Promise ◽  
Classification Models ◽  
Machine Learning Classification ◽  
Central Interest ◽  
Human Carbonic Anhydrase ◽  
In Silico Models

AbstractThe development of selective inhibitors of the clinically relevant human Carbonic Anhydrase (hCA) isoforms IX and XII has become a major topic in drug research, due to their deregulation in several types of cancer. Indeed, the selective inhibition of these two isoforms, especially with respect to the homeostatic isoform II, holds great promise to develop anticancer drugs with limited side effects. Therefore, the development of in silico models able to predict the activity and selectivity against the desired isoform(s) is of central interest. In this work, we have developed a series of machine learning classification models, trained on high confidence data extracted from ChEMBL, able to predict the activity and selectivity profiles of ligands for human Carbonic Anhydrase isoforms II, IX and XII. The training datasets were built with a procedure that made use of flexible bioactivity thresholds to obtain well-balanced active and inactive classes. We used multiple algorithms and sampling sizes to finally select activity models able to classify active or inactive molecules with excellent performances. Remarkably, the results herein reported turned out to be better than those obtained by models built with the classic approach of selecting an a priori activity threshold. The sequential application of such validated models enables virtual screening to be performed in a fast and more reliable way to predict the activity and selectivity profiles against the investigated isoforms.

scholarly journals Synthesis and Human Carbonic Anhydrase I, II, IX, and XII Inhibition Studies of Sulphonamides Incorporating Mono-, Bi- and Tricyclic Imide Moieties

2021 ◽  
Vol 14 (7) ◽  
pp. 693
Author(s):  
Kalyan K. Sethi ◽  
KM Abha Mishra ◽  
Saurabh M. Verma ◽  
Daniela Vullo ◽  
Fabrizio Carta ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Carbonic Anhydrase ◽  
Docking Studies ◽  
Carbonic Anhydrases ◽  
Molecular Docking Studies ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Carbonic Anhydrase I ◽  
Human Carbonic Anhydrase ◽  
Inhibition Studies

New derivatives were synthesised by reaction of amino-containing aromatic sulphonamides with mono-, bi-, and tricyclic anhydrides. These sulphonamides were investigated as human carbonic anhydrases (hCAs, EC 4.2.1.1) I, II, IX, and XII inhibitors. hCA I was inhibited with inhibition constants (Kis) ranging from 49 to >10,000 nM. The physiologically dominant hCA II was significantly inhibited by most of the sulphonamide with the Kis ranging between 2.4 and 4515 nM. hCA IX and hCA XII were inhibited by these sulphonamides in the range of 9.7 to 7766 nM and 14 to 316 nM, respectively. The structure–activity relationships (SAR) are rationalised with the help of molecular docking studies.

Polypharmacology of epacadostat: a potent and selective inhibitor of the tumor associated carbonic anhydrases IX and XII

2019 ◽  
Vol 55 (40) ◽  
pp. 5720-5723 ◽  
Author(s):  
Andrea Angeli ◽  
Marta Ferraroni ◽  
Alessio Nocentini ◽  
Silvia Selleri ◽  
Paola Gratteri ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Selective Inhibitor ◽  
Carbonic Anhydrase Inhibitor ◽  
Carbonic Anhydrases ◽  
Indoleamine 2,3 Dioxygenase

Epacadostat (EPA), a selective indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor, has been investigatedin vitroas a human (h) Carbonic Anhydrase Inhibitor (CAI).

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