Ebselen

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Ebselen
Ebselen-2D-skeletal.png
Ebselen-3D-balls.png
Ebselen-3D-vdW.png
Names
Preferred IUPAC name
2-Phenyl-1,2-benzoselenazol-3(2H)-one
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.132.190 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C13H9NOSe/c15-13-11-8-4-5-9-12(11)16-14(13)10-6-2-1-3-7-10/h1-9H Yes check.svgY
    Key: DYEFUKCXAQOFHX-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C13H9NOSe/c15-13-11-8-4-5-9-12(11)16-14(13)10-6-2-1-3-7-10/h1-9H
    Key: DYEFUKCXAQOFHX-UHFFFAOYAZ
  • C1=CC=C(C=C1)N2C(=O)C3=CC=CC=C3[Se]2
  • O=C1c3ccccc3[Se]N1c2ccccc2
Properties
C13H9NOSe
Molar mass 274.17666
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Ebselen (also called PZ 51, DR3305, and SPI-1005), is a synthetic organoselenium drug molecule with anti-inflammatory, anti-oxidant and cytoprotective activity. It acts as a mimic of glutathione peroxidase and can also react with peroxynitrite. [1] It is being investigated as a possible treatment for reperfusion injury and stroke, [2] [3] Ménière's disease, [4] [5] hearing loss and tinnitus, [6] [7] and bipolar disorder. [8] [9]

Contents

Additionally, ebselen may be effective against Clostridioides difficile infections [10] and has been shown to have antifungal activity against Aspergillus fumigatus . [11]

Ebselen is a potent scavenger of hydrogen peroxide as well as hydroperoxides including membrane bound phospholipid and cholesterylester hydroperoxides. Several ebselen analogs have been shown to scavenge hydrogen peroxide in the presence of thiols. [12]

Possible anti-SARS-CoV-2 activity

Preliminary studies demonstrate that Ebselen exhibits promising inhibitory activity against SARS-CoV-2 in cell-based assays. [13] [14] [15] The effect was attributed to irreversible inhibition of the main protease via a covalent bond formation with the thiol group of the active center's cysteine (Cys-145). [13]

Synthesis

Generally, synthesis of the characteristic scaffold of ebselen, the benzoisoselenazolone ring system, can be achieved either through reaction of primary amines (RNH2) with 2-(chloroseleno)benzoyl chloride (Route I), [16] by ortho-lithiation of benzanilides followed by oxidative cyclization (Route II) mediated by cupric bromide (CuBr2), [17] or through the efficient Cu-catalyzed selenation / heterocyclization of o-halobenzamides, a methodology developed by Kumar et al. [18] (Route III).

Ebselen Routes.png

History

The first patent for 2-Phenyl-1,2-benzoselenazol-3(2H)-one was filed in 1980 and granted in 1982. [19]

Related Research Articles

Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants are frequently added to industrial products, such as polymers, fuels, and lubricants, to extend their usable lifetimes. Food are also treated with antioxidants to forestall spoilage, in particular the rancidification of oils and fats. In cells, antioxidants such as glutathione, mycothiol or bacillithiol, and enzyme systems like superoxide dismutase, can prevent damage from oxidative stress.

<span class="mw-page-title-main">Ménière's disease</span> Disorder of the inner ear

Ménière's disease (MD) is a disease of the inner ear that is characterized by potentially severe and incapacitating episodes of vertigo, tinnitus, hearing loss, and a feeling of fullness in the ear. Typically, only one ear is affected initially, but over time, both ears may become involved. Episodes generally last from 20 minutes to a few hours. The time between episodes varies. The hearing loss and ringing in the ears can become constant over time.

<span class="mw-page-title-main">Peroxidase</span> Peroxide-decomposing enzyme

Peroxidases or peroxide reductases are a large group of enzymes which play a role in various biological processes. They are named after the fact that they commonly break up peroxides.

Tinnitus is a variety of sound that is heard when no corresponding external sound is present. Nearly everyone experiences faint "normal tinnitus" in a completely quiet room; but it is of concern only if it is bothersome, interferes with normal hearing, or is associated with other problems. The word tinnitus comes from the Latin tinnire, "to ring". In some people, it interferes with concentration, and can be associated with anxiety and depression.

<span class="mw-page-title-main">Glutathione peroxidase</span> Enzyme family protecting the organism from oxidative damages

Glutathione peroxidase (GPx) is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage. The biochemical function of glutathione peroxidase is to reduce lipid hydroperoxides to their corresponding alcohols and to reduce free hydrogen peroxide to water.

<span class="mw-page-title-main">Acetylcysteine</span> Medication used to treat overdose of paracetamol

Acetylcysteine, also known as N-acetylcysteine (NAC), is a medication that is used to treat paracetamol overdose and to loosen thick mucus in individuals with chronic bronchopulmonary disorders like pneumonia and bronchitis. It has been used to treat lactobezoar in infants. It can be taken intravenously, by mouth, or inhaled as a mist. Some people use it as a dietary supplement.

<span class="mw-page-title-main">Glutathione disulfide</span> Chemical compound

Glutathione disulfide (GSSG) is a disulfide derived from two glutathione molecules.

<span class="mw-page-title-main">Gliotoxin</span> Chemical compound

Gliotoxin is a sulfur-containing mycotoxin that belongs to a class of naturally occurring 2,5-diketopiperazines produced by several species of fungi, especially those of marine origin. It is the most prominent member of the epipolythiopiperazines, a large class of natural products featuring a diketopiperazine with di- or polysulfide linkage. These highly bioactive compounds have been the subject of numerous studies aimed at new therapeutics. Gliotoxin was originally isolated from Gliocladium fimbriatum, and was named accordingly. It is an epipolythiodioxopiperazine metabolite that is one of the most abundantly produced metabolites in human invasive Aspergillosis (IA).

<span class="mw-page-title-main">Peroxiredoxin</span> Family of antioxidant enzymes

Peroxiredoxins are a ubiquitous family of antioxidant enzymes that also control cytokine-induced peroxide levels and thereby mediate signal transduction in mammalian cells. The family members in humans are PRDX1, PRDX2, PRDX3, PRDX4, PRDX5, and PRDX6. The physiological importance of peroxiredoxins is indicated by their relative abundance. Their function is the reduction of peroxides, specifically hydrogen peroxide, alkyl hydroperoxides, and peroxynitrite.

<span class="mw-page-title-main">GPX1</span> Protein-coding gene in the species Homo sapiens

Glutathione peroxidase 1, also known as GPx1, is an enzyme that in humans is encoded by the GPX1 gene on chromosome 3. This gene encodes a member of the glutathione peroxidase family. Glutathione peroxidase functions in the detoxification of hydrogen peroxide, and is one of the most important antioxidant enzymes in humans.

In enzymology, a phospholipid-hydroperoxide glutathione peroxidase (EC 1.11.1.12) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">GPX4</span> Mammalian protein found in Homo sapiens

Glutathione peroxidase 4, also known as GPX4, is an enzyme that in humans is encoded by the GPX4 gene. GPX4 is a phospholipid hydroperoxidase that protects cells against membrane lipid peroxidation.

<span class="mw-page-title-main">PRDX6</span> Protein-coding gene in the species Homo sapiens

Peroxiredoxin-6 is a protein that in humans is encoded by the PRDX6 gene. It is a member of the peroxiredoxin family of antioxidant enzymes.

<span class="mw-page-title-main">GPX7</span> Protein-coding gene in the species Homo sapiens

Glutathione peroxidase 7 is an enzyme that in humans is encoded by the GPX7 gene.

Selenium deficiency occurs when an organism lacks the required levels of selenium, a critical nutrient in many species. Deficiency, although relatively rare in healthy well-nourished individuals, can have significant negative results, affecting the health of the heart and the nervous system; contributing to depression, anxiety, and dementia; and interfering with reproduction and gestation.

<span class="mw-page-title-main">Tetrandrine</span> Chemical compound

Tetrandrine, a bis-benzylisoquinoline alkaloid, is a calcium channel blocker. It is isolated from the plant Stephania tetrandra, and other Chinese and Japanese herbs.

<span class="mw-page-title-main">GPX3</span> Enzyme in humans

Glutathione peroxidase 3 (GPx-3), also known as plasma glutathione peroxidase (GPx-P) or extracellular glutathione peroxidase is an enzyme that in humans is encoded by the GPX3 gene.

<span class="mw-page-title-main">3C-like protease</span> Class of enzymes

The 3C-like protease (3CLpro) or main protease (Mpro), formally known as C30 endopeptidase or 3-chymotrypsin-like protease, is the main protease found in coronaviruses. It cleaves the coronavirus polyprotein at eleven conserved sites. It is a cysteine protease and a member of the PA clan of proteases. It has a cysteine-histidine catalytic dyad at its active site and cleaves a Gln–(Ser/Ala/Gly) peptide bond.

<span class="mw-page-title-main">3CLpro-1</span> Chemical compound

3CLpro-1 is an antiviral drug related to rupintrivir which acts as a 3CL protease inhibitor and was originally developed for the treatment of human enterovirus 71. It is one of the most potent of a large series of compounds developed as inhibitors of the viral enzyme 3CL protease, with an in vitroIC50 of 200 nM. It also shows activity against coronavirus diseases such as SARS and MERS, and is under investigation as a potential treatment agent for the viral disease COVID-19.

<span class="mw-page-title-main">IDX-184</span> Chemical compound

IDX-184 is an antiviral drug which was developed as a treatment for hepatitis C, acting as a NS5B RNA polymerase inhibitor. While it showed reasonable effectiveness in early clinical trials it did not progress past Phase IIb. However research using this drug has continued as it shows potentially useful activity against other emerging viral diseases such as Zika virus, and coronaviruses including MERS, and SARS-CoV-2.

References

  1. ↑ Schewe T (October 1995). "Molecular actions of ebselen--an antiinflammatory antioxidant". General Pharmacology. 26 (6): 1153–69. doi:10.1016/0306-3623(95)00003-J. PMID   7590103.
  2. ↑ Parnham M, Sies H (March 2000). "Ebselen: prospective therapy for cerebral ischaemia". Expert Opinion on Investigational Drugs. 9 (3): 607–19. doi:10.1517/13543784.9.3.607. PMID   11060699. S2CID   42599736.
  3. ↑ Yamaguchi T, Sano K, Takakura K, Saito I, Shinohara Y, Asano T, Yasuhara H (January 1998). "Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Ebselen Study Group". Stroke. 29 (1): 12–7. doi: 10.1161/01.STR.29.1.12 . PMID   9445321.
  4. ↑ "SPI-1005 for the Treatment of Meniere's Disease". Sound Pharmaceuticals . Retrieved 7 November 2022.
  5. ↑ "Sound Pharma initiates enrollment in pivotal Phase 3 clinical trial of SPI-1005 for the treatment of hearing loss and tinnitus in Meniere's disease". Sound Pharmaceuticals . 2022-07-28. Retrieved 7 November 2022.
  6. ↑ Kil J, Pierce C, Tran H, Gu R, Lynch ED (April 2007). "Ebselen treatment reduces noise induced hearing loss via the mimicry and induction of glutathione peroxidase". Hearing Research. 226 (1–2): 44–51. doi:10.1016/j.heares.2006.08.006. PMID   17030476. S2CID   39896274.
  7. ↑ Kil, Jonathan; Harruff, E. Emily; Longenecker, Ryan J. (2022). "Development of ebselen for the treatment of sensorineural hearing loss and tinnitus". Hearing Research. Elsevier BV. 413: 108209. doi:10.1016/j.heares.2021.108209. ISSN   0378-5955. PMID   33678494. S2CID   231956488.
  8. ↑ Singh N, Halliday AC, Thomas JM, Kuznetsova OV, Baldwin R, Woon EC, et al. (2013). "A safe lithium mimetic for bipolar disorder". Nature Communications. 4: 1332. Bibcode:2013NatCo...4.1332S. doi:10.1038/ncomms2320. PMC   3605789 . PMID   23299882.
  9. ↑ "New drug for bipolar disorder may offer fewer side effects". University of Oxford Latest News. 2013-01-08. Retrieved 12 January 2013.
  10. ↑ "Drug disarms deadly C. difficile bacteria without destroying healthy gut flora". Medical Express.
  11. ↑ Marshall AC, Kidd SE, Lamont-Friedrich SJ, Arentz G, Hoffmann P, Coad BR, Bruning JB (March 2019). "Structure, Mechanism, and Inhibition of Aspergillus fumigatus Thioredoxin Reductase". Antimicrobial Agents and Chemotherapy. 63 (3): e02281-18. doi: 10.1128/AAC.02281-18 . PMC   6395915 . PMID   30642940.
  12. ↑ Satheeshkumar K, Mugesh G (April 2011). "Synthesis and antioxidant activity of peptide-based ebselen analogues". Chemistry: A European Journal. 17 (17): 4849–57. doi:10.1002/chem.201003417. PMID   21400619.
  13. 1 2 Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, et al. (June 2020). "Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors". Nature. 582 (7811): 289–293. Bibcode:2020Natur.582..289J. doi: 10.1038/s41586-020-2223-y . PMID   32272481.
  14. ↑ Weglarz-Tomczak E, Tomczak JM, Talma M, Burda-Grabowska M, Giurg M, Brul S (February 2021). "Identification of ebselen and its analogues as potent covalent inhibitors of papain-like protease from SARS-CoV-2". Scientific Reports. 11 (1): 3640. Bibcode:2021NatSR..11.3640W. doi:10.1038/s41598-021-83229-6. PMC   7878891 . PMID   33574416.
  15. ↑ Xiang R, Yu Z, Wang Y, Wang L, Huo S, Li Y, et al. (July 2021). "Recent advances in developing small-molecule inhibitors against SARS-CoV-2". Acta Pharmaceutica Sinica B. 12 (4): 1591–1623. doi:10.1016/j.apsb.2021.06.016. PMC   8260826 . PMID   34249607.
  16. ↑ Kamigata N, Iizuka H, Izuoka A, Kobayashi M (July 1986). "Photochemical Reaction of 2-Aryl-1, 2-benzisoselenazol-3 (2 H)-ones". Bulletin of the Chemical Society of Japan. 59 (7): 2179–83. doi: 10.1246/bcsj.59.2179 .
  17. ↑ Engman L, Hallberg A (1989-06-01). "Expedient synthesis of ebselen and related compounds". The Journal of Organic Chemistry. 54 (12): 2964–2966. doi:10.1021/jo00273a035. ISSN   0022-3263.
  18. ↑ Balkrishna SJ, Bhakuni BS, Chopra D, Kumar S (December 2010). "Cu-catalyzed efficient synthetic methodology for ebselen and related Se-N heterocycles". Organic Letters. 12 (23): 5394–7. doi:10.1021/ol102027j. PMID   21053969.
  19. ↑ DE3027073A1,Etschenberg, Eugen Dr; Renson, Marcel Prof Dipl-Chem Jupille& Winkelmann, Johannes Dr 5000 Köln,"2-phenyl-1,2-benzisoselenazol-3(2h)-on enthaltende pharmazeutische praeparate und ihre verwendung",issued 1982-02-18
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