Ebselen

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] hearing loss and tinnitus,[4] and bipolar disorder.[5][6]

Ebselen
Names
IUPAC name
2-Phenyl-1,2-benzoselenazol-3-one
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.132.190
UNII
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).
N verify (what is YN ?)
Infobox references

Additionally, ebselen may be effective against Clostridium difficile infections[7] and has been shown to have antifungal activity against Aspergillus fumigatus.[8]

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.[9]

Possible anti-COVID-19 activity

Preliminary studies demonstrate that Ebselen exhibits promising inhibitory activity against COVID-19 in cell-based assays.[10] 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).[10]

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),[11][12] by ortho-lithiation of benzanilides followed by oxidative cyclization (Route II) mediated by cupric bromide (CuBr2),[13] or through the efficient Cu-catalyzed selenation / heterocyclization of o-halobenzamides, a methodology developed by Kumar et al.[14] (Route III).

References
  1. Schewe T (1995). "Molecular actions of ebselen--an antiinflammatory antioxidant". Gen Pharmacol. 26 (6): 1153–69. doi:10.1016/0306-3623(95)00003-J. PMID 7590103.
  2. Parnham M, Sies H (2000). "Ebselen: prospective therapy for cerebral ischaemia". Expert Opin Investig Drugs. 9 (3): 607–19. doi:10.1517/13543784.9.3.607. PMID 11060699.
  3. Yamaguchi T, Sano K, Takakura K, Saito I, Shinohara Y, Asano T, Yasuhara H (1 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. Kil, Jonathan; Pierce, Carol; Tran, Huy; Gu, Rende; Lynch, Eric D (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.
  5. Singh, N.; Halliday, A. C.; Thomas, J. M.; Kuznetsova, O. V.; Baldwin, R.; Woon, E. C. Y.; Aley, P. K.; Antoniadou, I.; Sharp, T.; Vasudevan, S. R.; Churchill, G. C. (2013). "A safe lithium mimetic for bipolar disorder". Nature Communications. 4: 1332. Bibcode:2013NatCo...4.1332S. doi:10.1038/ncomms2320. PMC 3605789. PMID 23299882.
  6. "New drug for bipolar disorder may offer fewer side effects". University of Oxford Latest News. 2013-01-08. Retrieved 12 January 2013.
  7. "Drug disarms deadly C. difficile bacteria without destroying healthy gut flora". Medical Express.
  8. Marshall, Andrew C.; Kidd, Sarah E.; Lamont-Friedrich, Stephanie J.; Arentz, Georgia; Hoffmann, Peter; Coad, Bryan R.; Bruning, John B. (26 February 2019). "Structure, Mechanism, and Inhibition of Thioredoxin Reductase". Antimicrobial Agents and Chemotherapy. 63 (3): e02281-18. doi:10.1128/AAC.02281-18. PMC 6395915. PMID 30642940.
  9. Satheeshkumar K, Mugesh G (2011). "Synthesis and Antioxidant Activity of Peptide-Based Ebselen Analogues". Chem. Eur. J. 17 (17): 4849–57. doi:10.1002/chem.201003417. PMID 21400619.
  10. Jin, Z. et al. Structure of Mpro from COVID-19 virus and discovery of its inhibitors. Nature https://doi.org/10.1038/s41586-020-2223-y (2019).
  11. Kamigata, Nobumasa; Iizuka, Hirokazu; Izuoka, Akira; Kobayashi, Michio (1986-01-01). "Photochemical Reaction of 2-Aryl-1,2-benzisoselenazol-3(2H)-ones". Bulletin of the Chemical Society of Japan. 59 (7): 2179–2183. doi:10.1246/bcsj.59.2179.
  12. Elsherbini, Mohamed; Hamama, Wafaa S.; Zoorob, Hanafi H.; Bhowmick, Debasish; Mugesh, Govindasamy; Wirth, Thomas (2014-11-01). "Synthesis and Antioxidant Activities of Novel Chiral Ebselen Analogues". Heteroatom Chemistry. 25 (5): 320–325. doi:10.1002/hc.21164. ISSN 1098-1071.
  13. Engman, Lars; Hallberg, Anders (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.
  14. Balkrishna, Shah Jaimin; Bhakuni, Bhagat Singh; Chopra, Deepak; Kumar, Sangit (2010-12-03). "Cu-Catalyzed Efficient Synthetic Methodology for Ebselen and Related Se−N Heterocycles". Organic Letters. 12 (23): 5394–5397. doi:10.1021/ol102027j. ISSN 1523-7060. PMID 21053969.
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