Anti-infective carbonic anhydrase inhibitors: a patent and literature review

Capasso, Clemente; Supuran, Claudiu T.

doi:10.1517/13543776.2013.778245

Cited by 205 publications

(116 citation statements)

References 86 publications

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“…Thus, the CAs have become remarkable therapeutic targets for the treatment of a wide range of disorders. Several CA inhibitors show anticancer 7 , diuretics 8 , antiglaucoma 9 , antiinfective 10 and antiobesity 11 activities.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, cytotoxicity and carbonic anhydrase inhibitory activities of new pyrazolines

Küçükoğlu

Oral

Aydin

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of polymethoxylated-pyrazoline benzene sulfonamides were synthesized, investigated for their cytotoxic activities on tumor and non-tumor cell lines and inhibitory effects on carbonic anhydrase isoenzymes (hCA I and hCA II). Although tumor selectivity (TS) of the compounds were less than the reference compounds 5-Fluorouracil and Melphalan, trimethoxy derivatives 4, 5, and 6 were more selective than dimethoxy derivatives 2 and 3 as judged by the cytotoxicity assay with the cells both types originated from the gingival tissue. The compound 6 (4-[3-(4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl] benzene sulfonamide) showed the highest TS values and can be considered as a lead molecule of the series for further investigations. All compounds synthesized showed superior CA inhibitory activity than the reference compound acetazolamide on hCA I, and II isoenzymes, with inhibition constants in the range of 26.5-55.5 nM against hCA I and of 18.9-28.8 nM against hCA II, respectively.

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Section: Introductionmentioning

confidence: 99%

Synthesis, cytotoxicity and carbonic anhydrase inhibitory activities of new pyrazolines

Küçükoğlu

Oral

Aydin

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Apart from the classical applications of the CA inhibitors (CAIs) as diuretics, antiglaucoma and antiepileptic agents [83][84][85][86][87][88][89][90][91] of pharmaceuticals that suppress the activity of carbonic anhydrase, ultimately many such agents were shown to be effective as antiobesity and anticancer agents [91][92][93] . Moreover, the inhibition of CAs from pathogenic organisms (such as bacteria, fungi and protozoa) started to be considered as an interesting approach for designing anti-infective agents with a new mechanism of action [1][2][3]94 . These studies allowed the identification of new CAs in the genome of pathogens, such as bacteria, fungi and protozoa.…”

Section: Discussionmentioning

confidence: 99%

A magnificent enzyme superfamily: carbonic anhydrases, their purification and characterization

Guler

Capasso

Supuran

2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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128

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In this paper, we reviewed the purification and characterization methods of the a-carbonic anhydrase (CA, EC 4.2.1.1) class. Six genetic families (a-, b-, g-, d-, z-and Z-CAs) all know to date, all encoding such enzymes in organisms widely distributed over the phylogenetic tree. Starting from the manuscripts published in the 1930s on the isolation and purification of a-CAs from blood and other tissues, and ending with the recent discovery of the last genetic family in protozoa, the Z-CAs, considered for long time an a-CA, we present historically the numerous and different procedures which were employed for obtaining these catalysts in pure form. a-CAs possess important application in medicine (as many human a-CA isoforms are drug targets) as well as biotechnological processes, in which the enzymes are ultimately used for CO 2 capture in order to mitigate the global warming effects due to greenhouse gases. Recently, it was discovered an involvement of CAs in cancerogenesis as well as infection caused by pathogenic agents such as bacteria, fungi and protozoa. Inhibition studies of CAs identified in the genome of the aforementioned organisms might lead to the discovery of innovative drugs with a novel mechanism of action.

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“…1A). Anions are an important class of CAIs, which were useful for designing novel types of more complex inhibitors possessing an organic scaffold, which afforded the discovery of totally new families of such pharmacologic agents [24,[36][37][38][39][40][41][42]]. …”

Section: Anionsmentioning

confidence: 99%

“…The main classes of antibiotics clinically used nowadays act towards the inhibition of four classical targets: a) cell wall biosynthesis; b) protein biosynthesis; c) DNA and RNA biosynthesis; d) folate biosynthesis [56]. Recently, carbonic anhydrases (CAs, EC 4.2.1.1) started to be investigated in detail in pathogenic bacteria, in the search for antibiotics with a novel mechanism of action, since it has been demonstrated that in many bacteria, CAs are essential for the life cycle of the microoorganism and that their inhibition leads to growth impairment or growth defects of the pathogen [24,34,[57][58][59].…”

Section: Carbonic Anhydrases and Their Implication In Bacterial Virulmentioning

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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Anti-infective carbonic anhydrase inhibitors: a patent and literature review

Cited by 205 publications

References 86 publications

Synthesis, cytotoxicity and carbonic anhydrase inhibitory activities of new pyrazolines

Synthesis, cytotoxicity and carbonic anhydrase inhibitory activities of new pyrazolines

A magnificent enzyme superfamily: carbonic anhydrases, their purification and characterization

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

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