Exploiting the hydrophobic and hydrophilic binding sites for designing carbonic anhydrase inhibitors

Simone, Giuseppina De; Alterio, Vincenzo; Supuran, Claudiu T.

doi:10.1517/17460441.2013.795145

Cited by 231 publications

(183 citation statements)

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“…57,58,23,31,60 The kinetic parameters for the PhaCAc-catalyzed CO 2 hydration to bicarbonate and protons, were: k cat of 1.4 Â 10 5 s À1 and a k cat /K m of 1.9 Â 10 6 M À1 Â s À1 . This activity is inhibited by the sulfonamide CA inhibitor (CAI) acetazolamide, with a K I of 403 nM, in the same range as the c-CA PgiCA from P. gingivalis or the human slow isoform hCA I (Table 1).…”

Section: Tablementioning

confidence: 99%

“…[55][56][57][58][59][60] A panel of 40 such derivatives were included in this study. Derivatives 1-24 and AAZ-HCT are either simple aromatic/heterocyclic sulfonamides widely used as building blocks for obtaining new families of such pharmacological agents, [55][56][57][58][59][60] or they are clinically used agents, among which acetazolamide AAZ, methazolamide MZA, ethoxzolamide EZA and dichlorophenamide DCP, are the classical, systemically acting antiglaucoma CA inhibitors (CAIs). Dorzolamide DZA and brinzolamide BRZ are topically-acting antiglaucoma agents, benzolamide BZA is an orphan drug belonging to this class of pharmacological agents, whereas topiramate TPM, zonisamide ZNS and sulthiame SLT are widely used antiepileptic drugs.…”

Section: Tablementioning

confidence: 99%

“…26,[39][40][41][42][43][44][45][46][47][48][49][50] Their biochemical features are known in detail for at least four classes, together with their distribution and role in various organisms. 32,33,41,[48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] Inhibition and activation studies of many such enzymes from vertebrates, protozoa, fungi and bacteria have shown that they are drug targets for obtaining pharmacological agents of the diuretic, antiglaucoma, antiobesity, antiepileptic, anticancer or anti-infective type. [55][56][57][58]60 Many such enzymes also possess biotechnologic applications for biomimetic CO 2 capture processes.…”

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confidence: 99%

“…32,33,41,[48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] Inhibition and activation studies of many such enzymes from vertebrates, protozoa, fungi and bacteria have shown that they are drug targets for obtaining pharmacological agents of the diuretic, antiglaucoma, antiobesity, antiepileptic, anticancer or anti-infective type. [55][56][57][58]60 Many such enzymes also possess biotechnologic applications for biomimetic CO 2 capture processes. [55][56][57][58][59][60] The cloning and characterization of many other http://dx.doi.org/10.1016/j.bmcl.2015.06.079 0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.…”

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confidence: 99%

“…[55][56][57][58]60 Many such enzymes also possess biotechnologic applications for biomimetic CO 2 capture processes. [55][56][57][58][59][60] The cloning and characterization of many other http://dx.doi.org/10.1016/j.bmcl.2015.06.079 0960-894X/Ó 2015 Elsevier Ltd. All rights reserved. such enzymes will probably lead to the discovery of other CA families as well as enzymes with potentially important technologic applications.…”

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Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic bacterium Pseudoalteromonas haloplanktis

Vullo

Luca

Prete

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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a b s t r a c tThe Antarctic bacterium Pseudoalteromonas haloplanktis encodes for a c-class carbonic anhydrase (CA, EC 4.2.1.1), which was cloned, purified and characterized. The enzyme (PhaCAc) has a good catalytic activity for the physiologic reaction of CO 2 hydration to bicarbonate and protons, with a k cat of 1.4 Â 10 5 s À1 and a k cat /K m of 1.9 Â 10 6 M À1 Â s À1 . A series of sulfonamides and a sulfamate were investigated as inhibitors of the new enzyme. Methazolamide and indisulam showed the best inhibitory properties (K I s of 86.7-94.7 nM). This contribution shed new light on c-CAs inhibition profiles with a relevant class of pharmacologic agents.Ó 2015 Elsevier Ltd. All rights reserved.Marine psychrophiles act as processors of the polar marine primary productivity constituting the base for the entire polar food web and, ultimately, feeding krill, fish, whales, penguins, and seabirds. 1,2 They play, in fact, a significant role in the so called 'substance turnover'. Moreover, a feature common to all psychrophiles are their remarkable ability to thrive under extremely cold and salty conditions. 3 Cold-adapted organisms have developed a number of adjustments at the molecular level to maintain metabolic functions at low temperatures, such as the production of enzymes, note as 'cold-enzyme'. 4-11 These enzymes are characterized by a specific activity at low and moderate temperatures higher than their mesophilic counterparts over a temperature range roughly covering 0-30°C and by a relative instability. 6,7,[11][12][13] Probably, in the case of psychrophilic microorganisms the selective pressure is essentially exerted towards the specific activity and not towards stability factors as happens in mesophilic or in thermophilic enzymes. The molecular structure of a 'cold-enzyme' is primarily characterized by an adequate plasticity of the molecule at the environmental temperature in order to accommodate the substrates with a minimum of energy expenditure. 14 'Cold-enzymes' naturally achieved a good compromise between activity and stability. There is a continuum in the adaptation of a protein to its environment. [4][5][6][7][8][9][10][11]13,[15][16][17][18][19][20][21][22] In fact, all known structural factors and weak interactions involved in protein stability are either reduced in number or modified in psychrophilic enzymes in order to increase their flexibility; but the same structural factors are also implicate for increasing the stability of the thermophilic proteins. [23][24][25][26][27][28][29] Carbonic anhydrases (CAs; EC 4.2.1.1) are metalloenzymes that catalyze CO 2 hydration to bicarbonate and protons. 4,5,[30][31][32][33][34][35][36][37][38] These enzymes are involved in a multitude of physiologic processes in organisms all over the phylogenetic tree, with six genetically distinct CA classes known to date: the a-, b-, c-, d-, f-and g-CAs. 26,[39][40][41][42][43][44][45][46][47][48][49][50] Their biochemical features are known in detail for at least four classes, together with their distribution and ...

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Section: Tablementioning

confidence: 99%

Section: Tablementioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic bacterium Pseudoalteromonas haloplanktis

Vullo

Luca

Prete

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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Synthesis and Carbonic Anhydrase Inhibition of Novel 2‐(4‐(Aryl)thiazole‐2‐yl)‐3a,4,7,7a‐tetrahydro‐1H‐4,7‐methanoisoindole‐1,3(2H)‐dione Derivatives

Koçyiğit

Aslan

Gülçın

et al. 2016

Archiv der Pharmazie

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Carbonic anhydrase (CA, EC 4.2.1.1) is a member of the metalloenzyme family. It catalyzes the rapid conversion of carbon dioxide (CO ) and water to bicarbonate (HCO ) and protons (H ) and also plays an important role in biochemical and physiological processes. In this study, a number of novel 2-(4-(aryl)thiazole-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione derivatives were synthesized and evaluated for their inhibitory characteristics against the human CA isoenzymes I and II (hCA I and hCA II). The structures of the new molecules 8a-i were confirmed by means of IR, H NMR, C NMR, and elemental analysis. These compounds exhibited excellent inhibitory effects, in the low nanomolar range, with K values in the range of 27.07-37.80 nM against hCA I and in the range of 11.80-25.81 nM against hCA II. Our findings suggest that the new isoindolylthiazole derivatives have superior inhibitory effect over acetazolamide (AZA), which is used as clinical CA inhibitor with K values of 34.50 and 28.93 nM against the hCA I and hCA II isoenzymes, respectively.

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Design and development of novel series of indole‐3‐sulfonamide ureido derivatives as selective carbonic anhydrase II inhibitors

Singh

Choli

Swain

et al. 2021

Archiv der Pharmazie

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Indole is a privileged moiety with a wide range of bioactivities, making it a popular scaffold in drug design and development studies as well as in synthetic chemistry.Here, novel urea derivatives of indole, containing sulfonamide at position-3 of indole, were synthesized using a well-known tail approach, as carbonic anhydrases (CAs; EC 4.2.1.1) inhibitors. All the newly synthesized molecules were screened for their CA-inhibitory activity against four clinically relevant isoforms of human-origin carbonic anhydrase (hCA), that is, hCA I, hCA II, hCA IX, and hCA XII. These compounds were specifically active against hCA II, more than against hCA I, hCA IX, and hCA XII. Derivative 6l was found to be most active, with a K i value of 7.7 µM against hCA II.

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Exploiting the hydrophobic and hydrophilic binding sites for designing carbonic anhydrase inhibitors

Cited by 231 publications

References 105 publications

Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic bacterium Pseudoalteromonas haloplanktis

Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic bacterium Pseudoalteromonas haloplanktis

Synthesis and Carbonic Anhydrase Inhibition of Novel 2‐(4‐(Aryl)thiazole‐2‐yl)‐3a,4,7,7a‐tetrahydro‐1H‐4,7‐methanoisoindole‐1,3(2H)‐dione Derivatives

Design and development of novel series of indole‐3‐sulfonamide ureido derivatives as selective carbonic anhydrase II inhibitors

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