Dithiocarbamates strongly inhibit the β-class carbonic anhydrases from<i>Mycobacterium tuberculosis</i>

Maresca, Alfonso; Carta, Fabrizio; Vullo, Daniela; Supuran, Claudiu T.

doi:10.3109/14756366.2011.641015

Cited by 137 publications

(92 citation statements)

References 36 publications

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“…Currently a sulfonamide CA IX inhibitor (SLC-0111) entered in Phase I clinical studies for the treatment of hypoxic, advanced stage solid tumors [8][9][10]. Furthermore, novel CAI classes such as the polyamines, [11] phenols, [12] dithiocarbamates, [13] xanthates [14] coumarins, thiocoumarins, 2-thioxo-coumarins and coumarinoximes [1,4,[15][16][17] were discovered and the inhibition mechanisms of many of these compounds were explained by using kinetic, spectroscopic and X-ray crystallographic techniques [2,6,12,13].…”

Section: Introductionmentioning

confidence: 99%

Isatin-pyrazole benzenesulfonamide hybrids potently inhibit tumor-associated carbonic anhydrase isoforms IX and XII

Ibrahim

Abou‐Seri

Tanç

et al. 2015

European Journal of Medicinal Chemistry

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104

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a b s t r a c tNew series of benzenesulfonamide derivatives incorporating pyrazole and isatin moieties were prepared using celecoxib as lead molecule. Biological evaluation of the target compounds was performed against the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more precisely against the human isoforms hCA I, II (cytosolic), IX and XII (transmembrane, tumor-associated enzymes). Most of the tested compounds efficiently inhibited hCA I, II and IX, with K I s of 2.5e102 nM, being more effective than the reference drug acetazolamide. Compounds 11e, 11f, 16e and 16f were found to inhibit hCA XII with Ki of 3.7, 6.5, 5.4 and 7.2 nM, respectively. Compounds 11e and 16e, with 5-NO 2 substitution on the isatin ring, were found to be selective inhibitors of hCA IX and hCA XII. Docking studies revealed that the NO 2 group of both compounds participate in interactions with Asp132 within the hCA IX active site, and with residues Lys67 and Asp130 in hCA XII, respectively.

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Section: Introductionmentioning

confidence: 99%

Isatin-pyrazole benzenesulfonamide hybrids potently inhibit tumor-associated carbonic anhydrase isoforms IX and XII

Ibrahim

Abou‐Seri

Tanç

et al. 2015

European Journal of Medicinal Chemistry

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104

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“…Inhibition of bacterial CAs is indeed a topic of great interest, with the possibility to uncover novel mechanisms of pathogenesis or classes of antibiotics with new characteristics, distinct of the classical agents for which drug resistance problems emerged [20][21][22][23][24][25][26][27][28][29] . The 3-hydroxyphenyl glycosides preferentially inhibited pathogen CAs over human CAs showing that this moiety therefore represents a lead for the development of novel anti-infectives with a new mechanism of action.…”

Section: Resultsmentioning

confidence: 99%

Inhibition ofβ-carbonic anhydrases fromBrucella suiswithC-cinnamoyl glycosides incorporating the phenol moiety

Riafrecha

Vullo

Ouahrani‐Bettache

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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A small series of C-glycosides containing the phenol moiety was tested for the inhibition of the b-class carbonic anhydrases (bCAs, EC 4.2.1.1) from Brucella suis. Many compounds showed activities in the micromolar or submicromolar range and excellent selectivity for pathogen CAs over human isozymes. Glycosides incorporating the 3-hydroxyphenyl moiety showed the best inhibition profile, and therefore this functionality represents lead for the development of novel anti-infectives with a new mechanism of action.

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“…Dithiocarbamates (DTCs) were discovered as a completely new class of CAIs only recently, after the investigation of some inorganic anions acting in this way [45][46][47][48][49][50]. Indeed, the simple inorganic compound trithiocarbonate (TTC, CS 3 2-), [51] for which an X-ray crystal structure in complex with the isoform hCA II was available, showed that the inhibitor is bound to the Zn(II) ion from the enzyme catalytic site through one of its three equivalent sulfur atoms, whereas a second such atom interacted with the conserved Thr199 amino acid residue.…”

Section: Dithiocarbamatesmentioning

confidence: 99%

“…VchCAβ belongs to the type II subclass β-CAs, characterized by four protein-derived ligands that coordinate the catalytic zinc ion, contrary to the type I β-CAs that have only two cysteines and one histidine residues in the zinc coordination sphere with a fourth coordination site occupied by a water molecule/hydroxide ion acting as nucleophile in the catalytic cycle [63]. The crystal structure was determined at pH 8.0, when a bicarbonate ion bound in a non-catalytic binding pocket close to the zinc ion was also observed [48]. At pH 8.3, the enzyme showed a significant catalytic activity for the physiological reaction of CO 2 [63].This is in fact the situation for all type II β-CAs, which at pH values > 8 become of type I, with the asp residue being involved in a salt bridge with a neighboring conserved Arg, and an incoming water molecule/hydroxide ion replacing the Asp residue [49][50][51][52][53][54].…”

Section: Vibrio Choleraementioning

confidence: 99%

Inhibition of Bacterial Carbonic Anhydrases as a Novel Approach to Escape Drug Resistance

Capasso

Supuran

2017

CTMC

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Background: Clinically used antibiotics act through one of these four mechanisms: cell wall biosynthesis inhibition, inhibition of protein biosynthesis, interference with DNA and RNA synthesis and the folate pathway. Objective:The metalloenzymes carbonic anhydrases (CAs, EC 4.2.1.1) widespread in microorganisms and present as three genetically distinct families may be considered for the design of antiinfective agents with a different mechanism of action compared to the clinically used antibiotics. CAs are crucial for the life cycle of the pathogen, interfering with pH regulation and biosynthetic processes in which CO 2 or bicarbonate are substrates. CA inhibition was shown to lead to debilitation or growth defects of several pathogenic bacteria. Method:CAs catalyzes the interconversion between carbon dioxide to bicarbonate, leading to the formation of protons, and thus affecting pH homeostasis. Several classes of CA inhibitors (CAIs) are known to date, among which the metal complexing anions, the unsubstituted sulfonamides, the dithiocarbamates, etc., which bind to the Zn(II) ion of the enzyme either by substituting the non-protein zinc ligand or add to the metal coordination sphere.Results: Effective inhibitors for many bacterial CAs belonging to the α-, β-, and γ-CA classes were detected, some of which inhibited bacterial growth in vivo. Few of the inhibitors investigated so far were also selective for the bacterial over the human CA isoforms, which may pose problems for their wide clinical applications. Conclusion:Structure-based drug design campaigns might lead to the achievement of the desired selectivity/potency for preferentially inhibiting bacterial but not the host CAs.

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Dithiocarbamates strongly inhibit the β-class carbonic anhydrases fromMycobacterium tuberculosis

Cited by 137 publications

References 36 publications

Isatin-pyrazole benzenesulfonamide hybrids potently inhibit tumor-associated carbonic anhydrase isoforms IX and XII

Isatin-pyrazole benzenesulfonamide hybrids potently inhibit tumor-associated carbonic anhydrase isoforms IX and XII

Inhibition ofβ-carbonic anhydrases fromBrucella suiswithC-cinnamoyl glycosides incorporating the phenol moiety

Inhibition of Bacterial Carbonic Anhydrases as a Novel Approach to Escape Drug Resistance

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