In vitro assessment of the growth and plasma membrane H+ -ATPase inhibitory activity of ebselen and structurally related selenium- and sulfur-containing compounds in Candida albicans.

Ebselen (EB, compound 1) is an investigational organoselenium compound that reduces fungal growth, in part, through inhibition of the fungal plasma membrane H+ -ATPase (Pma1p). In the present study, the growth inhibitory activity of EB and of five structural analogs was assessed in a fluconazole (FLU)-resistant strain of Candida albicans (S2). While none of the compounds were more effective than EB at inhibiting fungal growth (IC50  âˆ¼ 18 µM), two compounds, compounds 5 and 6, were similar in potency. Medium acidification assays performed with S2 yeast cells revealed that compounds 4 and 6, but not compounds 2, 3, or 5, exerted an inhibitory activity comparable to EB (IC50  âˆ¼ 14 µM). Using a partially purified Pma1p preparation obtained from S2 yeast cells, EB and all the analogs demonstrated a similar inhibitory activity. Taken together, these results indicate that EB analogs are worth exploring further for use as growth inhibitors of FLU-resistant fungi.

Developments in Synthetic Application of Selenium(IV) Oxide and Organoselenium Compounds as Oxygen Donors and Oxygen-Transfer Agents.

A variety of selenium compounds were proven to be useful reagents and catalysts for organic synthesis over the past several decades. The most interesting aspect, which emerged in recent years, concerns application of hydroperoxide/selenium(IV) oxide and hydroperoxide/organoselenium catalyst systems, as "green reagents" for the oxidation of different organic functional groups. The topic of oxidations catalyzed by organoselenium derivatives has rapidly expanded in the last fifteen years This paper is devoted to the synthetic applications of the oxidation reactions mediated by selenium compounds such as selenium(IV) oxide, areneseleninic acids, their anhydrides, selenides, diselenides, benzisoselenazol-3(2H)-ones and other less often used other organoselenium compounds. All these compounds have been successfully applied for various oxidations useful in practical organic syntheses such as epoxidation, 1,2-dihydroxylation, and α-oxyfunctionalization of alkenes, as well as for ring contraction of cycloalkanones, conversion of halomethyl, hydroxymethyl or active methylene groups into formyl groups, oxidation of carbonyl compounds into carboxylic acids and/or lactones, sulfides into sulfoxides, and secondary amines into nitrones and regeneration of parent carbonyl compounds from their azomethine derivatives. Other reactions such as dehydrogenation and aromatization, active carbon-carbon bond cleavage, oxidative amidation, bromolactonization and oxidation of bromide for subsequent reactions with alkenes are also successfully mediated by selenium (IV) oxide or organoselenium compounds. The oxidation mechanisms of ionic or free radical character depending on the substrate and oxidant are discussed. Coverage of the literature up to early 2015 is provided. Links have been made to reviews that summarize earlier literature and to the methods of preparation of organoselenium reagents and catalysts.

Ebselen reduces the toxicity of mechlorethamine in A-431 cells via inhibition of apoptosis.

A series of test compounds were evaluated for an ability to reduce the toxicity of the nitrogen mustard mechlorethamine (HN2) in vitro. The test compounds included resveratrol, pterostilbene, vitamin C, ebselen, ebselen diselenide, and ebselen-sulfur. Among them, ebselen demonstrated the highest degree of protection against HN2 toxicity. To this end, pretreatment of the cells with ebselen offered protection against the toxicant whereas no protection was observed when cells were first incubated with HN2 and then treated with ebselen. Significant increases in caspase 3 and caspase 9 activities were observed in response to HN2, and ebselen was found to reduce these effects. Taken together, the data presented here indicate that ebselen is an effective countermeasure to nitrogen mustard in vitro, which is worthy of future investigation in vivo.

Crucial role of selenium in the virucidal activity of benzisoselenazol-3(2H)-ones and related diselenides.

Various N-substituted benzisoselenazol-3(2H)-ones and their non-selenium-containing analogues have been synthesized and tested against selected viruses (HHV-1, EMCV and VSV) to determine the extent to which selenium plays a role in antiviral activity. The data presented here show that the presence of selenium is crucial for the antiviral properties of benzisoselenazol-3(2H)-ones since their isostructural analogues having different groups but lacking selenium either did not show any antiviral activity or their activity was substantially lower. The open-chain analogues of benzisoselenazol-3(2H)-ones--diselenides also exhibited high antiviral activity while selenides and disulfides were completely inactive towards model viruses.

Evaluation of the antifungal and plasma membrane H+-ATPase inhibitory action of ebselen and two ebselen analogs in S. cerevisiae cultures.

The plasma membrane H(+)-ATPase pump (Pma1p) has been proposed as a viable target for antifungal drugs since this high capacity proton pump plays a critical role in the intracellular regulation of pH and in nutrient uptake of yeast and other fungi. In recent years, this and other laboratories have verified that the antifungal activity of 2-phenylbenzisoselenazol-3(2H)-one, an organoselenium compound commonly referred to as ebselen (1), stems, at least in part, from its inhibitory action on the fungal Pma1p. In the present study, the antifungal efficacy of 2-(3-pyridinyl)-benzisoselenazol-3(2H)-one (2) and 2-phenylbenzisoselenazol-3(2H)-one 1-oxide (3), two ebselen analogs, was evaluated using a strain of S. cerevisiae and compared against that of 1. In addition, the study also examined the inhibitory potential of these three compounds toward the Pma1p of S. cerevisiae. Based on mean IC(50) values, the antifungal potency was found to decrease in the order 3 > 1 > 2. However, in terms of inhibitory action on Pma1p, the potency decreased in the order 1 > 3 > 2. The magnitude of these activities appears to be correlated with the corresponding log P values, with compound 2 being the most hydrophilic and the least active of the three.

New organoselenium compounds active against pathogenic bacteria, fungi and viruses.

Different N-substituted benzisoselenazol-3(2H)-ones, analogues of ebselen were designed as new antiviral and antimicrobial agents. We report their synthesis, chemical properties as well as study on biological activity against broad spectrum of pathogenic microorganisms (Staphylococcus aureus, Staphylococcus simulans, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Candida albicans, Aspergillus niger) and viruses (herpes simplex virus type 1 (HSV-1), encephalomyocarditis virus (EMCV), vesicular stomatitis virus (VSV)), in vitro. Most of them exhibited high activity against viruses (HSV-1, EMCV) and gram-positive bacteria strains (S. aureus, S. simulans), while their activity against gram-negative bacteria strains (E. coli, P. aeruginosa, K. pneumoniae) was substantially lower. Some of tested compounds were active against yeast C. albicans and filamentous fungus A. niger.