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

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.

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Computational Studies on Isolated Compounds of Sclerochloa dura; their Efficacy towards Carbonic Anhydrase Inhibition and Anti-cancer Drug Targets

Letters in Drug Design & Discovery ◽

10.2174/1570180818666210719125810 ◽

2021 ◽

Vol 18 ◽

Author(s):

Majid Ali ◽

Asma Zaidi ◽

Umar Farooq ◽

Rizwana Sarwar ◽

Syed Majid Bukhari

Keyword(s):

Carbonic Anhydrase ◽

Binding Affinity ◽

Anticancer Drug ◽

Active Site ◽

Drug Targets ◽

Docking Studies ◽

Cancer Drug ◽

Hydroxyl Groups ◽

Carbonic Anhydrases

Background: In the previous study, we reported the isolation of six compounds from Sclerochloa dura and their in-vitro anti-inflammatory potential by their ability to inhibit phospholipase A2 (PLA2). The objective of the current study is to inspect the effect of these compounds on other expected targets. Methods: For this purpose, various targets and percentage activities are predicted through CoFFer (QSAR) web service. All six compounds under investigation represented 99-100% activity towards carbonic anhydrases (CAs) and 90-100% activity towards anticancer drug targets. As the active site of most of the carbonic anhydrase isozymes is conserved, we selected cytosolic human carbonic anhydrase II (hCA II) for docking studies which is ubiquitous and involved in various human disorders such as glaucoma, pulmonary edema, and epilepsy. Anticancer drug targets include vascular endothelial growth factor receptor 2 (VEGFR2), glucocorticoid receptor (GR), and tyrosine-protein kinase (c-SRC). Interaction of these compounds with hCA II (PDB ID: 3P4V) and anticancer drug targets such as VEGFR2 (ID: 3WZD), GR (ID: 5G5W), and c-SRC (ID: 2SRC) was analyzed through molecular docking studies using MOE (Molecular Operating Environment). Results: The findings suggested that most of these compounds represent excellent binding affinity with hCA II by interacting with zinc-coordinated water molecules through sulfonic acid and hydroxyl groups present in the blends. Similarly, five out of six compounds represented excellent interaction with VEGFR2. Interactions with GR indicated that compounds 2, 3, and 6 binds effectively compared to their co-crystallized ligands. However, among these, the excellent binding affinity with c-SRC was demonstrated by compounds 3 and 6. Conclusion: This study revealed that all these compounds exhibited excellent interaction with the active site of hCA II, however in the light of previously reported data and due to membrane barrier, only compound 1 (due to long hydrophobic tail) and compound 4 (due to absence of bulky carbohydrate groups), can only penetrate inside the cytosol. Compounds 2, 3, 4, and 6 containing bulky carbohydrate moieties cannot penetrate inside the cell, therefore, they might have selective nature towards membrane-bounded tumor-associated hCA IX. This anti-tumor property of compounds was also proved by docking studies with VEGFR2, GR, and c-SRC. Therefore, these compounds may have a synergistic effect against inflammation and cancer. The ADMET studies show that compounds have moderate absorption and permeability along with slight toxicity.

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Chromene-Containing Aromatic Sulfonamides with Carbonic Anhydrase Inhibitory Properties

International Journal of Molecular Sciences ◽

10.3390/ijms22105082 ◽

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22115482 ◽

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.

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

Pharmaceuticals ◽

10.3390/ph14070693 ◽

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.

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Carbonic Anhydrase Inhibitors Targeting Metabolism and Tumor Microenvironment

Metabolites ◽

10.3390/metabo10100412 ◽

2020 ◽

Vol 10 (10) ◽

pp. 412 ◽

Cited By ~ 1

Author(s):

Andrea Angeli ◽

Fabrizio Carta ◽

Alessio Nocentini ◽

Jean-Yves Winum ◽

Raivis Zalubovskis ◽

...

Keyword(s):

Tumor Microenvironment ◽

Carbonic Anhydrase ◽

Drug Targets ◽

Ph Regulation ◽

Hypoxia Inducible Factor ◽

Lead Compounds ◽

Hypoxia Inducible Factor 1 ◽

Ca Ix ◽

Activation Of Transcription ◽

Hif Pathway

The tumor microenvironment is crucial for the growth of cancer cells, triggering particular biochemical and physiological changes, which frequently influence the outcome of anticancer therapies. The biochemical rationale behind many of these phenomena resides in the activation of transcription factors such as hypoxia-inducible factor 1 and 2 (HIF-1/2). In turn, the HIF pathway activates a number of genes including those involved in glucose metabolism, angiogenesis, and pH regulation. Several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, such as CA IX and XII, actively participate in these processes and were validated as antitumor/antimetastatic drug targets. Here, we review the field of CA inhibitors (CAIs), which selectively inhibit the cancer-associated CA isoforms. Particular focus was on the identification of lead compounds and various inhibitor classes, and the measurement of CA inhibitory on-/off-target effects. In addition, the preclinical data that resulted in the identification of SLC-0111, a sulfonamide in Phase Ib/II clinical trials for the treatment of hypoxic, advanced solid tumors, are detailed.

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Benzylaminoethyureido-Tailed Benzenesulfonamides: Design, Synthesis, Kinetic and X-ray Investigations on Human Carbonic Anhydrases

International Journal of Molecular Sciences ◽

10.3390/ijms21072560 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2560 ◽

Cited By ~ 2

Author(s):

Majid Ali ◽

Murat Bozdag ◽

Umar Farooq ◽

Andrea Angeli ◽

Fabrizio Carta ◽

...

Keyword(s):

Carbonic Anhydrase ◽

Design Strategy ◽

Binding Mode ◽

Crystallographic Analysis ◽

Carbonic Anhydrases ◽

Detailed Structure ◽

Design Synthesis ◽

X Ray ◽

Structure Activity ◽

New Compounds

A drug design strategy of carbonic anhydrase inhibitors (CAIs) belonging to sulfonamides incorporating ureidoethylaminobenzyl tails is presented. A variety of substitution patterns on the ring and the tails, located on para- or meta- positions with respect to the sulfonamide warheads were incorporated in the new compounds. Inhibition of human carbonic anhydrases (hCA) isoforms I, II, IX and XII, involving various pathologies, was assessed with the new compounds. Selective inhibitory profile towards hCA II was observed, the most active compounds being low nM inhibitors (KIs of 2.8–9.2 nM, respectively). Extensive X-ray crystallographic analysis of several sulfonamides in an adduct with hCA I allowed an in-depth understanding of their binding mode and to lay a detailed structure-activity relationship.

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Extending the Inhibition Profiles of Coumarin-Based Compounds Against Human Carbonic Anhydrases: Synthesis, Biological, and In Silico Evaluation

Molecules ◽

10.3390/molecules24193580 ◽

2019 ◽

Vol 24 (19) ◽

pp. 3580 ◽

Cited By ~ 2

Author(s):

Kartsev ◽

Geronikaki ◽

Bua ◽

Nocentini ◽

Petrou ◽

...

Keyword(s):

Active Site ◽

Inhibitory Activity ◽

Binding Mode ◽

Carbonic Anhydrases ◽

Reference Drug ◽

Physiological Conditions ◽

Computational Procedures ◽

Living Organisms ◽

Human Isoforms ◽

Potent Inhibitory Activity

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO2 hydration in all living organisms and are actively involved in the regulation of a plethora of pathological and physiological conditions. A set of new coumarin/ dihydrocoumarin derivatives was here synthesized, characterized, and tested as human CA inhibitors. Their inhibitory activity was evaluated against the cytosolic human isoforms hCA I and II and the transmembrane hCA IX and hCA XII. Two compounds showed potent inhibitory activity against hCA IX, being more active or equipotent with the reference drug acetazolamide. Computational procedures were used to investigate the binding mode of this class of compounds within the active site of hCA IX and XII that are validated as anti-tumor targets.

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Novel Diamide-Based Benzenesulfonamides as Selective Carbonic Anhydrase IX Inhibitors Endowed with Antitumor Activity: Synthesis, Biological Evaluation and In Silico Insights

International Journal of Molecular Sciences ◽

10.3390/ijms20102484 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2484 ◽

Cited By ~ 5

Author(s):

Mohamed A. Abdelrahman ◽

Wagdy M. Eldehna ◽

Alessio Nocentini ◽

Silvia Bua ◽

Sara T. Al-Rashood ◽

...

Keyword(s):

Antitumor Activity ◽

Carbonic Anhydrase ◽

Biological Evaluation ◽

Single Digit ◽

Reference Drug ◽

Docking Simulations ◽

Ca Ix ◽

Bioisosteric Replacement ◽

Line Compound ◽

Synthesis And Biological Evaluation

In this work, we present the synthesis and biological evaluation of novel series of diamide-based benzenesulfonamides 5a–h as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IX and XII. The target tumor-associated isoforms hCA IX and XII were undeniably the most affected ones (KIs: 8.3–123.3 and 9.8–134.5 nM, respectively). Notably, diamides 5a and 5h stood out as a single-digit nanomolar hCA IX inhibitors (KIs = 8.8 and 8.3 nM). The SAR outcomes highlighted that bioisosteric replacement of the benzylidene moiety, compounds 5a–g, with the hetero 2-furylidene moiety, compound 5h, achieved the best IX/I and IX/II selectivity herein reported with SIs of 985 and 13.8, respectively. Molecular docking simulations of the prepared diamides within CA IX active site revealed the ability of 5h to establish an additional H-bond between the heterocyclic oxygen and HE/Gln67. Moreover, benzenesulfonamides 5a, 5b and 5h were evaluated for their antitumor activity against renal cancer UO-31 cell line. Compound 5h was the most potent derivative with about 1.5-fold more enhanced activity (IC50 = 4.89 ± 0.22 μM) than the reference drug Staurosporine (IC50 = 7.25 ± 0.43 μM). Moreover, 5a and 5h were able to induce apoptosis in UO-31 cells as evidenced by the significant increase in the percent of annexinV-FITC positive apoptotic cells by 22.5- and 26.5-folds, respectively.

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

Organic & Biomolecular Chemistry ◽

10.1039/c5ob00688k ◽

2015 ◽

Vol 13 (23) ◽

pp. 6493-6499 ◽

Cited By ~ 35

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.

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