A new approach to antiglaucoma drugs: carbonic anhydrase inhibitors with or without NO donating moieties. Mechanism of action and preliminary pharmacology

Fabrizi, Francesca; Mincione, Francesco; Somma, Teresa; Scozzafava, Gabriele; Galassi, F.; Masini, Emanuela; Impagnatiello, Francesco; Supuran, Claudiu T.

doi:10.3109/14756366.2011.597749

Cited by 150 publications

(119 citation statements)

References 25 publications

(36 reference statements)

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“…They reduce bicarbonate secretion in the aqueous humour by inhibiting CA isoforms present in the ciliary processes (CA II, IV and XII) with a consequent reduction of IOP 46,47 . Nitric oxide (NO), a radical gas produced by the enzyme nitric oxide synthase (NOS), is also involved in vasodilation, aqueous humour outflow within the eye, local modulation of ocular blood flow and retinal ganglion cells death by apoptosis 39,48,49 . It appeared thus of interest to combine these two pharmacophores, a sulphonamide CAI, and a moiety able to donate NO, of the nitrate ester type, in the molecule of a hybrid drug 39,48,49 .…”

Section: Anti-glaucoma Sulphonamides − Hybrid Drugs Incorporating Sulmentioning

confidence: 99%

“…Nitric oxide (NO), a radical gas produced by the enzyme nitric oxide synthase (NOS), is also involved in vasodilation, aqueous humour outflow within the eye, local modulation of ocular blood flow and retinal ganglion cells death by apoptosis 39,48,49 . It appeared thus of interest to combine these two pharmacophores, a sulphonamide CAI, and a moiety able to donate NO, of the nitrate ester type, in the molecule of a hybrid drug 39,48,49 . In this way, a large number of sulphonamides with NO-donating properties were reported in the last several years, among which those of types 16-18 were the most interesting 39,48,49 .…”

Section: Anti-glaucoma Sulphonamides − Hybrid Drugs Incorporating Sulmentioning

confidence: 99%

“…For example, anti-glaucoma agents should possess appropriate hydrophilicity and water solubility in order to be formulated as eye drops but a balanced lipophilicity for being able to penetrate through the plasma membranes and arrive at the ciliary processes where the enzymes responsible for aqueous humour secretion are found (i.e. CA II, IV and XII) [37][38][39] . For targeting CA IX and XII, which are transmembrane isoforms with an extracellular active site and are predominantly found in tumours 40 , charged, membraneimpermeant derivatives are preferred, which selectively inhibit only these and not the cytosolic/mitochondrial CAs [41][42][43][44][45] .…”

Section: Journal Of Enzyme Inhibition and Medicinal Chemistrymentioning

confidence: 99%

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Structure-based drug discovery of carbonic anhydrase inhibitors

Supuran

2012

Journal of Enzyme Inhibition and Medicinal Chemistry

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565

451

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Section: Anti-glaucoma Sulphonamides − Hybrid Drugs Incorporating Sulmentioning

confidence: 99%

Section: Anti-glaucoma Sulphonamides − Hybrid Drugs Incorporating Sulmentioning

confidence: 99%

Section: Journal Of Enzyme Inhibition and Medicinal Chemistrymentioning

confidence: 99%

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Structure-based drug discovery of carbonic anhydrase inhibitors

Supuran

2012

Journal of Enzyme Inhibition and Medicinal Chemistry

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565

451

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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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“…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 .…”

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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129

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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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A new approach to antiglaucoma drugs: carbonic anhydrase inhibitors with or without NO donating moieties. Mechanism of action and preliminary pharmacology

Cited by 150 publications

References 25 publications

Structure-based drug discovery of carbonic anhydrase inhibitors

Structure-based drug discovery of carbonic anhydrase inhibitors

Synthesis, cytotoxicity and carbonic anhydrase inhibitory activities of new pyrazolines

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

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