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Capasso, C.; Supuran, C. Carbonic Anhydrases Inhibitors. Encyclopedia. Available online: https://encyclopedia.pub/entry/9381 (accessed on 24 April 2024).
Capasso C, Supuran C. Carbonic Anhydrases Inhibitors. Encyclopedia. Available at: https://encyclopedia.pub/entry/9381. Accessed April 24, 2024.
Capasso, Clemente, Claudiu Supuran. "Carbonic Anhydrases Inhibitors" Encyclopedia, https://encyclopedia.pub/entry/9381 (accessed April 24, 2024).
Capasso, C., & Supuran, C. (2021, May 07). Carbonic Anhydrases Inhibitors. In Encyclopedia. https://encyclopedia.pub/entry/9381
Capasso, Clemente and Claudiu Supuran. "Carbonic Anhydrases Inhibitors." Encyclopedia. Web. 07 May, 2021.
Carbonic Anhydrases Inhibitors
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This entry is adapted from the peer-reviewed paper 10.3390/ijms22094324

Carbon dioxide (CO2), a vital molecule of the carbon cycle, is a critical component in living organisms’ metabolism, performing functions that lead to the building of compounds fundamental for the life cycle. In all living organisms, the CO2/bicarbonate (HCO3−) balancing is governed by a superfamily of enzymes, known as carbonic anhydrases (CAs, EC 4.2.1.1). CAs catalyze the pivotal physiological reaction, consisting of the reversible hydration of the CO2 to HCO3− and protons.

carbon dioxide carbonic anhydrases CO2-sensing antifungals CA inhibitors

1. Introduction

The fossil fuel use, land-use changes as well as the natural carbon sources on land and in oceans has drastically influenced the growth rate of atmospheric CO2 [1]. In the last twenty years, human CO2 emissions have been enormously accelerated, considering the overall rise in energy consummation, the greater use of coal to produce energy, increased consumption per capita, and population development [1]. Changes in atmospheric CO2 mirrors the balance between carbon emissions due to human activity and the dynamics of many terrestrial and ocean processes that remove or emit CO2 [2]. The increased CO2 favors the photosynthetic activity of plants and increases carbon storage in the plants themselves and soil [2]. Cheng et al. believe that carbon storage seems to be mainly due to fungi (the so-called Arbuscular Mycorrhizal Fungi), which settle near the roots of about 80% of plant species, providing essential nutrients to the plants in exchange for carbohydrates [3]. CO2, a key molecule of the carbon cycle, is a critical component in the metabolism of living organisms, performing functions which lead to the building of compounds fundamental for the life cycle [4]. At the same time, CO2 is a waste product since it is the end-product of respiration, reaching a concentration of about 5% in the human bloodstream and tissues. This concentration is higher than the level of CO2 in the atmosphere (about 0.036%) [4]. Intriguingly, opportunistic and pathogenic fungi sense the CO2 difference, which influences fungal differentiation, determining the expression of those fungal features essential for virulent or non-virulent traits [5]. Pathogenic fungi are responsible for superficial diseases such as dermatophytes (infections of skin, hairs, and nails), or may lead to systemic illness (candidiasis, aspergillosis, cryptococcosis, mucormycosis, and others) [6][7][8][9]. Two molecules are crucial for the fungal CO2-sensing: (1) bicarbonate (HCO3−), which is a meiosis- and sporulation-promoting ion [10], and (2) adenylyl cyclase (AC) that is involved in the spore formation [11][12][13]. In Cryptococcus, bicarbonate directly activates a soluble form of AC necessary for the polysaccharide capsule formation [14][15][16][17]. AC catalyzes cyclic AMP (cAMP) synthesis, an essential intracellular regulatory molecule, which permits a link between CO2/HCO3−/pH chemosensing and signaling [18]. cAMP signaling is involved in many metabolic reactions as well as in fungal development and virulence [19]. The fungal virulence of Cryptococcus neoformans, the etiological agent responsible for cryptococcosis [9], is induced by high CO2 levels in mammalian hosts, causing the production of a massive polysaccharide capsule, which inhibits phagocytosis and impairs cell-mediated immune response [14][15][20]. However, it also true that other factors than high CO2 levels contribute to inhibit mating in the host as demonstrated by the use of a murine model of cryptococcosis. The carbonic anhydrase mutants for Can1 and Can2 (the two CAs encoded by the genome of C. neoformans) were both as virulent as wild type (wt), and quantitative measurements of fungal burden demonstrated that the Can2 mutant proliferates equivalently to the wt strain in the lungs and brain of infected animals [20]. In Candida albicans, the CO2 levels, through the relationship of bicarbonate, adenyl cyclase and cAMP, influence the growth of filamentous structures (hyphae), which are associated with the fungal virulence, adherence, secretion of hydrolases, and cell death in the hosts [19][21][22][23]. Twenty-six thiazolidines against several Candida spp. and Gram-positive and Gram-negative bacteria were tested. Although lacking significant antibacterial activity, the tested compounds exhibited selective antifungal activity with an equal potency to fluconazole and clotrimazole. Interestingly, CA was considered the putative target that could mediate the antifungal effects of these compounds [24].

Fungal Enzymes Involved in the Bicarbonate Production (Physiological Role and Structural Features)

Cloning of the genomes of several pathogenic and non-pathogenic fungi provided the opportunity to identify a superfamily of ubiquitous metalloenzymes, known as carbonic anhydrases (CAs, EC 4.2.1.1), which catalyze a pivotal physiological reaction, consisting of the reversible hydration of the carbon dioxide to bicarbonate and protons [25][26][27][28][29][30][31]. The spontaneous reversible CO2 hydration reaction in the absence of the catalyst occurs very slowly with a rate constant of 0.15 s−1, which arrives at 50 s−1 for the reverse reaction of bicarbonate dehydration at the physiological pH [31]. CA increases the velocity of the CO2 hydration reaction up to 104-106-fold [31].

The CA superfamily is ubiquitously distributed in all living organisms and classified into eight CA classes (α, β, γ, δ, ζ, η, θ, and ι). Their distribution is quite varied from plants, animals, bacteria, and archaea. [25][26][27][28][29]. The genome of mammals, for example, encodes only for the α-CA class, of which 15 isoforms have been identified, which accomplish specialized functions in various tissues and organs [32][33][34][35][36]. In plants, α and β-CAs actively participate in photosynthesis and biosynthetic reactions associated with it, as well as in some aforementioned processes [37]. In Bacteria, Archaea, and cyanobacteria, α, β, γ, and ι -CA classes are present. Their role is to balance the CO2/HCO3− concentration ratio and a role in the carbon dioxide fixation [29][30][31][37][38][39]. Marine diatoms encode for α- δ-,ζ-, θ- and ι-CAs, which are involved in carbon dioxide fixation and metabolism [40][41][42]. In protozoa have been detected α- and η-CAs. Probably, the η-CA-class, recently discovered, has a pivotal role in de novo purine/pyrimidine biosynthetic pathways [43].

The fungal CO2-sensing, related to the CO2/HCO3−/pH-sensing, is directly stimulated by HCO3− produced in a CA-dependent manner. In the fungal kingdom, the typical CA class identified is represented by β-class, and the majority of fungi encode at least one β-CA [13][44][45]. The genomes of basidiomycetous and hemiascomycetous yeasts encode only for β-CAs. In contrast, most filamentous ascomycetes contain multiple β-CA genes and, in some of them, it is possible to find genes encoding for α-CAs [13][44][45]. Here, some examples demonstrating that CAs are abundant in fungi and yeasts (the last are microscopic fungi consisting of solitary cells that reproduce by budding) as reported in the following examples. Saccharomyces cerevisiae, Candida albicans, and Candida glabrata have only one β-CA, whereas multiple copies of β-CA and α-CA-encoding genes were reported in other fungi [44][45]. Recently, it has been evidenced that CAs play an important role in fungal pathogen sensing and the control of sexual growth [44][45]. The β-CAs identified in Candida albicans and Candida glabrata indicated with the acronyms CaNce103 and CgNce103, respectively, are necessary for the development of these fungi in environments characterized by low-oxygen conditions, such as the skin [44][45]. The CA (Can2) encoded by the genome of Cryptococcus neoformans allows the growth of the yeast in its natural habitat. It is relevant to note how the link between AC, cAMP signaling, and CO2/HCO3− sensing is conserved in most fungi since it is an essential mediator of fungal metabolism and pathogenesis [13][44][45]. Again, the gene Nce103 identified in the genome of Saccharomyces cerevisiae encodes for a β-CA (ScCA), which is involved in the production of the bicarbonate essential for the enzyme catalyzing carboxylation reactions, such as the pyruvate carboxylase (PC), acetyl-CoA carboxylase (ACC), carbamoyl phosphate synthase (CPSase), and phosphoribosylaminoimidazole (AIR) carboxylase [46][47].

In 2009, the first crystal structure of the β-CA encoded in the genome of a fungus, i.e., Cryptococcus neoformans, was reported by Schlicker and coworkers [45]. It showed a dimeric organization similar to that found in the CA belonging to the plant-type β-class (the two cysteines and a histidine responsible for zinc coordination are conserved in the active site of such enzymes). Intriguingly, a Can2 (acronym used for the CA from C. neoformans) three-dimensional structure showed a peculiar N-terminal extension, which interacts with the entrance of the catalytic pocket of the dimer. The N-terminus is an internal regulator or an interaction site for a regulatory protein, affecting the Can2 activity [45]. It can be considered a switch for the activation/inactivation of the protein, which is regulated by physiological factors, like pH, small molecule, or proteins. [45].

In 2011, the structure of the first fungal α-CA was obtained, which was identified in the fungus Aspergillus oryzae [48]. Like for other α-CAs, the enzyme showed a central core formed by a twisted β sheet consisting of eight mostly anti-parallel strands. The ion cofactor resulted in an atom of Zn(II) coordinated to the three histidines of the catalytic pocket, which is at the bottom of a deep cavity in the protein center [48].

In 2014, the structures of two β-CAs belonging to the fungus Sordaria macrospora were resolved by X-ray crystallography [49]. Like Can2, the two β-CAs from S. macrospora showed a high structural similarity with plant-like β-CAs, but it was assembled in a tetrameric and not a dimeric form. The two CAs (CAS1 and CAS2) were distinguished for the type of conformations they assumed: CAS1 resulted in the open “type- I” conformation, while the CAS2 adopted a close “type-II” conformation [49]. Finally, between 2020 and 2021, CafA and CafB, two of the four β-CAs encoded by the genome of the fungus Aspergillus fumigatus, were crystallized and the structure resolved at 1.8 and 2.0 Å, respectively [50][51]. The catalytic sites of CafA and CafB look similar to those of other β-CAs. CafA showed the typical open conformation. Surprisingly, CafB revealed a unique active site at a low pH or in an oxidative environment, resulting in an inactive enzyme, with a disulfide bond formed by the two zinc-ligating cysteines [50]. Of course, CafB also adopts the typical active/inactive configurations in which a conserved aspartic acid is implicated in switching the enzyme in its open/closed state [52].

2. Main Class of CA Inhibitors (Sulfonamides and Anions)

2.1. Substituted Benzene-Sulfonamides

The first antimicrobial drug widely used in clinical settings was Prontosil [53], a sulfanilamide prodrug, which is isosteric/isostructural with p-aminobenzoic acid (PABA), the substrate of dihydropteroate synthase (DHPS) [54][55]. After sulfanilamide, a range of analogs, the sulfa drug class, are still used as antibacterials, even if many of them show substantial drug resistance issues. Sulfa drugs are derived from sulfonamides, and the presence of primary sulfonamide moieties in sulfanilamide characterized most of the investigated CAIs until recently [32][56][57][58]. Primary sulfonamides/sulfamates/sulfamides possess the general formula R-X-SO2NH2, where R can be an aromatic, heterocyclic, aliphatic, or sugar scaffold, X = nothing, O or NH (Figure 1).

Ijms 22 04324 g001 550

Figure 1. Sulfonamide/sulfamate/sulfamide of types 1–24 (pink background) and AAZ-EPA (gray background) investigated as fungal CA inhibitors. Legend: AAZ, acetazolamide; MZA, methazolamide; EZA, ethoxzolamide; DCP, dichlorophenamide; DZA, dorzolamide; BRZ, brinznolamide; BZA, benzolamide; TPM, topiramate; ZNS, zonisamide; SLP, sulpiride; IND, indisulam; VLX, valdecoxib; CLX, celecoxib; SLT, sulthiame; HCT, hydrochlorothiazide; FAM, famotidine; EPA, epacadostat.

Most of the sulfonamides acting as CAIs bind Zn (II) in a tetrahedral geometry, showing an extended network of hydrogen bonds with the enzyme amino acid residues, as seen by the enzyme-inhibitor X-ray crystallographic data [32][58][59]. The aromatic/heterocyclic part of the inhibitor interacts with the hydrophilic and hydrophobic residues of the catalytic cavity [32][58]. Compounds containing -SO2NH2 group, including clinically licensed drugs, are generally considered CAIs [27][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75]. Some examples include: AAZ, MZA, EZA, and DCP, which are systemically acting antiglaucoma CAIs; DZA and BRZ are antiglaucoma agents; BZA belongs to the same pharmacological class; ZNS, SLT, and TPM are antiepileptic drugs; and SLP and IND, with COX2 selective inhibitors CLX and VLX. The diuretic hydrochlorothiazide (HCT) is also known to act as a CAI [35][76][77]. FAM is a competitive histamine H2-receptor antagonist [76], and EPA is an inhibitor of the heme-containing enzyme, indoleamine 2,3-dioxygenase-1 (IDO1), but they also act as CAIs [77] (see Figure 1). Table 1 shows selected inhibition data with some of these compounds against selected fungal CAs.

Table 1. Inhibition data of human isoenzymes (CA I and CA II) and fungal CAs (MreCA, MgCA, CAS1, CAS2, CAS3; Figure 1) by a stopped-flow CO2 hydrase assay. The other fungal CAs have been previously reviewed by Elleuche and Poggeler (see references [78][79]).

Inhibitor KI (nM) *
hCA I 1
(α-CA)		 hCA II 1
(α-CA)		 MgCA 2
(β-CA)		 MreCA 2
(β-CA)		 CAS1 1
(β-CA)		 CAS2 1
(β-CA)		 CAS3 1
(β-CA)
1 28,000 300 980 412 361 386 90
2 25,000 240 24.5 462 144 3480 84
3 79 8 15.2 >10,000 225 3630 83
4 78,500 320 674 404 47.1 6900 560
5 25,000 170 17.4 >10,000 323 8720 726
6 21,000 160 7.9 >10,000 241 7650 441
7 8300 60 11.6 459 43.2 7360 585
8 9800 110 12.1 >10,000 79.6 9120 2078
9 6500 40 34.9 >10,000 580 12,000 712
10 7300 54 54.3 >10,000 >50,000 23,500 350
11 5800 63 9 676 890 18,700 235
12 8400 75 9.2 >10,000 3350 >50,000 90
13 8600 60 7900 >10,000 8650 48.1 88
14 9300 19 8500 >10,000 7215 280 94
15 5500 80 23.6 >10,000 3160 143 605
16 9500 94 10.4 651 4520 92.5 82
17 21,000 125 6.3 >10,000 >50,000 390 507
18 164 46 6.8 >10,000 4443 3250 226
19 109 33 3500 779 475 6760 91
20 6 2 23.4 91 363 9880 85
21 69 11 11.8 740 4550 4060 95
22 164 46 9.4 374 1985 25,200 85
23 109 33 4530 >10,000 282 >50,000 89
24 95 30 256 >10,000 294 >50,000 84
AAZ 250 12 7600 10 445 816 94
MZA 50 14 7455 390 421 8140 91
EZA 25 8 3800 379 440 3170 95
DCP 1200 38 34.6 306 1220 5790 73
DZA 50,000 9 7900 81 360 742 274
BRZ 45,000 3 8400 70 451 739 61
BZA 15 9 48.2 715 2115 410 54
TPM 250 10 146 383 414 673 363
ZNS 56 35 765 >10,000 1820 1885 710
SLP 1200 40 32 485 1715 670 493
IND 31 15 n.d. 87 4240 216 94
VLX 54,000 43 3150 77 4425 3730 831
CLX 50,000 21 3480 140 2513 857 669
SLT 374 9 n.d. 67 3210 496 4838
SAC 18,540 5959 n.d. 620 5280 7075 191
HCT 328 290 n.d. 850 3350 6680 545
FAM n.d. n.d. n.d. >10,000 n.d. n.d. n.d.
EPA n.d. n.d. n.d. n.d. n.d. n.d. n.d.

* Errors were in the range of ±5–10% on three different assays. 1 From reference [80] and [81]; 2 From reference [82]; n.d.: not detected.

2.2. Inorganic Metal-Complexing Anions or More Complicated Species

These CA inhibitors include inorganic anions as well as several more complex species such as carboxylates, which are in fact organic anions [58][59]. Anions may bind either in the tetrahedral geometry of the metal ion or as trigonal–bipyramidal adducts [83]. Anion inhibitors show KIs in a millimolar range, diversely from the sulfonamides mentioned above, which is generally showed as KIs in the micro to nanomolar range. But their investigation as CA inhibitors offers the possibility to better understand the inhibition/catalytic mechanisms of the CAs, for improving the design of novel types of inhibitors that may have clinical applications [58][59]. A list of anions and their CA inhibitory action against selected fungal CAs is shown in Table 2.

Table 2. Inhibition constants obtained using anionic inhibitors versus the α-CA isozymes of human origin (hCA I and hCA II), and Table 1. CAS2, CAS3; for the acronyms, see the text) by a stopped flow CO2 hydrase assay.

Anion KI (mM) *
hCA I 1
(α-CA)		 hCA II 1
(α-CA)		 MgCA 2
(β-CA)		 MreCA 2
(β-CA)		 CAS1 1
(β-CA)		 CAS2 1
(β-CA)		 CAS3 1
(β-CA)
F− >300 >300 7.13 >50 >100 >100 >100
Cl− 6 200 7.98 >50 9.2 >100 >100
Br− 4 63 18.6 >50 9.3 >100 >100
I− 0.3 26 8.73 8.6 8.6 7.7 9.9
CNO− 0.0007 0.03 6.81 >50 0.9 0.82 3.2
SCN− 0.2 1.60 8.39 >50 5.4 5.6 7.3
CN− 0.0005 0.02 7.19 >50 0.94 0.75 8.7
N3− 0.0012 1.51 45.2 >50 >100 6.1 7.2
NO2− 8.4 63 7.56 >50 >100 >100 8.3
NO3− 7 35 8.13 9 >100 >100 8.5
HCO3− 12 85 0.59 0.86 3.3 7.3 >100
CO32− 15 73 >100 >50 >100 8.8 8
HSO3− 18 89 >100 >50 3.3 7.3 >100
SO42− 63 >200 19.5 >50 >100 4.8 >100
HS− 0.0006 0.04 11.9 >50 0.89 8.5 8.3
SnO32− 0.57 0.83 5.07 0.56 4.3 0.92 7.9
SeO42− 118 112 7.41 1.7 2.4 9.2 3.4
TeO42− 0.66 0.92 5.75 0.56 2.5 6.3 8.1
OsO52− 0.92 0.95 6.16 8.5 n.d. n.d. n.d.
P2O74− 25.77 48.50 6.03 >50 3.1 0.96 >100
V2O74− 0.54 0.57 6.89 >50 >100 1.4 >100
B4O72− 0.64 0.95 8.45 0.4 6.7 6.9 5.9
ReO4− 0.11 0.75 16.7 >50 8.2 >100 8.8
RuO4− 0.101 0.69 8.82 7.4 3.9 >100 9.2
S2O82− 0.107 0.084 >100 >50 5 >100 >100
SeCN− 0.085 0.086 1.73 0.65 2.9 9.3 7.1
CS32− 0.0087 0.0088 1.77 0.92 0.79 >100 8.6
Et2NCS2− 0.00079 0.0031 0.30 0.075 0.38 0.93 0.89
CF3SO3− n.d. n.d. 2.28 4.5 n.d. n.d. n.d.
PF6− n.d. n.d. 6.47 3.9 n.d. n.d. n.d.
ClO4− >200 >200 >100 9.2 >100 >100 >100
BF4− >200 >200 >100 383 >100 >100 >100
FSO3− 0.79 0.46 4.06 >50 0.93 8.4 >100
NH(SO3)22− 0.31 0.76 21.4 >50 0.88 9.2 >100
H2NSO2NH 0.31 1.13 0.094 0.72 0.084 0.048 0.094
H2NSO3H 0.021 0.39 0.083 7.7 0.069 0.072 0.095
Ph-B(OH)2 58.6 23.1 0.089 8.7 0.009 0.056 0.097
Ph-AsO3H2 31.7 49.2 0.090 0.83 0.035 0.054 0.091

* Errors were in the range of ±5–10% on three different assays. 1 From reference [84]; 2 From reference [85]; n.d.: not detected.

Anions inhibit fungal CAs by coordinating to the metal ion within the enzyme active site, as exemplified in Figure 2 for Can2 complexed with acetate. As for all β-CAs, Can2 is a dimer and the active site contains amino acid residues from both monomers. The zinc ion is coordinated as shown in Figure 2, by Cys68, His124, and Cys127, whereas acetate is the fourth zin ligand, being coordinated monodentately by one of the oxygen atoms. The same type of inhibition mechanism is valid for all anions shown in Table 2, although few X-ray crystal structures of such adducts are available to date [45].

Ijms 22 04324 g002 550

Figure 2. Active site view of Can2 (pdb 2W3N) complexed to the anion inhibitor acetate [45]. Protomers A and B are colored green and cyan respectively. Residues from protomers A and B are labeled black and light blu, respectively. The Zn2+ ion, represented as a grey sphere, is coordinated by two cysteines and one histidine residue from monomer A and by one acetate ion as a ligand. The salt bridge in the Asp-Arg dyad is represented as a yellow dashed line.

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  30. 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. Enzym. Inhib. Med. Chem. 2015, 30, 325–332.
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  38. Supuran, C.T.; Capasso, C. Carbonic Anhydrase from Porphyromonas Gingivalis as a Drug Target. Pathogens 2017, 6, 30.
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  40. Rogato, A.; Del Prete, S.; Nocentini, A.; Carginale, V.; Supuran, C.T.; Capasso, C. Phaeodactylum tricornutum as a model organism for testing the membrane penetrability of sulphonamide carbonic anhydrase inhibitors. J. Enzym. Inhib. Med. Chem. 2019, 34, 510–518.
  41. Angeli, A.; Pinteala, M.; Maier, S.S.; Del Prete, S.; Capasso, C.; Simionescu, B.C.; Supuran, C.T. Inhibition of alpha-, beta-, gamma-, delta-, zeta- and eta-class carbonic anhydrases from bacteria, fungi, algae, diatoms and protozoans with famotidine. J Enzym. Inhib. Med. Chem. 2019, 34, 644–650.
  42. Berrino, E.; Bozdag, M.; Del Prete, S.; Alasmary, F.A.S.; Alqahtani, L.S.; AlOthman, Z.; Capasso, C.; Supuran, C.T. Inhibition of alpha-, beta-, gamma-, and delta-carbonic anhydrases from bacteria and diatoms with N’-aryl-N-hydroxy-ureas. J. Enzym. Inhib. Med. Chem. 2018, 33, 1194–1198.
  43. Angeli, A.; Del Prete, S.; Alasmary, F.A.S.; Alqahtani, L.S.; AlOthman, Z.; Donald, W.A.; Capasso, C.; Supuran, C.T. The first activation studies of the eta-carbonic anhydrase from the malaria parasite Plasmodium falciparum with amines and amino acids. Bioorg. Chem. 2018, 80, 94–98.
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  45. Schlicker, C.; Hall, R.A.; Vullo, D.; Middelhaufe, S.; Gertz, M.; Supuran, C.T.; Muhlschlegel, F.A.; Steegborn, C. Structure and inhibition of the CO2-sensing carbonic anhydrase Can2 from the pathogenic fungus Cryptococcus neoformans. J. Mol. Biol. 2009, 385, 1207–1220.
  46. Isik, S.; Kockar, F.; Aydin, M.; Arslan, O.; Guler, O.O.; Innocenti, A.; Scozzafava, A.; Supuran, C.T. Carbonic anhydrase inhibitors: Inhibition of the beta-class enzyme from the yeast Saccharomyces cerevisiae with sulfonamides and sulfamates. Bioorg. Med. Chem. 2009, 17, 1158–1163.
  47. Isik, S.; Kockar, F.; Arslan, O.; Guler, O.O.; Innocenti, A.; Supuran, C.T. Carbonic anhydrase inhibitors. Inhibition of the beta-class enzyme from the yeast Saccharomyces cerevisiae with anions. Bioorg. Med. Chem. Lett. 2008, 18, 6327–6331.
  48. Cuesta-Seijo, J.A.; Borchert, M.S.; Navarro-Poulsen, J.C.; Schnorr, K.M.; Mortensen, S.B.; Lo Leggio, L. Structure of a dimeric fungal alpha-type carbonic anhydrase. FEBS Lett. 2011, 585, 1042–1048.
  49. Lehneck, R.; Neumann, P.; Vullo, D.; Elleuche, S.; Supuran, C.T.; Ficner, R.; Poggeler, S. Crystal structures of two tetrameric beta-carbonic anhydrases from the filamentous ascomycete Sordaria macrospora. FEBS J. 2014, 281, 1759–1772.
  50. Kim, S.; Yeon, J.; Sung, J.; Kim, N.J.; Hong, S.; Jin, M.S. Structural insights into novel mechanisms of inhibition of the major beta-carbonic anhydrase CafB from the pathogenic fungus Aspergillus fumigatus. J. Struct. Biol. 2021, 213, 107700.
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  54. Capasso, C.; Supuran, C.T. Sulfa and trimethoprim-like drugs—Antimetabolites acting as carbonic anhydrase, dihydropteroate synthase and dihydrofolate reductase inhibitors. J. Enzym. Inhib. Med. Chem. 2014, 29, 379–387.
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  56. Supuran, C.T. Carbonic anhydrase inhibition and the management of neuropathic pain. Expert Rev. Neurother. 2016, 16, 961–968.
  57. Supuran, C.T. Drug interaction considerations in the therapeutic use of carbonic anhydrase inhibitors. Expert Opin. Drug Metab. Toxicol. 2016, 12, 423–431.
  58. Supuran, C.T. Advances in structure-based drug discovery of carbonic anhydrase inhibitors. Expert Opin. Drug Discov. 2017, 12, 61–88.
  59. Supuran, C.T. How many carbonic anhydrase inhibition mechanisms exist? J. Enzym. Inhib. Med. Chem. 2016, 31, 345–360.
  60. Vullo, D.; Del Prete, S.; Fisher, G.M.; Andrews, K.T.; Poulsen, S.A.; Capasso, C.; Supuran, C.T. Sulfonamide inhibition studies of the eta-class carbonic anhydrase from the malaria pathogen Plasmodium falciparum. Bioorg. Med. Chem. 2015, 23, 526–531.
  61. Vullo, D.; De Luca, V.; Del Prete, S.; Carginale, V.; Scozzafava, A.; Capasso, C.; Supuran, C.T. Sulfonamide inhibition studies of the gamma-carbonic anhydrase from the Antarctic bacterium Pseudoalteromonas haloplanktis. Bioorg. Med. Chem. Lett. 2015, 25, 3550–3555.
  62. Vullo, D.; De Luca, V.; Del Prete, S.; Carginale, V.; Scozzafava, A.; Capasso, C.; Supuran, C.T. Sulfonamide inhibition studies of the gamma-carbonic anhydrase from the Antarctic cyanobacterium Nostoc commune. Bioorg. Med. Chem. 2015, 23, 1728–1734.
  63. Dedeoglu, N.; DeLuca, V.; Isik, S.; Yildirim, H.; Kockar, F.; Capasso, C.; Supuran, C.T. Sulfonamide inhibition study of the beta-class carbonic anhydrase from the caries producing pathogen Streptococcus mutans. Bioorg. Med. Chem. Lett. 2015, 25, 2291–2297.
  64. Alafeefy, A.M.; Ceruso, M.; Al-Tamimi, A.M.; Del Prete, S.; Supuran, C.T.; Capasso, C. Inhibition studies of quinazoline-sulfonamide derivatives against the gamma-CA (PgiCA) from the pathogenic bacterium, Porphyromonas gingivalis. J. Enzym. Inhib. Med. Chem. 2015, 30, 592–596.
  65. Alafeefy, A.M.; Abdel-Aziz, H.A.; Vullo, D.; Al-Tamimi, A.M.; Awaad, A.S.; Mohamed, M.A.; Capasso, C.; Supuran, C.T. Inhibition of human carbonic anhydrase isozymes I, II, IX and XII with a new series of sulfonamides incorporating aroylhydrazone-, [1,2,4]triazolo [3,4-b][1,3,4]thiadiazinyl- or 2-(cyanophenylmethylene)-1,3,4-thiadiazol-3(2H)-yl moieties. J. Enzym. Inhib. Med. Chem. 2015, 30, 52–56.
  66. Diaz, J.R.; Fernandez Baldo, M.; Echeverria, G.; Baldoni, H.; Vullo, D.; Soria, D.B.; Supuran, C.T.; Cami, G.E. A substituted sulfonamide and its Co (II), Cu (II), and Zn (II) complexes as potential antifungal agents. J. Enzym. Inhib. Med. Chem. 2016, 31 (Suppl. S2), 51–62.
  67. Del Prete, S.; Vullo, D.; De Luca, V.; Carginale, V.; Osman, S.M.; AlOthman, Z.; Supuran, C.T.; Capasso, C. Comparison of the sulfonamide inhibition profiles of the alpha-, beta- and gamma-carbonic anhydrases from the pathogenic bacterium Vibrio cholerae. Bioorg. Med. Chem. Lett. 2016, 26, 1941–1946.
  68. Del Prete, S.; Vullo, D.; De Luca, V.; Carginale, V.; Osman, S.M.; AlOthman, Z.; Supuran, C.T.; Capasso, C. Cloning, expression, purification and sulfonamide inhibition profile of the complete domain of the eta-carbonic anhydrase from Plasmodium falciparum. Bioorg. Med. Chem. Lett. 2016, 26, 4184–4190.
  69. Abdel Gawad, N.M.; Amin, N.H.; Elsaadi, M.T.; Mohamed, F.M.; Angeli, A.; De Luca, V.; Capasso, C.; Supuran, C.T. Synthesis of 4-(thiazol-2-ylamino)-benzenesulfonamides with carbonic anhydrase I, II and IX inhibitory activity and cytotoxic effects against breast cancer cell lines. Bioorg. Med. Chem. 2016, 24, 3043–3051.
  70. Supuran, C.T. Legionella pneumophila Carbonic Anhydrases: Underexplored Antibacterial Drug Targets. Pathogens 2016, 5, 44.
  71. Nishimori, I.; Vullo, D.; Minakuchi, T.; Scozzafava, A.; Capasso, C.; Supuran, C.T. Sulfonamide inhibition studies of two beta-carbonic anhydrases from the bacterial pathogen Legionella pneumophila. Bioorg. Med. Chem. 2014, 22, 2939–2946.
  72. Vullo, D.; Sai Kumar, R.S.; Scozzafava, A.; Capasso, C.; Ferry, J.G.; Supuran, C.T. Anion inhibition studies of a beta-carbonic anhydrase from Clostridium perfringens. Bioorg. Med. Chem. Lett. 2013, 23, 6706–6710.
  73. Nishimori, I.; Minakuchi, T.; Maresca, A.; Carta, F.; Scozzafava, A.; Supuran, C.T. The beta-carbonic anhydrases from Mycobacterium tuberculosis as drug targets. Curr. Pharm. Des. 2010, 16, 3300–3309.
  74. Carta, F.; Maresca, A.; Covarrubias, A.S.; Mowbray, S.L.; Jones, T.A.; Supuran, C.T. Carbonic anhydrase inhibitors. Characterization and inhibition studies of the most active beta-carbonic anhydrase from Mycobacterium tuberculosis, Rv3588c. Bioorg. Med. Chem. Lett. 2009, 19, 6649–6654.
  75. Supuran, C.T. Special Issue: Sulfonamides. Molecules 2017, 22, 1642.
  76. Nguyen, K.; Ahlawat, R. Famotidine. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2020.
  77. Komiya, T.; Huang, C.H. Updates in the Clinical Development of Epacadostat and Other Indoleamine 2,3-Dioxygenase 1 Inhibitors (IDO1) for Human Cancers. Front. Oncol. 2018, 8, 423.
  78. Carta, F.; Osman, S.M.; Vullo, D.; AlOthman, Z.; Del Prete, S.; Capasso, C.; Supuran, C.T. Poly(amidoamine) dendrimers show carbonic anhydrase inhibitory activity against alpha-, beta-, gamma- and eta-class enzymes. Bioorg. Med. Chem. 2015, 23, 6794–6798.
  79. Akdemir, A.; Guzel-Akdemir, O.; Karali, N.; Supuran, C.T. Isatin analogs as novel inhibitors of Candida spp. beta-carbonic anhydrase enzymes. Bioorg. Med. Chem. 2016, 24, 1648–1652.
  80. Teichert, I.; Poggeler, S.; Nowrousian, M. Sordaria macrospora: 25 years as a model organism for studying the molecular mechanisms of fruiting body development. Appl. Microbiol. Biotechnol. 2020, 104, 3691–3704.
  81. Elleuche, S.; Poggeler, S. Carbonic anhydrases in fungi. Microbiology 2010, 156, 23–29.
  82. Wang, L.; Clavaud, C.; Bar-Hen, A.; Cui, M.; Gao, J.; Liu, Y.; Liu, C.; Shibagaki, N.; Gueniche, A.; Jourdain, R.; et al. Characterization of the major bacterial-fungal populations colonizing dandruff scalps in Shanghai, China, shows microbial disequilibrium. Exp. Dermatol. 2015, 24, 398–400.
  83. De Simone, G.; Supuran, C.T. (In)organic anions as carbonic anhydrase inhibitors. J. Inorg. Biochem. 2012, 111, 117–129.
  84. 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 beta-Carbonic Anhydrases from Pathogenic Fungi: Activity and Modeling Study. ACS Med. Chem. Lett. 2017, 8, 1194–1198.
  85. 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 beta-carbonic anhydrase from the dandruff-producing fungus Malassezia globosa with monothiocarbamates. J. Enzym. Inhib. Med. Chem. 2017, 32, 1064–1070.
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Subjects: Biochemistry & Molecular Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Clemente Capasso
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Claudiu Supuran
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Update Date: 08 May 2021
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