Carbonic Anhydrase Inhibition with Sulfonamides Incorporating Pyrazole- and Pyridazinecarboxamide Moieties Provides Examples of Isoform-Selective Inhibitors

Angeli, Andrea; Карцев, В. Г.; Petrou, Anthi; Pinteala, Mariana; Броварец, В. С.; Vydzhak, R. N.; Panchishin, S. Ya.; Geronikaki, Athina

doi:10.3390/molecules26227023

Cited by 11 publications

(13 citation statements)

References 49 publications

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“…The aim of this study is to support and extend our previous studies [51][52][53] on hCA as a target against diverse pathological conditions. Thus, herein we report the synthesis of two different groups of compounds, one of which is pyrazolo [4,3-c]pyridine sulfonamides (1a-f) and the other sulfonamide derivatives of different hetrocyclic moieties (1g-1k), and the evaluation of their inhibitory activities towards four human CAs (I, II, IX, and XII) as well as 3β and 3γ CAs from different bacterial strains.…”

Section: Introductionmentioning

confidence: 55%

Pyrazolo[4,3-c]pyridine Sulfonamides as Carbonic Anhydrase Inhibitors: Synthesis, Biological and In Silico Studies

Angeli

Карцев²,

Petrou

et al. 2022

Pharmaceuticals

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Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho-/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. On the other hand, in microorganisms, the β- and γ- classes are expressed in addition to the α- class, showing substantial structural differences to the human isoforms. In this scenario, not only human but also bacterial CAs are of particular interest as new antibacterial agents with an alternative mechanism of action for fighting the emerging problem of extensive drug resistance afflicting most countries worldwide. Pyrazolo[4,3-c]pyridine sulfonamides were synthesized using methods of organic chemistry. Their inhibitory activity, assessed against the cytosolic human isoforms hCA I and hCA II, the transmembrane hCA IX and XII, and β- and γ-CAs from three different bacterial strains, was evaluated by a stopped-flow CO2 hydrase assay. Several of the investigated derivatives showed interesting inhibition activity towards the cytosolic associate isoforms hCA I and hCA II, as well as the 3β- and 3γ-CAs. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds within the active site of hCA IX. Four compounds (1f, 1g, 1h and 1k) were more potent than AAZ against hCA I. Furthermore, compound 1f also showed better activity than AAZ against the hCA II isoform. Moreover, ten compounds out of eleven appeared to be very potent against the γ-CA from E.coli, with a Ki much lower than that of the reference drug. Most of the compounds showed better activity than AAZ against hCA I as well as the γ-CA from E.coli and the β-CA from Burkholderia pseudomallei (BpsCAβ). Compounds 1f and 1k showed a good selectivity index against hCA I and hCA XII, while 1b was selective against all 3β-CA isoforms from E.coli, BpsCA, and VhCA and all 3γ-CA isoforms from E.coli, BpsCA and PgiCA.

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Section: Introductionmentioning

confidence: 55%

Pyrazolo[4,3-c]pyridine Sulfonamides as Carbonic Anhydrase Inhibitors: Synthesis, Biological and In Silico Studies

Angeli

Карцев²,

Petrou

et al. 2022

Pharmaceuticals

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“…In addition, they play an important role in the production and secretion of saliva and the regulation of saliva pH. Human carbonic anhydrases have 15 isoforms and their dysregulated expression is related to various diseases as carbonic anhydrase I, IV, IX, and XII isoforms are abnormally expressed in diseased conditions such as rheumatoid arthritis, cerebral ischemia, and cancers [ 165 ].…”

Section: Discussionmentioning

confidence: 99%

Gustatory and Saliva Secretory Dysfunctions in COVID-19 Patients with Zinc Deficiency

Tsuchiya

2022

Life

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Given the ever-progressing studies on coronavirus disease 2019 (COVID-19), it is critical to update our knowledge about COVID-19 symptomatology and pathophysiology. In the present narrative review, oral symptoms were overviewed using the latest data and their pathogenesis was hypothetically speculated. PubMed, LitCovid, ProQuest, and Google Scholar were searched for relevant studies from 1 April 2021 with a cutoff date of 31 January 2022. The literature search indicated that gustatory dysfunction and saliva secretory dysfunction are prevalent in COVID-19 patients and both dysfunctions persist after recovery from the disease, suggesting the pathogenic mechanism common to these cooccurring symptoms. COVID-19 patients are characterized by hypozincemia, in which zinc is possibly redistributed from blood to the liver at the expense of zinc in other tissues. If COVID-19 induces intracellular zinc deficiency, the activity of zinc-metalloenzyme carbonic anhydrase localized in taste buds and salivary glands may be influenced to adversely affect gustatory and saliva secretory functions. Zinc-binding metallothioneins and zinc transporters, which cooperatively control cellular zinc homeostasis, are expressed in oral tissues participating in taste and saliva secretion. Their expression dysregulation associated with COVID-19-induced zinc deficiency may have some effect on oral functions. Zinc supplementation is expected to improve oral symptoms in COVID-19 patients.

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“…[31] Most of the evaluated molecules exhibited micromolar-to-nanomolar CA inhibitory properties. Particularly, 2,4dichlorophenyl analog 1 (Figure 1 Modified sulfonamide derivatives were designed by introducing alkylamide linker in between pyrazole and benzenesulfonamide moieties by Angeli et al [32] Among the different isoforms of CA, hCA II was strongly inhibited by most of the evaluated molecules.…”

Section: Sulfonamide Derivativesmentioning

confidence: 99%

“…Modified sulfonamide derivatives were designed by introducing alkylamide linker in between pyrazole and benzenesulfonamide moieties by Angeli et al [ 32 ] Among the different isoforms of CA, h CA II was strongly inhibited by most of the evaluated molecules. Of the evaluated molecules in the pyrazole series, tricyclic pyrazole analog 4 (Figure 2) rendered the most potent h CA II and h CA IX inhibitory activity with K I values of 3.3 nM and 6.1 nM, respectively.…”

Section: Pyrazole Derivativesmentioning

confidence: 99%

Pyrazole/pyrazoline as an excellent pharmacophore in the design of carbonic anhydrase inhibitors (2018–2022)

Dorababu¹

2023

Archiv der Pharmazie

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Carbonic anhydrase (CA) is a metalloenzyme that catalyzes the interconversion between carbon dioxide and water and dissociated ions of carbonic acid. In addition, CA performs various other functions in animals and plants, depending on the part of the living being.CAs have been found in almost all organisms. Besides, CAs are associated with several diseases, such as glaucoma, obesity, epilepsy, cancer, and so on. CAs are also involved in

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Carbonic Anhydrase Inhibition with Sulfonamides Incorporating Pyrazole- and Pyridazinecarboxamide Moieties Provides Examples of Isoform-Selective Inhibitors

Cited by 11 publications

References 49 publications

Pyrazolo[4,3-c]pyridine Sulfonamides as Carbonic Anhydrase Inhibitors: Synthesis, Biological and In Silico Studies

Pyrazolo[4,3-c]pyridine Sulfonamides as Carbonic Anhydrase Inhibitors: Synthesis, Biological and In Silico Studies

Gustatory and Saliva Secretory Dysfunctions in COVID-19 Patients with Zinc Deficiency

Pyrazole/pyrazoline as an excellent pharmacophore in the design of carbonic anhydrase inhibitors (2018–2022)

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