Next Article in Journal
Untargeted Metabolomic Analysis of Rat Neuroblastoma Cells as a Model System to Study the Biochemical Effects of the Acute Administration of Methamphetamine
Next Article in Special Issue
Activation Studies of the β-Carbonic Anhydrase from the Pathogenic Protozoan Entamoeba histolytica with Amino Acids and Amines
Previous Article in Journal / Special Issue
Amino Acids as Building Blocks for Carbonic Anhydrase Inhibitors
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Benzamide-4-Sulfonamides Are Effective Human Carbonic Anhydrase I, II, VII, and IX Inhibitors

1
Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via U. Schiff 6, Sesto Fiorentino, 50019 Florence, Italy
2
Department of Chemistry, Faculty of Science, Lorestan University, Khorramabad 6813833946, Iran
*
Authors to whom correspondence should be addressed.
Metabolites 2018, 8(2), 37; https://doi.org/10.3390/metabo8020037
Submission received: 11 May 2018 / Revised: 26 May 2018 / Accepted: 30 May 2018 / Published: 1 June 2018
(This article belongs to the Special Issue Carbonic Anhydrases and Metabolism)

Abstract

:
A series of benzamides incorporating 4-sulfamoyl moieties were obtained by reacting 4-sulfamoyl benzoic acid with primary and secondary amines and amino acids. These sulfonamides were investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The human (h) isoforms hCA II, VII, and IX were inhibited in the low nanomolar or subnanomolar ranges, whereas hCA I was slightly less sensitive to inhibition (KIs of 5.3–334 nM). The β- and γ-class CAs from pathogenic bacteria and fungi, such as Vibrio cholerae and Malassezia globosa, were inhibited in the micromolar range by the sulfonamides reported in the paper. The benzamide-4-sulfonamides are a promising class of highly effective CA inhibitors.

Graphical Abstract

1. Introduction

Benzamides incorporating 3- or 4-sulfamoyl moieties, such as derivatives A and B (Figure 1) were investigated [1,2] as inhibitors of the zinc metallo-enzyme carbonic anhydrase (CA, EC 4.2.1.1) [3,4,5,6,7,8,9,10,11,12] in this study, in the search of agents with intraocular pressure lowering effects [1,2]. The incorporation of a wide range of amino acid (AA) or dipeptide AA moieties in molecules A and B led to enhanced water solubility for topical administration within the eye. These compounds showed remarkable in vitro inhibitory effects, assayed by an esterase method with 4-nitrophenyl acetate as substrate, against isoforms hCA II and IV, involved in aqueous humor production within the eye [1,2,3,4,5,6,7,8,9,10,11,12].
The CA inhibitors (CAIs) belonging to the sulfonamide and sulfamate types have been used clinically for several decades as diuretics [13,14], antiglaucoma agents [15], and anti-obesity drugs [16,17]. More recently, a large number of studies showed that CA inhibition has profound antitumor effects by inhibiting hypoxia-inducible isoforms hCA IX and XII, overexpressed in many hypoxic tumors [18,19,20,21,22]. Furthermore, several proof-of-concept studies demonstrated the involvement of some CA isoforms in neuropathic pain [23,24] and arthritis [25,26], with the CAIs of sulfonamide and coumarin [27,28,29,30] types demonstrating significant in vivo effects in animal models of these diseases. Thus, the field of drug design, synthesis, and in vivo investigations of various types of CAIs is highly dynamic, with the action of a large number of interesting new chemotypes on these widespread enzymes being constantly studied [27,28,29,30,31,32,33,34,35,36,37,38,39]. As they catalyze the interconversion between carbon dioxide (CO2) and bicarbonate with the formation of a proton, CAs are widespread in organisms all over the phylogenetic tree as seven distinct genetic families: the α-, β-, γ-, δ-, η-, ξ-, and θ-CAs [3,4,5,6,7,8,9,10,11,12,40,41,42,43,44,45,46,47]. CAs participate in crucial physiologic processes connected to pH homeostasis, metabolism, transport of gases and ions, and secretion of electrolytes in virtually all living beings [3,4,5,6,7,8,9,10,11,12,40,41,42,43,44,45,46,47].
Apart from the inhibition of human (h) or other vertebrate CA isoforms, the interest in inhibiting such enzymes present in various pathogenic organisms (bacteria, fungi, protozoa, or worms) has presented the possibility of designing anti-infective agents with a novel mechanism of action [40,41,42,43,44,45,46,47,48,49,50,51]. Thus, in this paper, we explored novel CAIs belonging to the sulfonamide class, incorporating benzamide moieties similar to compounds reported earlier, but that were investigated for the inhibition of isoforms involved in important diseases, such as glaucoma (hCA II), neuropathic pain (hCA VII), or tumors (hCA IX), and ubiquitous off target isoform hCA I. Furthermore, we investigated whether this chemotype shows inhibitory effects against β- and γ-class CAs from pathogenic bacteria (Vibrio cholerae) or fungi (Malassezia globosa).

2. Results

2.1. Chemistry

The classical coupling of carboxylic acid 1 with amines, in the presence of carbodiimides (EDCI) and hydroxybenzotriazole has been used for synthesis, as reported previously [1,2] (Scheme 1).
Compound 1 was condensed with compounds 3ae that possess primary or secondary amines as well amino acid derivatives 3fl in the presence of EDCI and 1-hydroxy-7-azabenzotriazole (HOAT) to obtain their corresponding amides (Scheme 1). By choosing variously substituted amines and amino acids, incorporating both simple aliphatic and heterocyclic scaffolds (for the amine) and aliphatic and aromatic amino acids, the physico-chemical properties and enzyme inhibitory properties of the new compounds could be modulated. For example, the amino acid derivatives 3f, 3g, 3h, 3j, and 3l may form sodium salts leading to water soluble CAIs.

2.2. Carbonic Anhydrase Inhibition

Sulfonamides 3a3l were tested as inhibitors of four hCAs involved in various pathologies, hCA I, II, VII, and IX, as well as three β- and γ-CAs from pathogenic organisms: the β-CAs from the bacterium Vibrio cholerae (VchCAβ) and the fungus Malassezia globosa (MgCA), and the γ-CA from the same pathogenic bacterium, VchCAγ–enzymes recently cloned and characterized by our group as potential anti-infective targets [52,53,54,55,56,57,58,59] (Table 1).

3. Discussion

The following structure-activity relationship (SAR) were determined from the data of Table 1, in which the standard sulfonamide inhibitor acetazolamide (AAZ) was also included for comparison.
The slow cytosolic isoform hCAI, involved in some ocular diseases (not glaucoma) [3,4,5,6,7], was inhibited by sulfonamides 3al reported here with KIs in the range of 5.3 to 334 nM. The ethyl- (3a) derivative was the weakest inhibitor, whereas 3c, 3f, 3i, and 3j showed medium potency inhibitory action, with a KIs in the range of 57.8 to 85.3. These compounds incorporate propargyl, valyl, aspartyl, and alanyl moieties. The remaining derivatives, 3b, 3d, 3e, 3g, 3h, 3k, and 3l showed very effective hCA I inhibitory properties, with a KIs in the range of 5.3 to 29.7 nM, being CAIs an order of magnitude better compared to acetazolamide (Table 1). Small changes in the scaffold (compare 3a and 3b) led to dramatic changes in the hCA I inhibitory effects, with the propyl derivative 3b being 40.7 times more effective an inhibitor compared with the ethyl derivative 3a.
All sulfonamides 3al reported here were excellent hCA II inhibitors, with a KIs in the range of 1.9 to 7.0 nM, thus being more effective than AAZ (Table 1). With this highly effective inhibition and small range in the variation of the KIs, the SAR is flat and the only conclusion is that all the explored substitution patterns led to highly effective hCA II inhibitors. This is also the dominant cytosolic isoform, involved in glaucoma, diuresis, respiration, and electrolyte secretion in a multitude of tissues [3,4,5,6,7,8,9,10,11,12], meaning these results are highly significant.
The third cytosolic isoform investigated here, hCA VII, predominantly found in the brain and involved in epileptogenesis and neuropathic pain [16,17,18,19,20,21,22,23,24], was also effectively inhibited by sulfonamides 3al, which showed a KIs in the range of 0.4 to 26.7 nM. Most of these compounds were sub-nanomolar hCA VII inhibitors (e.g., 3b3d, 3g3i, 3k, 3l), being more effective by an order of magnitude compared with the standard AAZ, whereas few of them showed the same potency as AAZ (3e, 3f, 3j) and only the ethyl derivative 3a was a less effective inhibitor compared to AAZ, with a KI of 26.7 nM. Overall, the SAR is extremely simple, and except for the ethyl derivative mentioned above, all the substitution patterns from derivatives 3b3l indicated all compounds are highly effective hCA VII inhibitors.
The tumor-associated, hypoxia-inducible isoform hCA IX was effectively inhibited by sulfonamides 3al, with a KIs in the range of 8.0 to 26. 0 nMh. AAZ has an inhibition constant of 25.8 nM against this isoform. The most effective inhibitors, 3h and 3k, with a KIs of 8.0–9.3 nM, incorporated amino acyl moieties, but all substitution patterns present in compound 3, of the amine or amino acid type, led to highly effective hCA IX inhibition.
Conversely, the β- and γ-CAs from pathogenic organisms investigated here were poorly inhibited by these compounds, which showed activity in the micromolar range, with few exceptions (Table 1). Thus, for VchCAβ, the KIs was in the range of 0.41 to 8.58 µM; for MgCA, in the range of 87.3 nM to 7.67 µM; and for VchCAγ, in the range of 0.27 to 4.45 µM. Notably, 3j compounds, which incorporate the alanyl moiety, showed a good inhibitory effect against the Malassezia enzyme, one of the causative agents of dandruff. Acetazolamide is a highly ineffective MgCA inhibitor, and most other sulfonamides investigated here, although less effective than 3j, showed a better activity compared with the standard sulfonamide CAI. Overall, β- and γ-CAs are less sensitive to inhibition with sulfonamides compared with α-CAs [3,4,5,6,7,8,9,10,11,12,13,14].

4. Materials and Methods

4.1. Chemistry

Amines, 4-sulfamoyl-benzoic acid, buffers, solvents, and acetazolamide (AAZ) were commercially available, obtained as highest purity reagents from Sigma-Aldrich/Merck, Milan, Italy. Nuclear magnetic resonance (1H NMR, 13C NMR) spectra were recorded using a Bruker Avance III 400 MHz spectrometer (Bruker, Billerica, MA, USA) in dimethyl sulfoxide (DMSO-d6I). Chemical shifts are reported in parts per million (ppm) and the coupling constants (J) are expressed in Hertz (Hz). Splitting patterns were designated as follows: s, singlet; d, doublet; t, triplet; m, multiplet; brs, broad singlet; and dd, double of doubles. The assignment of exchangeable protons (OH and NH) was confirmed by the addition of D2O. Analytical thin-layer chromatography (TLC) was performed on Merck silica gel F-254 plates. Flash chromatography purifications were performed on Merck Silica gel 60 (230–400 mesh ASTM) as the stationary phase and MeOH/DCM were used as eluents.

4.1.1. General Procedure to Synthesize Compounds 3al

A solution of 4-carboxybenzene sulfonamide 1 (1.0 eq) in dry dimethylformamide (DMF, 3–5 mL) was treated with primary or secondary amines or amino acids 2al (1.2 eq), then followed by addition of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 1.5 eq.), 1-hydroxy-7-azabenzotriazole (HOAT, 1.5 eq), and triethylamine (Et3N, 3 eq). The reaction continued until the consumption of starting materials (TLC monitoring, 3–24 h) and quenched with water. The title compounds were either obtained from filtration of the precipitates formed followed by washing with water (3a3e, 3h, 3kl) or extracted from ethyl acetate (EtOAc). In the latter, the combined organic layers were washed with H2O (3 × 20 mL), dried over sodium sulfate, filtered, and concentrated in a vacuum to provide a residue that was triturated from dichloromethane (3fg, 3ij).

4.1.2. Characterization of Synthesized Compounds (3al)

N-Ethyl-4-Sulfamoylbenzamide (3a): 140 mg white solid, yield 83%; δH (400 MHz, DMSO-d6) 1.17 (3H, t, J 7.2), 3.33 (2H, m), 7.51 (2H, s, exchange with D2O, SO2NH2), 7.93 (2H, d, J 8.4), 8.02 (2H, d, J 8.4), 8.68 (1H, t, J 7.2 exchange with D2O, NH); δC (100 MHz, DMSO-d6) 15.5, 35.1, 126.5, 128.6, 138.5, 147.0, and 165.8; m/z (ESI positive) 229.0 [M + H]+.
N-Propyl-4-Sulfamoylbenzamide (3b): 120 mg white solid, yield 80%; δH (400 MHz, DMSO-d6) 0.93 (3H, t, J 7.2), 1.58 (2H, m), 3.27 (2H, q, J 7.2), 7.50 (2H, s, exchange with D2O, SO2NH2), 7.93 (2H, d, J 8.4), 8.02 (2H, d, J 8.4), 8.66 (1H, t, J 7.2, exchange with D2O, NH); δC (100 MHz, DMSO-d6) 12.3, 23.2, 42.0, 126.5, 128.7, 138.5, 147.0, 166.0; m/z (ESI positive) 243.1 [M + H]+.
N-(Prop-2-Yn-1-Yl)-4-Sulfamoylbenzamide (3c): 120 mg yellow solid, yield 74%; δH (400 Mhz, DMSO-d6) 3.18 (1H, T, J 2.5), 4.12 (2H, dd, J 5.5, 2.5), 7.52 (2H, s, exchange with D2O, SO2NH2), 7.94 (2H, d, J 8.8), 8.04 (2H, d, J 8.8), 9.16 (1H, t, J 5.5, exchange with D2O, NH); δc (100 Mhz, DMSO-d6) 29.5, 73.9, 81.9, 126.5, 128.8, 137.6, 147.3, 165.8; m/z (ESI Positive) 239.0 [M + H]+. Experimental data in agreement with reported data [61].
4-(Morpholine-4-Carbonyl)Benzenesulfonamide (3d): 10 mg pale yellow solid; 9% yield; δH (400 MHz, DMSO-d6) 3.65 (8H, m), 7.44 (2H, s, exchange with D2O, SO2NH2), 7.63 (2H, d, J 8.0), 7.92 (2H, d, J 8.0); δC (100 MHz, DMSO-d6) 66.9, 66.9, 126.7, 128.5, 139.7, 145.8, 168.8; m/z (ESI positive) 271.1 [M + H]+.
4-(Piperidine-1-Carbonyl)Benzenesulfonamide (3e): 12 mg yellow solid, yield 18%; δH (400 MHz, DMSO-d6) 1.50 (2H, m), 1.65 (4H, m), 3.25 (2H, m), 3.63 (2H, m), 7.48 (2H, s, exchange with D2O, SO2NH2), 7.59 (2H, d, J 8.0), 7.91 (2H, d, J 8.0); δC (100 MHz, DMSO-d6) 26.1, 26.7, 48.8, 126.7, 128.0, 140.7, 145.4, 168.5; m/z (ESI positive) 269.1 [M + H]+.
Methyl (4-Sulfamoylbenzoyl)-dl-Valinate (3f): 12 mg pale yellow solid, yield 10%; δH (400 MHz, DMSO-d6) 0.98 (3H, d, J 6.8), 1.02 (3H, d, J 6.8), 2.23 (1H, m), 3.70 (3H, s), 4.36 (1H, t, J 6.8), 7.53 (2H, s, exchange with D2O, SO2NH2), 7.94 (2H, d, J 8.4), 8.05 (2H, d, J 8.4), 8.83 (1H, d, J 6.8, exchange with D2O, NH); δC (100 MHz, DMSO-d6) 19.9, 20.0, 30.5, 52.6, 59.6, 126.4, 129.2, 137.7, 147.4, 167.0, 172.9; m/z (ESI positive) 315.0 [M + H]+.
Dimethyl (4-Sulfamoylbenzoyl)-d-Glutamate (3g): 14 mg pale yellow solid, yield 16%; δH (400 Mhz, DMSO-d6) 2.07 (2H, m), 2.16 (2H, m), 3.63 (3H, s), 3.70 (3H, s), 4.53 (1H, m), 7.52 (2H, s, exchange with D2O, SO2NH2), 7.94 (2H, d, J 8.8), 8.05 (2H, d, J 8.8), 8.83 (1H, d, J 7.3, exchange with D2O, NH); δC (100 Mhz, DMSO-d6) 26.6, 30.8, 52.3, 52.9, 53.0, 126.5, 129.0, 137.4, 147.5, 166.6, 172.9, 173.5; m/z (ESI Positive) 359.1 [M + H]+.
Methyl (4-Sulfamoylbenzoyl)-l-Leucinate (3h): 37 mg white solid, yield 25%; δH (400 Mhz, DMSO-d6) 0.92 (3H, d, J 6.4), 0.97 (3H, d, J 6.4), 1.63 (1H, m), 1.70–1.86 (2H, m), 3.69 (3H, s), 4.56 (1H, m), 7.52 (2H, s, exchange with D2O, SO2NH2), 7.95 (2H, d, J 8.3), 8.06 (2H, d, J 8.3), 8.94 (1H, d, J 6.4, exchange with D2O, NH); δC (100 Mhz, DMSO-d6) 22.1, 23.7, 25.3, 40.2, 51.9, 52.8, 126.5, 129.0, 137.5, 147.4, 166.5, 173.8; m/z (ESI Positive) 329.01 [M + H]+.
Dimethyl (4-Sulfamoylbenzoyl)-d-Aspartate (3i): 35 mg yellow solid, yield 50%; δH (400 Mhz, DMSO-d6) 2.86–3.04 (2H, m), 3.67 (3H, s), 3.70 (3H, s), 4.89 (1H, m), 7.52 (2H, s, exchange with D2O, SO2NH2), 7.96 (2H, d, J 8.7), 8.03 (2H, d, J 8.7), 9.13 (1H, d, J 7.6, exchange with D2O, NH); δC (100 Mhz, DMSO-d6) 36.2, 50.2, 52.6, 53.2, 126.6, 129.0, 137.2, 147.6, 166.1, 171.3, 171.9; m/z (ESI Positive) 345.0 [M + H]+.
Methyl (4-Sulfamoylbenzoyl)-dl-Alaninate (3j): 14 mg white solid, yield 13%; δH (400 Mhz, DMSO-d6) 1.46 (3H, d, J 7.3), 3,69 (3H, s), 4.54 (1H, m), 7.51 (2H, s, exchange with D2O, SO2NH2), 7.96 (2H, d, J 8.4), 8.06 (2H, d, J 8.4), 9.01 (1H, d, J 7.3, exchange with D2O, NH); δC (100 Mhz, DMSO-d6) 17.6, 49.3, 52.8, 126.5, 129.0, 137.4, 147.4, 166.2, 173.8; m/z (ESI Positive) 287.0 [M + H]+.
Ethyl 4-(4-Sulfamoylbenzamido)Butanoate (3k): 80 mg white solid, yield 58%; δH (400 Mhz, DMSO-d6) 1.20 (3H, t, J 7.2), 1.83 (2H, pent, J 6.8), 2.39 (2H, t, J 6.8), 3.31 (2H, m), 4.09 (2H, q, J 7.2), 7.47 (2H, s, exchange with D2O, SO2NH2), 7.91 (2H, d, J 8.0), 8.01 (2H, d, J 8.0), 8.66 (1H, t, J 6.8, exchange with D2O, NH); δC (100 Mhz, DMSO-d6) 15.0, 25.3, 31.9, 39.6, 60.6, 126.5, 128.7, 138.3, 147.1, 166.1, 173.5; m/z (ESI Positive) 315.0 [M + H]+.
Methyl (4-Sulfamoylbenzoyl)-l-Phenylalaninate (3l): 130 mg white solid, yield 72%; δH (400 Mhz, DMSO-d6) 3.10–3.25 (2H, m), 3.69 (3H, s), 4.70–4.76 (1H, m), 7.24 (1H, m), 7.32 (4H, m), 7.52 (2H, s, exchange with D2O, SO2NH2), 7.93 (2H, d, J 8.4), 7.98 (2H, d, J 8.4), 9.08 (1H, d, J 7.9, exchange with D2O, NH); δC (100 Mhz, DMSO-d6) 37.1, 52.9, 55.2, 126.5, 127.4, 128.9, 129.2, 130.0, 137.4, 138.4, 147.4, 166.3, 172.8; m/z (ESI Positive) 363.0 [M + H]+.

4.2. CA Enzyme Inhibition Assay

An Sx.18Mv-R Applied Photophysics (Oxford, U.K.) stopped-flow instrument was used to assay he catalytic activity of various CA isozymes for CO2 hydration reaction [60]. Phenol red, at a concentration of 0.2 mM, was used as an indicator, working at the absorbance maximum of 557 nm, with 10 mM Hepes (pH 7.5, for α-CAs) or TRIS (pH 8.3, for β- and γ-CAs) as buffers, 0.1 M sodium sulfate (Na2SO4) (for maintaining constant ionic strength), following the CA-catalyzed CO2 hydration reaction for a period of 10 s at 25 °C. The CO2 concentrations ranged from 1.7 to 17 mM for the determination of the kinetic parameters and inhibition constants. For each inhibitor, at least six traces of the initial 5–10% of the reaction were used for determining the initial velocity. The uncatalyzed rates were determined in the same manner and subtracted from the total observed rates. Stock solutions of inhibitors (10 mM) were prepared in distilled-deionized water. Dilutions up to 1 nM were performed thereafter with the assay buffer. Enzyme and inhibitor solutions were pre-incubated together for 15 min (standard assay at room temperature) prior to assay, to allow for the formation of the enzyme–inhibitor complex. The inhibition constants were obtained by non-linear least-squares methods using PRISM 3 and the Cheng-Prusoff equation, as reported earlier [62,63,64,65,66,67,68,69,70,71,72,73,74,75]. All CAs were recombinant proteins produced as reported earlier by our groups [52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76].

5. Conclusions

We report a series of benzamides incorporating 4-sulfamoyl moieties, which were obtained by reacting 4-sulfamoyl benzoic acid with primary and secondary amines and amino acids. These sulfonamides were investigated as inhibitors of several enzymes, including the human (h) isoforms hCA II, VII, and IX, involved in severe pathologies, such as glaucoma, epilepsy, neuropathic pain and cancer; and β- and γ-class CAs from pathogenic bacteria and fungi. hCA II, VII, and IX were inhibited in the low nanomolar or subnanomolar ranges by all investigated sulfonamides, whereas hCA I was slightly less sensitive to inhibition (KIs of 5.3–334 nM). The Vibrio cholerae and Malassezia globosa CAs were generally inhibited in the micromolar range by the sulfonamides reported in the paper. The benzamide-4-sulfonamides constitute a promising class of highly effective CA inhibitors. Further investigations will focus on extending the series of sulfanilamide possessing aliphatic tails with carbamide linkers, such as cyclic and aliphatic and aromatic, to investigate and obtain isoform selective inhibitors for their profiling and possible in vivo applications.

Author Contributions

M.A. synthesized and characterized the CAIs, A.A. performed the stopped-flow analysis. M.B. supervised to study and edited the manuscript. C.T.S. wrote and edited the manuscript. All authors read and approved the final paper

Funding

This research received no external funding

Conflicts of Interest

The authors declare no competing financial interest.

References

  1. Mincione, F.; Starnotti, M.; Menabuoni, L.; Scozzafava, A.; Casini, A.; Supuran, C.T. Carbonic anhydrase inhibitors: 4-sulfamoyl-benzenecarboxamides and 4-chloro-3-sulfamoyl-benzenecarboxamides with strong topical antiglaucoma properties. Bioorg. Med. Chem. Lett. 2001, 11, 1787–1791. [Google Scholar] [CrossRef]
  2. Casini, A.; Scozzafava, A.; Mincione, F.; Menabuoni, L.; Starnotti, M.; Supuran, C.T. Carbonic anhydrase inhibitors: Topically acting antiglaucoma sulfonamides incorporating esters and amides of 3- and 4-carboxybenzolamide. Bioorg. Med. Chem. Lett. 2003, 13, 2867–2873. [Google Scholar] [CrossRef]
  3. Supuran, C.T. Carbonic anhydrases: From biomedical applications of the inhibitors and activators to biotechnological use for CO2 capture. J. Enzyme Inhib. Med. Chem. 2013, 28, 229–230. [Google Scholar] [CrossRef] [PubMed]
  4. Supuran, C.T. How many carbonic anhydrase inhibition mechanisms exist? J. Enzyme Inhib. Med. Chem. 2016, 31, 345–360. [Google Scholar] [CrossRef] [PubMed]
  5. Alterio, V.; Di Fiore, A.; D’Ambrosio, K.; Supuran, C.T.; De Simone, G. Multiple binding modes of inhibitors to carbonic anhydrases: How to design specific drugs targeting 15 different isoforms? Chem. Rev. 2012, 112, 4421–4468. [Google Scholar] [CrossRef] [PubMed]
  6. Abbate, F.; Winum, J.Y.; Potter, B.V.; Casini, A.; Montero, J.L.; Scozzafava, A.; Supuran, C.T. Carbonic anhydrase inhibitors: X-ray crystallographic structure of the adduct of human isozyme II with EMATE, a dual inhibitor of carbonic anhydrases and steroid sulfatase. Bioorg. Med. Chem. Lett. 2004, 14, 231–234. [Google Scholar] [CrossRef] [PubMed]
  7. Capasso, C.; Supuran, C.T. An overview of the alpha-, beta-and gamma-carbonic anhydrases from Bacteria: Can bacterial carbonic anhydrases shed new light on evolution of bacteria? J. Enzyme Inhib. Med. Chem. 2015, 30, 325–332. [Google Scholar] [CrossRef] [PubMed]
  8. Supuran, C.T. Advances in structure-based drug discovery of carbonic anhydrase inhibitors. Expert Opin. Drug Discov. 2017, 12, 61–88. [Google Scholar] [CrossRef] [PubMed]
  9. Supuran, C.T. Structure and function of carbonic anhydrases. Biochem. J. 2016, 473, 2023–2032. [Google Scholar] [CrossRef] [PubMed]
  10. Supuran, C.T. Carbonic anhydrases: Novel therapeutic applications for inhibitors and activators. Nat. Rev. Drug Discov. 2008, 7, 168–181. [Google Scholar] [CrossRef] [PubMed]
  11. Neri, D.; Supuran, C.T. Interfering with pH regulation in tumours as a therapeutic strategy. Nat. Rev. Drug Discov. 2011, 10, 767–777. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Supuran, C.T.; Vullo, D.; Manole, G.; Casini, A.; Scozzafava, A. Designing of novel carbonic anhydrase inhibitors and activators. Curr. Med. Chem. Cardiovasc. Hematol. Agents 2004, 2, 49–68. [Google Scholar] [CrossRef] [PubMed]
  13. Carta, F.; Supuran, C.T. Diuretics with carbonic anhydrase inhibitory action: A patent and literature review (2005–2013). Expert Opin. Ther. Pat. 2013, 23, 681–691. [Google Scholar] [CrossRef] [PubMed]
  14. Temperini, C.; Cecchi, A.; Scozzafava, A.; Supuran, C.T. Carbonic anhydrase inhibitors. Sulfonamide diuretics revisited—Old leads for new applications? Org. Biomol. Chem. 2008, 6, 2499–2506. [Google Scholar] [CrossRef] [PubMed]
  15. Masini, E.; Carta, F.; Scozzafava, A.; Supuran, C.T. Antiglaucoma carbonic anhydrase inhibitors: A patent review. Expert Opin. Ther. Pat. 2013, 23, 705–716. [Google Scholar] [CrossRef] [PubMed]
  16. Scozzafava, A.; Supuran, C.T.; Carta, F. Antiobesity carbonic anhydrase inhibitors: A literature and patent review. Expert Opin. Ther. Pat. 2013, 23, 725–735. [Google Scholar] [CrossRef] [PubMed]
  17. Supuran, C.T. Carbonic anhydrases and metabolism. Metabolites 2018, 8, E25. [Google Scholar] [CrossRef] [PubMed]
  18. Monti, S.M.; Supuran, C.T.; De Simone, G. Anticancer carbonic anhydrase inhibitors: A patent review (2008–2013). Expert Opin. Ther. Pat. 2013, 23, 737–749. [Google Scholar] [CrossRef] [PubMed]
  19. Supuran, C.T. Carbonic Anhydrase Inhibition and the Management of Hypoxic Tumors. Metabolites 2017, 7, E48. [Google Scholar] [CrossRef] [PubMed]
  20. Ward, C.; Langdon, S.P.; Mullen, P.; Harris, A.L.; Harrison, D.J.; Supuran, C.T.; Kunkler, I.H. New strategies for targeting the hypoxic tumour microenvironment in breast cancer. Cancer Treat. Rev. 2013, 39, 171–179. [Google Scholar] [CrossRef] [PubMed]
  21. Garaj, V.; Puccetti, L.; Fasolis, G.; Winum, J.Y.; Montero, J.L.; Scozzafava, A.; Vullo, D.; Innocenti, A.; Supuran, C.T. Carbonic anhydrase inhibitors: Novel sulfonamides incorporating 1,3,5-triazine moieties as inhibitors of the cytosolic and tumour-associated carbonic anhydrase isozymes I, II and IX. Bioorg. Med. Chem. Lett. 2005, 15, 3102–3108. [Google Scholar] [CrossRef] [PubMed]
  22. Casey, J.R.; Morgan, P.E.; Vullo, D.; Scozzafava, A.; Mastrolorenzo, A.; Supuran, C.T. Carbonic anhydrase inhibitors. Design of selective, membrane-impermeant inhibitors targeting the human tumor-associated isozyme IX. J. Med. Chem. 2004, 47, 2337–2347. [Google Scholar] [CrossRef] [PubMed]
  23. Supuran, C.T. Carbonic anhydrase inhibition and the management of neuropathic pain. Expert Rev. Neurother. 2016, 16, 961–968. [Google Scholar] [CrossRef] [PubMed]
  24. Di Cesare Mannelli, L.; Micheli, L.; Carta, F.; Cozzi, A.; Ghelardini, C.; Supuran, C.T. Carbonic anhydrase inhibition for the management of cerebral ischemia: In vivo evaluation of sulfonamide and coumarin inhibitors. J. Enzyme Inhib. Med. Chem. 2016, 31, 894–899. [Google Scholar] [CrossRef] [PubMed]
  25. Margheri, F.; Ceruso, M.; Carta, F.; Laurenzana, A.; Maggi, L.; Lazzeri, S.; Simonini, G.; Annunziato, F.; Del Rosso, M.; Supuran, C.T.; et al. Overexpression of the transmembrane carbonic anhydrase isoforms IX and XII in the inflamed synovium. J. Enzyme Inhib. Med. Chem. 2016, 31, 60–63. [Google Scholar] [CrossRef] [PubMed]
  26. Bua, S.; Di Cesare Mannelli, L.; Vullo, D.; Ghelardini, C.; Bartolucci, G.; Scozzafava, A.; Supuran, C.T.; Carta, F. Design and Synthesis of Novel Nonsteroidal Anti-Inflammatory Drugs and Carbonic Anhydrase Inhibitors Hybrids (NSAIDs-CAIs) for the Treatment of Rheumatoid Arthritis. J. Med. Chem. 2017, 60, 1159–1170. [Google Scholar] [CrossRef] [PubMed]
  27. Maresca, A.; Temperini, C.; Vu, H.; Pham, N.B.; Poulsen, S.A.; Scozzafava, A.; Quinn, R.J.; Supuran, C.T. Non-zinc mediated inhibition of carbonic anhydrases: Coumarins are a new class of suicide inhibitors. J. Am. Chem. Soc. 2009, 131, 3057–3062. [Google Scholar] [CrossRef] [PubMed]
  28. Maresca, A.; Temperini, C.; Pochet, L.; Masereel, B.; Scozzafava, A.; Supuran, C.T. Deciphering the mechanism of carbonic anhydrase inhibition with coumarins and thiocoumarins. J. Med. Chem. 2010, 53, 335–344. [Google Scholar] [CrossRef] [PubMed]
  29. Carta, F.; Maresca, A.; Scozzafava, A.; Supuran, C.T. Novel coumarins and 2-thioxo-coumarins as inhibitors of the tumor-associated carbonic anhydrases IX and XII. Bioorg. Med. Chem. 2012, 20, 2266–2273. [Google Scholar] [CrossRef] [PubMed]
  30. Supuran, C.T. Carbonic anhydrase activators. Future Med. Chem. 2018, 10, 561–573. [Google Scholar] [CrossRef] [PubMed]
  31. Alterio, V.; Cadoni, R.; Esposito, D.; Vullo, D.; Fiore, A.D.; Monti, S.M.; Caporale, A.; Ruvo, M.; Sechi, M.; Dumy, P.; et al. Benzoxaborole as a new chemotype for carbonic anhydrase inhibition. Chem. Commun. 2016, 52, 11983–11986. [Google Scholar] [CrossRef] [PubMed]
  32. Nocentini, A.; Cadoni, R.; Del Prete, S.; Capasso, C.; Dumy, P.; Gratteri, P.; Supuran, C.T.; Winum, J.Y. Benzoxaboroles as Efficient Inhibitors of the β-Carbonic Anhydrases from Pathogenic Fungi: Activity and Modeling Study. ACS Med. Chem. Lett. 2017, 8, 1194–1198. [Google Scholar] [CrossRef] [PubMed]
  33. Tars, K.; Vullo, D.; Kazaks, K.; Leitans, J.; Lends, A.; Grandane, A.; Zalubovskis, R.; Scozzafava, A.; Supuran, C.T. Sulfocoumarins (1,2-benzoxathiine-2,2-dioxides): A class of potent and isoform-selective inhibitors of tumor-associated carbonic anhydrases. J. Med. Chem. 2013, 56, 293–300. [Google Scholar] [CrossRef] [PubMed]
  34. Métayer, B.; Mingot, A.; Vullo, D.; Supuran, C.T.; Thibaudeau, S. New superacid synthesized (fluorinated) tertiary benzenesulfonamides acting as selective hCA IX inhibitors: Toward a new mode of carbonic anhydrase inhibition by sulfonamides. Chem. Commun. 2013, 49, 6015–6017. [Google Scholar] [CrossRef] [PubMed]
  35. Métayer, B.; Mingot, A.; Vullo, D.; Supuran, C.T.; Thibaudeau, S. Superacid synthesized tertiary benzenesulfonamides and benzofuzed sultams act as selective hCA IX inhibitors: Toward understanding a new mode of inhibition by tertiary sulfonamides. Org. Biomol. Chem. 2013, 11, 7540–7549. [Google Scholar] [CrossRef] [PubMed]
  36. Supuran, C.T. Carbon-versus sulphur-based zinc binding groups for carbonic anhydrase inhibitors? J. Enzyme Inhib. Med. Chem. 2018, 33, 485–495. [Google Scholar] [CrossRef] [PubMed]
  37. Di Fiore, A.; Maresca, A.; Supuran, C.T.; De Simone, G. Hydroxamate represents a versatile zinc binding group for the development of new carbonic anhydrase inhibitors. Chem. Commun. 2012, 48, 8838–8840. [Google Scholar] [CrossRef] [PubMed]
  38. Marques, S.M.; Nuti, E.; Rossello, A.; Supuran, C.T.; Tuccinardi, T.; Martinelli, A.; Santos, M.A. Dual inhibitors of matrix metalloproteinases and carbonic anhydrases: Iminodiacetyl-based hydroxamate-benzenesulfonamide conjugates. J. Med. Chem. 2008, 51, 7968–7979. [Google Scholar] [CrossRef] [PubMed]
  39. Bozdag, M.; Carta, F.; Angeli, A.; Osman, S.M.; Alasmary, F.A.S.; AlOthman, Z.; Supuran, C.T. Synthesis of N′-phenyl-N-hydroxyureas and investigation of their inhibitory activities on human carbonic anhydrases. Bioorg. Chem. 2018, 78, 1–6. [Google Scholar] [CrossRef] [PubMed]
  40. Capasso, C.; Supuran, C.T. Bacterial, fungal and protozoan carbonic anhydrases as drug targets. Expert Opin. Ther. Targets 2015, 19, 1689–1704. [Google Scholar] [CrossRef] [PubMed]
  41. Vermelho, A.B.; Da Silva Cardoso, V.; Ricci Junior, E.; Dos Santos, E.P.; Supuran, C.T. Nanoemulsions of sulfonamide carbonic anhydrase inhibitors strongly inhibit the growth of Trypanosoma cruzi. J. Enzyme Inhib. Med. Chem. 2018, 33, 139–146. [Google Scholar] [CrossRef] [PubMed]
  42. de Menezes Dda, R.; Calvet, C.M.; Rodrigues, G.C.; de Souza Pereira, M.C.; Almeida, I.R.; de Aguiar, A.P.; Supuran, C.T.; Vermelho, A.B. Hydroxamic acid derivatives: A promising scaffold for rational compound optimization in Chagas disease. J. Enzyme Inhib. Med. Chem. 2016, 31, 964–973. [Google Scholar] [CrossRef] [PubMed]
  43. Nocentini, A.; Cadoni, R.; Dumy, P.; Supuran, C.T.; Winum, J.Y. Carbonic anhydrases from Trypanosoma cruzi and Leishmania donovani chagasi are inhibited by benzoxaboroles. J. Enzyme Inhib. Med. Chem. 2018, 33, 286–289. [Google Scholar] [CrossRef] [PubMed]
  44. Del Prete, S.; De Luca, V.; De Simone, G.; Supuran, C.T.; Capasso, C. Cloning, expression and purification of the complete domain of the η-carbonic anhydrase from Plasmodium falciparum. J. Enzyme Inhib. Med. Chem. 2016, 31, 54–59. [Google Scholar] [CrossRef] [PubMed]
  45. Supuran, C.T.; Capasso, C. The η-class carbonic anhydrases as drug targets for antimalarial agents. Expert Opin. Ther. Targets 2015, 19, 551–563. [Google Scholar] [CrossRef] [PubMed]
  46. Vullo, D.; Del Prete, S.; Fisher, G.M.; Andrews, K.T.; Poulsen, S.A.; Capasso, C.; Supuran, C.T. Sulfonamide inhibition studies of the η-class carbonic anhydrase from the malaria pathogen Plasmodium Falciparum. Bioorg. Med. Chem. 2015, 23, 526–531. [Google Scholar] [CrossRef] [PubMed]
  47. De Simone, G.; Di Fiore, A.; Capasso, C.; Supuran, C.T. The zinc coordination pattern in the η-carbonic anhydrase from Plasmodium falciparum is different from all other carbonic anhydrase genetic families. Bioorg. Med. Chem. Lett. 2015, 25, 1385–1389. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  48. Modak, J.K.; Liu, Y.C.; Supuran, C.T.; Roujeinikova, A. Structure-Activity Relationship for Sulfonamide Inhibition of Helicobacter pylori α-Carbonic Anhydrase. J. Med. Chem. 2016, 59, 11098–11109. [Google Scholar] [CrossRef] [PubMed]
  49. Buzás, G.M.; Supuran, C.T. The history and rationale of using carbonic anhydrase inhibitors in the treatment of peptic ulcers. In memoriam Ioan Puşcaş (1932–2015). J. Enzyme Inhib. Med. Chem. 2016, 31, 527–533. [Google Scholar] [CrossRef] [PubMed]
  50. Supuran, C.T. Bacterial carbonic anhydrases as drug targets: Toward novel antibiotics? Front. Pharmacol. 2011, 2, 34. [Google Scholar] [CrossRef] [PubMed]
  51. Nishimori, I.; Onishi, S.; Takeuchi, H.; Supuran, C.T. The alpha and beta classes carbonic anhydrases from Helicobacter pylori as novel drug targets. Curr. Pharm. Des. 2008, 14, 622–630. [Google Scholar] [CrossRef] [PubMed]
  52. De Vita, D.; Angeli, A.; Pandolfi, F.; Bortolami, M.; Costi, R.; Di Santo, R.; Suffredini, E.; Ceruso, M.; Del Prete, S.; Capasso, C.; et al. Inhibition of the α-carbonic anhydrase from Vibrio cholerae with amides and sulfonamides incorporating imidazole moieties. J. Enzyme Inhib. Med. Chem. 2017, 32, 798–804. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Del Prete, S.; Vullo, D.; De Luca, V.; Carginale, V.; Ferraroni, M.; Osman, S.M.; AlOthman, Z.; Supuran, C.T.; Capasso, C. Sulfonamide inhibition studies of the β-carbonic anhydrase from the pathogenic bacterium Vibrio cholerae. Bioorg. Med. Chem. 2016, 24, 1115–1120. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Del Prete, S.; Isik, S.; Vullo, D.; De Luca, V.; Carginale, V.; Scozzafava, A.; Supuran, C.T.; Capasso, C. DNA cloning, characterization, and inhibition studies of an α-carbonic anhydrase from the pathogenic bacterium Vibrio cholerae. J. Med. Chem. 2012, 55, 10742–10748. [Google Scholar] [CrossRef] [PubMed]
  55. Del Prete, S.; Vullo, D.; De Luca, V.; Carginale, V.; di Fonzo, P.; Osman, S.M.; AlOthman, Z.; Supuran, C.T.; Capasso, C. Anion inhibition profiles of α-, β- and γ-carbonic anhydrases from the pathogenic bacterium Vibrio cholerae. Bioorg. Med. Chem. 2016, 24, 3413–3417. [Google Scholar] [CrossRef] [PubMed]
  56. Angeli, A.; Del Prete, S.; Osman, S.M.; Alasmary, F.A.S.; AlOthman, Z.; Donald, W.A.; Capasso, C.; Supuran, C.T. Activation studies of the α- and β-carbonic anhydrases from the pathogenic bacterium Vibrio cholerae with amines and amino acids. J. Enzyme Inhib. Med. Chem. 2018, 33, 227–233. [Google Scholar] [CrossRef] [PubMed]
  57. Del Prete, S.; De Luca, V.; Vullo, D.; Osman, S.M.; AlOthman, Z.; Carginale, V.; Supuran, C.T.; Capasso, C. A new procedure for the cloning, expression and purification of the β-carbonic anhydrase from the pathogenic yeast Malassezia globosa, an anti-dandruff drug target. J. Enzyme Inhib. Med. Chem. 2016, 31, 1156–1161. [Google Scholar] [CrossRef] [PubMed]
  58. Nocentini, A.; Vullo, D.; Del Prete, S.; Osman, S.M.; Alasmary, F.A.S.; AlOthman, Z.; Capasso, C.; Carta, F.; Gratteri, P.; Supuran, C.T. Inhibition of the β-carbonic anhydrase from the dandruff-producing fungus Malassezia globosa with monothiocarbamates. J. Enzyme Inhib. Med. Chem. 2017, 32, 1064–1070. [Google Scholar] [CrossRef] [PubMed]
  59. Angiolella, L.; Carradori, S.; Maccallini, C.; Giusiano, G.; Supuran, C.T. Targeting Malassezia species for Novel Synthetic and Natural Antidandruff Agents. Curr. Med. Chem. 2017, 24, 2392–2412. [Google Scholar] [CrossRef] [PubMed]
  60. Khalifah, R.G. The carbon dioxide hydration activity of carbonic anhydrase. I. Stop-flow kinetic studies on the native human isoenzymes B and C. J. Biol. Chem. 1971, 246, 2561–2573. [Google Scholar] [PubMed]
  61. Wilkinson, B.L.; Bornaghi, L.F.; Houston, T.A.; Innocenti, A.; Supuran, C.T.; Poulsen, S.A. A novel class of carbonic anhydrase inhibitors: Glycoconjugate benzene sulfonamides prepared by “click-tailing”. J. Med. Chem. 2006, 49, 6539–6548. [Google Scholar] [CrossRef] [PubMed]
  62. Diaz, J.R.; Fernández Baldo, M.; Echeverría, G.; Baldoni, H.; Vullo, D.; Soria, D.B.; Supuran, C.T.; Camí, G.E. A substituted sulfonamide and its Co (II), Cu (II), and Zn (II) complexes as potential antifungal agents. J. Enzyme Inhib. Med. Chem. 2016, 31, 51–62. [Google Scholar] [CrossRef] [PubMed]
  63. Menchise, V.; De Simone, G.; Alterio, V.; Di Fiore, A.; Pedone, C.; Scozzafava, A.; Supuran, C.T. Carbonic anhydrase inhibitors: Stacking with Phe131 determines active site binding region of inhibitors as exemplified by the X-ray crystal structure of a membrane-impermeant antitumor sulfonamide complexed with isozyme II. J. Med. Chem. 2005, 48, 5721–5727. [Google Scholar] [CrossRef] [PubMed]
  64. Supuran, C.T.; Mincione, F.; Scozzafava, A.; Briganti, F.; Mincione, G.; Ilies, M.A. Carbonic anhydrase inhibitors—Part 52. Metal complexes of heterocyclic sulfonamides: A new class of strong topical intraocular pressure-lowering agents in rabbits. Eur. J. Med. Chem. 1998, 33, 247–254. [Google Scholar] [CrossRef]
  65. Şentürk, M.; Gülçin, İ.; Beydemir, Ş.; Küfrevioğlu, O.İ.; Supuran, C.T. In vitro inhibition of human carbonic anhydrase I and II isozymes with natural phenolic compounds. Chem. Biol. Drug Des. 2011, 77, 494–499. [Google Scholar] [CrossRef] [PubMed]
  66. Fabrizi, F.; Mincione, F.; Somma, T.; Scozzafava, G.; Galassi, F.; Masini, E.; Impagnatiello, F.; Supuran, C.T. A new approach to antiglaucoma drugs: Carbonic anhydrase inhibitors with or without NO donating moieties. Mechanism of action and preliminary pharmacology. J. Enzyme Inhib. Med. Chem. 2012, 27, 138–147. [Google Scholar] [CrossRef] [PubMed]
  67. Krall, N.; Pretto, F.; Decurtins, W.; Bernardes, G.J.; Supuran, C.T.; Neri, D. A Small-Molecule Drug Conjugate for the Treatment of Carbonic Anhydrase IX Expressing Tumors. Angew. Chem. Int. Ed. Engl. 2014, 53, 4231–4235. [Google Scholar] [CrossRef] [PubMed]
  68. Rehman, S.U.; Chohan, Z.H.; Gulnaz, F.; Supuran, C.T. In-vitro antibacterial, antifungal and cytotoxic activities of some coumarins and their metal complexes. J. Enzyme Inhib. Med. Chem. 2005, 20, 333–340. [Google Scholar] [CrossRef] [PubMed]
  69. Clare, B.W.; Supuran, C.T. Carbonic anhydrase activators. 3: Structure-activity correlations for a series of isozyme II activators. J. Pharm. Sci. 1994, 83, 768–773. [Google Scholar] [CrossRef] [PubMed]
  70. Dubois, L.; Peeters, S.; Lieuwes, N.G.; Geusens, N.; Thiry, A.; Wigfield, S.; Carta, F.; McIntyre, A.; Scozzafava, A.; Dogné, J.M.; et al. Specific inhibition of carbonic anhydrase IX activity enhances the in vivo therapeutic effect of tumor irradiation. Radiother. Oncol. 2011, 99, 424–431. [Google Scholar] [CrossRef] [PubMed]
  71. Chohan, Z.H.; Munawar, A.; Supuran, C.T. Transition metal ion complexes of Schiff-bases. Synthesis, characterization and antibacterial properties. Met. Based Drugs 2001, 8, 137–143. [Google Scholar] [CrossRef] [PubMed]
  72. Zimmerman, S.A.; Ferry, J.G.; Supuran, C.T. Inhibition of the archaeal β-class (Cab) and γ-class (Cam) carbonic anhydrases. Curr. Top. Med. Chem. 2007, 7, 901–908. [Google Scholar] [CrossRef] [PubMed]
  73. Supuran, C.T.; Nicolae, A.; Popescu, A. Carbonic anhydrase inhibitors. Part 35. Synthesis of Schiff bases derived from sulfanilamide and aromatic aldehydes: The first inhibitors with equally high affinity towards cytosolic and membrane-bound isozymes. Eur. J. Med. Chem. 1996, 31, 431–438. [Google Scholar] [CrossRef]
  74. Pacchiano, F.; Aggarwal, M.; Avvaru, B.S.; Robbins, A.H.; Scozzafava, A.; McKenna, R.; Supuran, C.T. Selective hydrophobic pocket binding observed within the carbonic anhydrase II active site accommodate different 4-substituted-ureido-benzenesulfonamides and correlate to inhibitor potency. Chem. Commun. 2010, 46, 8371–8373. [Google Scholar] [CrossRef] [PubMed]
  75. Ozensoy Guler, O.; Capasso, C.; Supuran, C.T. A magnificent enzyme superfamily: Carbonic anhydrases, their purification and characterization. J. Enzyme Inhib. Med. Chem. 2016, 31, 689–694. [Google Scholar] [CrossRef] [PubMed]
  76. De Simone, G.; Langella, E.; Esposito, D.; Supuran, C.T.; Monti, S.M.; Winum, J.Y.; Alterio, V. Insights into the binding mode of sulphamates and sulphamides to hCA II: Crystallographic studies and binding free energy calculations. J. Enzyme Inhib. Med. Chem. 2017, 32, 1002–1011. [Google Scholar] [CrossRef] [PubMed]
Figure 1. (A,B) Sulfonamides incorporating benzamide moieties, amino acid (AA) and dipeptide AA moieties [1,2].
Figure 1. (A,B) Sulfonamides incorporating benzamide moieties, amino acid (AA) and dipeptide AA moieties [1,2].
Metabolites 08 00037 g001
Scheme 1. Synthesis of compounds 3al.
Scheme 1. Synthesis of compounds 3al.
Metabolites 08 00037 sch001
Table 1. Inhibition data of human carbonic anhydrase (CA) isoforms hCA I, II, VII, IX, and pathogenic bacteria and fungi β- and γ-CAs with compounds 3a3l in comparison with the standard sulfonamide inhibitor AAZ by a stopped flow carbon dioxide (CO2) hydrase assay [60].
Table 1. Inhibition data of human carbonic anhydrase (CA) isoforms hCA I, II, VII, IX, and pathogenic bacteria and fungi β- and γ-CAs with compounds 3a3l in comparison with the standard sulfonamide inhibitor AAZ by a stopped flow carbon dioxide (CO2) hydrase assay [60].
KI (nM) a
CpdhCA IhCA IIhCA VIIhCA IXVchCAβMgCAVchCAγ
3a3345.326.715.970827669929
3b8.23.50.426.076803921636
3c67.61.90.622.97415781383
3d8.76.20.810.785875880693
3e29.77.06.218.17493985453
3f57.84.53.716.0817255004458
3g8.25.20.619.7862632503
3h5.63.70.48.0719763891
3i75.76.10.712.19106946744
3j85.36.13.721.541287.3271
3k5.34.00.49.39536695756
3l5.63.30.519.2663517409
AAZ250.012.15.725.845174000473
a Mean from three different assay using a stopped flow technique. Errors were in the range of ±5% to 10% of the reported values.

Share and Cite

MDPI and ACS Style

Abdoli, M.; Bozdag, M.; Angeli, A.; Supuran, C.T. Benzamide-4-Sulfonamides Are Effective Human Carbonic Anhydrase I, II, VII, and IX Inhibitors. Metabolites 2018, 8, 37. https://doi.org/10.3390/metabo8020037

AMA Style

Abdoli M, Bozdag M, Angeli A, Supuran CT. Benzamide-4-Sulfonamides Are Effective Human Carbonic Anhydrase I, II, VII, and IX Inhibitors. Metabolites. 2018; 8(2):37. https://doi.org/10.3390/metabo8020037

Chicago/Turabian Style

Abdoli, Morteza, Murat Bozdag, Andrea Angeli, and Claudiu T. Supuran. 2018. "Benzamide-4-Sulfonamides Are Effective Human Carbonic Anhydrase I, II, VII, and IX Inhibitors" Metabolites 8, no. 2: 37. https://doi.org/10.3390/metabo8020037

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop