60940-34-3

Usage

Uses

Used in Pharmaceutical Industry:
Ebselen is used as an anti-inflammatory agent for its ability to modulate inflammatory pathways and reduce inflammation. It has been identified as a potent anti-inflammatory compound, with recent studies highlighting its effectiveness in inhibiting both vasospasm and tissue damage in cerebral stroke/ischemia animal models.
Ebselen is used as an antioxidant for its ability to protect against oxidative stress and reduce the oxidation of LDL, which contributes to the development of various diseases, including atherosclerosis and cardiovascular disorders.
Ebselen is used as a lipoxygenase inhibitor for its capacity to inhibit enzymes involved in inflammatory processes, thereby reducing inflammation and oxidative stress.
Ebselen is used as a modulator of KVβ subunits, which contributes to its anti-inflammatory properties and potential use in treating conditions associated with inflammation.
Used in Neuroprotection:
Ebselen is used as a neuroprotective agent for its ability to provide significant protection against ischemic damage in both gray and white matter, as well as in the ventral posterior nucleus of rodent brains. It has been shown to reduce neuronal death induced by ischemia and reperfusion in the hippocampal CA1 region of gerbils.
Ebselen is used as a treatment for bipolar disorder due to its ability to inhibit inositol monophosphatase, making it a potential safe treatment option for this condition.
Ebselen is used in the metabolic system for its involvement in controlling the expression of gamma-aminobutyric acid shunt enzymes, supplying the tricarboxylic acid cycle, and significantly inhibiting acetylcholinesterase activity, which demonstrates its engagement in the metabolic system and potential use in treating neurodegenerative disorders.

Reactions

Ebselen is a substrate for mammalian TrxR and can be converted to ebselen selenol by consuming NADPH.The reduction reaction acts with an apparent KM value of 2.5 mM and a kcat of 588 min-1. Oxidants such as H2O2 react with ebselen selenol to produce ebselen selenenic acid (EbSeOH), and spontaneously produce H2O and ebselen to form a redox cycling mechanism for ebselen. Upon the addition of Trx to TrxR, NADPH and ebselen, the reaction rate increases several-fold. This may be achieved by a very fast oxidation of reduced Trx by ebselen at a reaction rate constant42107 M1 s1.This rate is orders of magnitude faster than the reaction of reduced Trx with a substrate such as insulin disulfides. Thus, ebselen can compete with disulfide substrates for the reduction by Trx. These results indicate that ebselen can serve as a mediator in the redox environment via the Trx system.

Biochem/physiol Actions

Ebselen, a glutathione-peroxidase-mimic, elicits anti-inflammatory activity. It also has anti-atherosclerotic functionality. Ebselen displays antibacterial action on) multidrug-resistant Staphylococcus aureus (MRSA) infections and could be a potential therapeutic target for treating MRSA based skin infection. It is regarded as neuroprotective agent and elicits chemopreventive functionality in inflammation-associated carcinogenesis.

Clinical Use

Ebselen and its analogs have also been shown to be inhibitors of Bacillus anthracis TrxR. The ebselen analogs displayed antibacterial activity on Bacillus subtilis, S. aureus, Bacillus cereus and M. tuberculosis. There existed a high resistance barrier for the bacteria to develop ebselen-resistant strains and isolating resistant mutants was found to be difficult and, ultimately, unsuccessful.28 The reason for the difficulty of developing ebselen-resistant bacteria may be because ebselen has exerted a multiple drug-target mechanism, although the exact mechanism is not yet known. In addition to the thioredoxin and GSH systems, ebselen has been reported to have some other potential targets in bacteria, which may help it to overcome the bacterial drug resistance. Ebselen was identified as an inhibitor of diguanylate cyclases by a high-throughput screening in another study by covalent binding to Cys residues.29 This may block the cyclic-di-GMP signaling pathway, regulating biofilm formation, flagella-mediated motility in Pseudomonas aeruginosa, and thus its pathogenesis. Ebselen was identified as an inhibitor of the cysteine protease domain (CPD) in the Clostridium difficile major virulence factor toxin B (TcdB) by another high-throughput screening study. A CPD can bind with one or two ebselen molecules with a covalent modification probably occurring at the active site Cys. The treatment of ebselen blocked the toxic effects of TcdB and the pathology of C. difficile infection in mice.30 Another study also indicated that ebselen is a potent inhibitor of the M. tuberculosis Ag85 complex by binding covalently to a Cys residue (C209) located near the Ag85C active site, which is central to the synthesis of major components of the inner and outer leaflets of the mycobacterial outer membrane.

References

1) Schewe et al. (1995), Molecular actions of ebselen – an anti-inflammatory antioxidant; Gen. Pharmacol., 26 1153 2) Parnham et al. (2000), Ebselen: prospective therapy for cerebral ischaemia; Expert. Opin. Investig. Drugs, 9 607 3) Masumoto et al. (1996), Kinetic study of the reaction of ebselen with peroxynitite; FEBS Lett., 398 179 4) Nakamura et al. (2002), Ebselen, a glutathione peroxidase mimetic seleno-organic compound, as a multifunctional antioxidant. Implication for inflammation-associated carcinogenesis; J. Biol. Chem., 277 2687

InChI:InChI=1/C13H9NOSe/c15-13-11-8-4-5-9-12(11)16-14(13)10-6-2-1-3-7-10/h1-9H

Upstream product

• 93-98-1 N-phenyl benzoyl amide 
• 6512-83-0 2,2'-diselanediyl-di-benzoic acid 
• 7782-49-2 selenium 
• 6833-13-2 2-chlorobenzanilide 
• 136918-14-4 phthalimide 
• 110-05-4 di-tert-butyl peroxide 
• 106663-84-7 2,2‘-diselenobis(N-phenylbenzamide) 
• 60975-10-2 3-chloro-2-phenyl-benzo[d]isoselenazolium; chloride 
• 1441-85-6 2-(chloroseleno)benzoyl chloride 
• 62-53-3 aniline 
• 134-20-3 2-carbomethoxyaniline 
• 609-67-6 2-Iodobenzoyl chloride 
• 2099-63-0 anthranilic acid hydrochloride 
• 15310-01-7 benodanil 

Downstream Products

• 106663-84-7 2,2‘-diselenobis(N-phenylbenzamide) 
• 133956-02-2 S-(2-phenylcarbamoyl-phenylselenyl)-DL-mercaptosuccinic acid 
• 104030-69-5 S-(2-phenylcarbamoyl-phenylselenyl)-DL-2-mercaptopropionylglycine 
• 1022195-20-5 C₂₈H₂₄N₂O₂S₂Se₂ 
• 1022195-18-1 2-[(naphthalen-2-ylsulfanyl)seleno]benzanilide 
• 1338061-86-1 C₅₉H₆₄N₁₂O₈SSe 
• 1338061-87-2 C₇₀H₈₅N₁₉O₁₈S₂Se₂ 
• 101563-03-5 S-(2-phenylcarbamoyl-phenylselenyl)-L-cysteinethylester 
• 60940-41-2 benzo[d]isoselenazol-3-yl-phenyl-amine 
• 104473-83-8 2-phenyl-1,2-benzioselenazol-3(2H)-one selenoxide 

Relevant academic research and scientific papers

Thermal and Photoinduced Copper-Promoted C-Se Bond Formation: Synthesis of 2-Alkyl-1,2-benzisoselenazol-3(2H)-ones and Evaluation against Mycobacterium tuberculosis

2-Alkyl-1,2-benzisoselenazol-3(2H)-ones, represented by ebselen (1a), are being studied intensively for a range of medicinal applications. We describe both a new thermal and photoinduced copper-mediated cross-coupling between potassium selenocyanate (KSeCN) and N-substituted ortho-halobenzamides to form 2-alkyl-1,2-benzisoselenazol-3(2H)-ones containing a C-Se-N bond. The copper ligand (1,10-phenanthroline) facilitates C-Se bond formation during heating via a mechanism that likely involves atom transfer (AT), whereas, in the absence of ligand, photoinduced activation likely proceeds through a single electron transfer (SET) mechanism. A library of 15 2-alkyl-1,2-benzisoselenazol-3(2H)-ones was prepared. One member of the library was azide-containing derivative 1j that was competent to undergo a strain-promoted azide-alkyne cycloaddition. The library was evaluated for inhibition of Mycobacterium tuberculosis (Mtb) growth and Mtb Antigen 85C (Mtb Ag85C) activity. Compound 1f was most potent with a minimal inhibitory concentration (MIC) of 12.5 μg/mL and an Mtb Ag85C apparent IC50 of 8.8 μM.

Structure-Guided Discovery of the Novel Covalent Allosteric Site and Covalent Inhibitors of Fructose-1,6-Bisphosphate Aldolase to Overcome the Azole Resistance of Candidiasis

Fructose-1,6-bisphosphate aldolase (FBA) represents an attractive new antifungal target. Here, we employed a structure-based optimization strategy to discover a novel covalent binding site (C292 site) and the first-in-class covalent allosteric inhibitors

Inhibition of Pseudomonas aeruginosa Alginate Synthesis by Ebselen Oxide and Its Analogues

Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen that is frequently found in the airways of cystic fibrosis (CF) patients due to the dehydrated mucus that collapses the underlying cilia and prevents mucociliary clearance. During this life-long chronic infection, P. aeruginosa cell accumulates mutations that lead to inactivation of the mucA gene that results in the constitutive expression of algD-algA operon and the production of alginate exopolysaccharide. The viscous alginate polysaccharide further occludes the airways of CF patients and serves as a protective matrix to shield P. aeruginosa from host immune cells and antibiotic therapy. Development of inhibitors of alginate production by P. aeruginosa would reduce the negative impact from this viscous polysaccharide. In addition to transcriptional regulation, alginate biosynthesis requires allosteric activation by bis (3′-5′)-cyclic dimeric guanosine monophosphate (c-di-GMP) binding to an Alg44 protein. Previously, we found that ebselen (Eb) and ebselen oxide (EbO) inhibited diguanylate cyclase from synthesizing c-di-GMP. In this study, we show that EbO, Eb, ebsulfur (EbS), and their analogues inhibit alginate production. Eb and EbS can covalently modify the cysteine 98 (C98) residue of Alg44 and prevent its ability to bind c-di-GMP. However, P. aeruginosa with Alg44 C98 substituted with alanine or serine was still inhibited for alginate production by Eb and EbS. Our results indicate that EbO, Eb, and EbS are lead compounds for reducing alginate production by P. aeruginosa. Future development of these inhibitors could provide a potential treatment for CF patients infected with mucoid P. aeruginosa.

Discovery and Mechanism of SARS-CoV-2 Main Protease Inhibitors

The emergence of a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents an urgent public health crisis. Without available targeted therapies, treatment options remain limited for COVID-19 patients. Using medicinal chemistry and rational drug design strategies, we identify a 2-phenyl-1,2-benzoselenazol-3-one class of compounds targeting the SARS-CoV-2 main protease (Mpro). FRET-based screening against recombinant SARS-CoV-2 Mpro identified six compounds that inhibit proteolysis with nanomolar IC50 values. Preincubation dilution experiments and molecular docking determined that the inhibition of SARS-CoV-2 Mpro can occur by either covalent or noncovalent mechanisms, and lead E04 was determined to inhibit Mpro competitively. Lead E24 inhibited viral replication with a nanomolar EC50 value (844 nM) in SARS-CoV-2-infected Vero E6 cells and was further confirmed to impair SARS-CoV-2 replication in human lung epithelial cells and human-induced pluripotent stem cell-derived 3D lung organoids. Altogether, these studies provide a structural framework and mechanism of Mpro inhibition that should facilitate the design of future COVID-19 treatments.

Synthesis of Benzoisoselenazolones via Rh(III)-Catalyzed Direct Annulative Selenation by Using Elemental Selenium

Isoselenazolone derivatives have attracted significant research interest because of their potent therapeutic activities and indispensable applications in organic synthesis. Efficient construction of functionalized isoselenazolone scaffolds is still challenging, and thus new synthetic approaches with improved operational simplicity have been of particular interest. In this manuscript, we introduce a rhodium-catalyzed direct selenium annulation by using stable and tractable elemental selenium. A series of benzamides as well as acrylamides were successfully coupled with selenium under mild reaction conditions, and the obtained isoselenazolones could be pivotal synthetic precursors for several organoselenium compounds. Based on the designed control experiments and X-ray absorption spectroscopy measurements, we propose an unprecedented selenation mechanism involving a highly electrophilic Se(IV) species as the reactive selenium donor. The reaction mechanism was further verified by a computational study.

Fast and easy conversion oforthoamidoaryldiselenides into the corresponding ebselen-like derivatives driven by theoretical investigations

DFT calculations performed on amidoaryldiselenides as electrophilic derivatives evidenced the presence of a prevalent Se?O weak interaction when selenium is bonded to a Se atom (diselenides), a Br atom (selenenyl bromide) and an O atom (selenenic acid), while for selenenyl iodide derivatives, a prevalent contribution of the Se?N interaction was predicted. Thisin silicoobservation has been experimentally exploited for the efficient synthesis of a small library ofN-substituted benzoisoselenazol-3(2H)-ones and benzoisothiazol-3(2H)-ones considering the pharmacological relevance of ebselen recently reported also as an antiviral agent against Sars-Cov2.

Ebselen bearing polar functionality: Identification of potent antibacterial agents against multidrug-resistant Gram-negative bacteria

Antibiotic-resistant bacteria has become one of the greatest challenges to global human health today. Innovative strategies are needed to identify new therapeutic leads to tackle infections of drug-resistant Gram-negative bacteria. We herein synthesize a series of EB analogues to investigate their antibacterial activities. Select polar functionality at N-terminus of EB exhibited higher activities against multi-drug-resistant Gram-negative pathogens, including E. coli, P. aeruginosa and K. pneumoniae. EB analogue 4g and 4i exhibited potent antibacterial activities against E. coli-ESBL (MIC = 1–4 μg/mL) and E. coli producing NDM-1 (MIC = 4–32 μg/mL), which is superior to the traditional antibiotics (cefazolin, imipenem). Furthermore, the time-kill kinetics studies and the inhibition zone tests indicated that analogue 4i effectively and rapidly cause death of E. coli-ESBL and E. coli-NDM-1. Additionally, accumulation assays and SEM images showed that 4i could permeate bacterial membranes, leading to an irregular cell morphology. Importantly, bacterial resistance for analogue 4i was difficult to induce against E. coli-ESBL. EB analogues here reported low cytotoxicity against L-929 cells and mice model in vivo. We believe that EB analogues with polar functionality could play a pivotal role in the development of novel antibacterial agents in eradicating multi-drug-resistant Gram-negative pathogens infections.

Water-dependent synthesis of biologically active diaryl diselenides

A new one-step method for the synthesis of diaryl diselenides has been developed. The reaction of o-iodobenzamides with dilithium diselenide can be controlled by the presence of water providing a simple and efficient protocol to obtain benzisoselenazolones or diaryl diselenides. A series of N-Aryl ebselen derivatives and the corresponding diselenides was obtained. All synthesized compounds were tested in vitro as antioxidants and cytotoxic agents. N-(2,3,4-Trimethoxyphenyl)benzisoselenazol-3(2H)-one was the best in vitro antioxidant and the corresponding diselenide the most potent cytotoxic agent against prostate cancer cell line DU145, being inactive towards healthy prostate cell line PNT1A. Formula parented.

Aglycone Ebselen and β- D -Xyloside Primed Glycosaminoglycans Co-contribute to Ebselen β- D -Xyloside-Induced Cytotoxicity

Most β-d-xylosides with hydrophobic aglycones are nontoxic primers for glycosaminoglycan assembly in animal cells. However, when Ebselen was conjugated to d-xylose, d-glucose, d-galactose, and d-lactose (8A-D), only Ebselen β-d-xyloside (8A) showed significant cytotoxicity in human cancer cells. The following facts indicated that the aglycone Ebselen and β-d-xyloside primed glycosaminoglycans co-contributed to the observed cytotoxicity: 1. Ebselen induced S phase cell cycle arrest, whereas 8A induced G2/M cell cycle arrest; 2. 8A augmented early and late phase cancer cell apoptosis significantly compared to that of Ebselen and 8B-D; 3. Both 8A and phenyl-β-d-xyloside primed glycosaminoglycans with similar disaccharide compositions in CHO-pgsA745 cells; 4. Glycosaminoglycans could be detected inside of cells only when treated with 8A, indicating Ebselen contributed to the unique property of intracellular localization of the primed glycosaminoglycans. Thus, 8A represents a lead compound for the development of novel antitumor strategy by targeting glycosaminoglycans.

SUBSTITUTED ISOSELENAZOLONE ANTI-INFLAMMATORY, ANTI-CANCER, CYTOPROTECTIVE, NEUROPROTECTIVE, AND ANTI-OXIDANT AGENTS

Compounds, compositions, and methods for the treatment of infections, inflammation, cancers, tinnitus, Meniere's disease, hearing loss, or bipolar disorder, or for providing cytoprotection against Clostridium difficile toxins, are disclosed.