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 (IC  ∼ 18 μM), two compounds, compounds 5 and 6, were similar in potency.

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.

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.

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.

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.

Azaanalogues of ebselen as antimicrobial and antiviral agents: synthesis and properties.

The different analogues of ebselen-unsubstituted benzisoselenazol-3(2H)-one (2a) 2-pyridylbenzisoselenazol-3(2H)-ones (2b-h) and 7-azabenzisoselenazol-3(2H)-ones (3a-j) were designed as new selenium-containing antiviral and antimicrobial agents and synthesized. Some of them were found in the antiviral assay in vitro to be strong inhibitors of cythopatic activity of herpes simplex virus type 1--HSV-1 (compounds 2a,b,f,h, 3a-j) and encephalomyocarditis virus--EMCV (compounds 2a,h, 3a-f,k,l). The compounds 2a,h and 3a-e,j were found to have an appreciable activity against Gram-positive bacteria (Staphylococcus aureus and Bacillus) in vitro, some of them inhibited growth of pathogenic yeasts (Candida albicans) (3a,b) and filamentous fungi (3a-e,f).

Functionalized alkyl and aryl diselenides as antimicrobial and antiviral agents: synthesis and properties.

The different dialkyl and diaryl diselenides with carbamoyl and sulfamoyl moieties 2, 3, 5 and other substituents in the ortho position of benzene ring 4, 7, 8 as well as derivatives of 1,2,4-benzoselenadiazine (6) were designed as antiviral and antimicrobial agents and synthesized. Some of them, particularly 8a and 8b, were found in the antiviral assay in vitro to be strong inhibitors of cytopathic activity encephalomyocarditis virus (EMCV). The compound 4a and 8a were found to have a broad spectrum of acivity against bacteria, yeasts and pathogenic fungi in vitro.

Antifungal activity of 2-(4-chlorophenyl)-1,2-benzisoselenazol-3(2H)-one, the analog of Ebselen.

The antimicrobial activity of 8 selenoorganic compounds (3-benzisoselenazoles, 1-benzisoselenazolone oxide and 4-disaryl diselenides) was investigated. It was found that selenoorganic compounds from benzisoselenazolone group suppress growth of some fungi and bacteria. The growth of Saccharomyces cerevisiae sigma 127-8b and Candida albicans 258 strains was strongly inhibited by the 2-(4-chlorophenyl)-1,2-benzisoselenazol-3(2H)-one.

Seleno-organic compounds as immunostimulants: an approach to the structure-activity relationship.

Our studies on the seleno-organic compounds were focused at their activities as the modest cytokine inducers in human peripheral blood leukocyte cultures. Our bioassays used in the screening methods were based on the quantitative determinations of mainly two types of cytokines: interferons (IFNs) and tumor necrosis factors (TNFs). More recently we have found that several of the compounds have direct immunotropic actions in vitro and in vivo, in mice and in chickens.

Immunotropic activities of benzisoselenazolones and organic diselenides in mice.

We have investigated the immunotropic effects of 23 seleno-organic compounds (8 benzisoselenazolones, 3 benzisoselenazolone oxides and 12 organic diselenides). All of the compounds increased the rosette formation of sheep red blood cells (SRBC) with spleen cells obtained from thymectomized C53BL/6 mice and incubated in vitro in the presence of imuran. Furthermore, 16 of the compounds were also assayed in vitro in the hydrocortisone test performed with C57BL/6 mouse thymocytes.

Effect of benzisoselenazolones and organic diselenides on graft versus host reaction and immunoglobulins levels in chickens.

Two week old chickens were treated once daily for 5 days with AE8--1-pyridyl-1,2-benzisoselenazol-3(2H)-one, AE22--bis-2-(N-phenyle-carboxamido) 1 pyridyl diselenide and AE31--bis(phenylo-diselenide with R3 = CONHC18H37). Their whole blood alone or blood mixed with thymus cells were used to generate graft versus host (GvH) reaction in 15 day old chicken embryos. The treatment of the chickens with the compounds stimulated the GvH reaction modifying activity of the donor cells as measured by increase of the spleen weight of the recipient chicken embryos.

Carboxyebselen a potent and selective inhibitor of endothelial nitric oxide synthase.

Ebselen (Ebs) a glutathione peroxidase like agent has been recently described as an inhibitor of nitric oxide synthase (NOS). Presently, we report that carboxyebselen (HOOC-Ebs), a hydrophyllic derivative of Ebs inhibits NOS present in enzymatic preparations from bovine endothelium, porcine cerebella, and murine spleen, however, it is both more potent and more selective for the constitutive endothelial NOS than Ebs. Unlike Ebs, HOOC-Ebs (0.

Simultaneous induction of interferon gamma and tumor necrosis factor alpha by different seleno-organic compounds in human peripheral blood leukocytes.

Ebselen is known as anti-inflammatory and anti-oxidant selenium containing drug. We have synthetized 13 seleno-organic compounds, analogs of ebselen. Seven of them were found to be inducers of interferon gamma (IFN-gamma) and/or tumor necrosis factor alpha (TNF-alpha) in human peripheral blood leukocytes (PBL) cultures.

Effects of some lipophilic carboxylic acid on release of interferon gamma from the human peripheral blood leukocytes.

Lipophilic carboxylic acids and their salts were tested for the ability of interferon induction in the cultures of human peripheral blood leukocytes. Of 13 tested organic compounds, two were selected: decyl-malonic acid and sodium salt of octylmethane-tri-(2-oxabutanoic)acid--which stimulated the synthesis of low amounts of gamma interferon.

Organoselenides as potential immunostimulants and inducers of interferon gamma and other cytokines in human peripheral blood leukocytes.

A number of organoselenium compounds have been described as anti-inflammatory, antioxidant, glutathione peroxidase-like agents and inhibitors of prostaglandin synthesis. Here we report that bis [2-(N-phenyl-carboxamido)]phenyl diselenide, 2-phenyl-1,2-benzisoselenazol-3(2H)-one (Ebselen) and related compounds are inducers of interferon gamma (IFN-gamma) and tumor necrosis factor (TNF) in human peripheral blood leukocytes. The IFN and TNF response was rapid, occurring within 20 h, and high--up to 1000 and 2000 units ml-1--and was clearly related to the dosage and the structure of the compounds.

Choline and halogen derivatives of CMA (9-oxo-10-acridine acetic acids) as tools for monitoring the interaction of the interferon inducers via a specific receptor.

New choline and halogen derivatives of CMA (9-oxo-10-acridine acetic acid) were investigated as interferon (IFN) inducers in mice and in the mouse bone marrow-derived macrophage cultures. Two of the choline derivatives, DMCMA and CSCMA, were active IFN inducers presumably because they were hydrolyzed so as to release CMA. The halogen analogues of CMA were inactive or weak IFN inducers in vivo and in vitro.

Competition of sodium salt of 9-oxo-10-acridineacetic acid with analogs during induction of interferon in the mouse bone marrow-derived macrophages.

Analogs of 9-oxo-10-acridineacetic acid (CMA) including new synthetic compounds, were found to be valuable tools for investigating the mechanism of interferon (IFN) induction. Experiments were performed on the long-term cultures of mouse bone marrow-derived macrophages which are unusually susceptible to IFN induction by CMA. CMA in the optimal nontoxic concentration of 600 micrograms/ml may induce in the macrophages up to 3.

Interaction of sodium salt of 9-oxo-10-acridineacetic acid (CMA) and its analogs with serum albumin. A model for study on binding of the interferon inducer with receptor.

Equilibrium dialysis, gel filtration and SDS polyacrylamide gel electrophoresis were used to study the interaction of sodium salt of 9-oxo-10-acridineacetic acid (CMA) as well as its analogs 7, 8, 11, 13 - 16 with proteins. The compounds were found to bind mainly to serum albumins. Several other proteins had no affinity to the compounds.

Induction of interferon in mice by sodium salt of 9-oxo-10-acridineacetic acid: specific enhancement by analogs.

9-oxo-10-acridineacetic acid bearing the common name of 10-carboxymethyl-9-acridanone or CMA (6) was found to be a very potent interferon (IFN) inducer in adult Balb/c mice. Seven structural analogs of CMA were synthetized and assayed for the interferon inducing ability. Three of the compounds had new chemical structures.

[Introduction of a preventive dental care program in an aluminum plant].

The paper presente experience acquired due to three years' oral prophylaxis programme designed for aluminum plant workers occupationally exposed to various hazards, particularly high concentrations of fluoride compounds. The programme covered oral health education, oral cavity irrigations and antidotum mouth-rinsing. The results indicate improvement of the dental health owing to the programme.