RESUMO
Although Candida albicans is the most frequently identified Candida species in clinical settings, a significant number of infections related to the non-albicans Candida (NAC) species, Candida krusei, has been reported. Both species are able to produce biofilms and have been an important resistance-related factor to antimicrobial resistance. In addition, the microbial relationship is common in the human body, contributing to the formation of polymicrobial biofilms. Considering the great number of reports showing the increase in cases of resistance to the available antifungal drugs, the development of new and effective antifungal agents is critical. The inhibitory effect of Organoselenium Compounds (OCs) on the development of Candida albicans and Candida krusei was recently demonstrated, supporting the potential of these compounds as efficient antifungal drugs. In addition, OCs were able to reduce the viability and the development of biofilms, a very important step in colonization and infection caused by fungi. Thus, the objective of this study was to investigate the effect of the Organoselenium Compounds (p-MeOPhSe)2, (PhSe)2, and (p-Cl-PhSe)2 on the development of dual-species biofilms of Candida albicans and Candida krusei produced using either RPMI-1640 or Sabouraud Dextrose Broth (SDB) media. The development of dual-species biofilms was evaluated by the determination of both metabolic activity, using a metabolic assay based on the reduction of XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide sodium salt) assay and identification of either Candida albicans and Candida krusei on CHROMagar Candida medium. Biofilm formation using RPMI-1640 was inhibited in 90, 55, and 20% by 30 µM (p-MeOPhSe)2, (PhSe)2, and (p-Cl-PhSe)2, respectively. However, biofilms produced using SDB presented an inhibition of 62, 30 and 15% in the presence of 30 µM (p-MeOPhSe)2, (PhSe)2, and (p-Cl-PhSe)2, respectively. The metabolic activity of 24 h biofilms was inhibited by 35, 30 and 20% by 30 µM (p-MeOPhSe)2, (PhSe)2, and (p-Cl-PhSe)2, respectively, with RPMI-1640; however, 24 h biofilms formed using SDB were not modified by the OCs. In addition, a great reduction in the number of CFUs of Candida albicans (93%) in biofilms produced using RPMI-1640 in the presence of 30 µM (p-MeOPhSe)2 was observed. However, biofilms formed using SDB and treated with 30 µM (p-MeOPhSe)2 presented a reduction of 97 and 69% in the number of CFUs of Candida albicans and Candida krusei, respectively. These results demonstrated that Organoselenium Compounds, mainly (p-MeOPhSe)2, are able to decrease the metabolic activity of dual-species biofilms by reducing both Candida albicans and Candida krusei cell number during biofilm formation using either RPMI-1640 or SDB. Taken together, these results demonstrated the potential of the OCs to inhibit the development of dual-species biofilms of Candida albicans and Candida krusei.
RESUMO
The chemical and biological interest in this element and the molecules bearing selenium has been exponentially growing over the years. Selenium, formerly designated as a toxin, becomes a vital trace element for life that appears as selenocysteine and its dimeric form, selenocystine, in the active sites of selenoproteins, which catalyze a wide variety of reactions, including the detoxification of reactive oxygen species and modulation of redox activities. From the point of view of drug developments, organoselenium drugs are isosteres of sulfur-containing and oxygen-containing drugs with the advantage that the presence of the selenium atom confers antioxidant properties and high lipophilicity, which would increase cell membrane permeation leading to better oral bioavailability. This statement is the paramount relevance considering the big number of clinically employed compounds bearing sulfur or oxygen atoms in their structures including nucleosides and carbohydrates. Thus, in this article we have focused on the relevant features of the application of selenium in medicinal chemistry. With the increasing interest in selenium chemistry, we have attempted to highlight the most significant published data on this subject, mainly concentrating the analysis on the last years. In consequence, the recent advances of relevant pharmacological organoselenium compounds are discussed.
Assuntos
Compostos Organosselênicos , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Humanos , Química Farmacêutica , Estrutura Molecular , Animais , Antioxidantes/química , Antioxidantes/farmacologiaRESUMO
Selenium, originally described as a toxin, turns out to be a crucial trace element for life that appears as selenocysteine and its dimer, selenocystine. From the point of view of drug developments, selenium-containing drugs are isosteres of sulfur and oxygen with the advantage that the presence of the selenium atom confers antioxidant properties and high lipophilicity, which would increase cell membrane permeation leading to better oral bioavailability. In this article, we have focused on the relevant features of the selenium atom, above all, the corresponding synthetic approaches to access a variety of organoselenium molecules along with the proposed reaction mechanisms. The preparation and biological properties of selenosugars, including selenoglycosides, selenonucleosides, selenopeptides, and other selenium-containing compounds will be treated. We have attempted to condense the most important aspects and interesting examples of the chemistry of selenium into a single article.
RESUMO
BACKGROUND: Candida auris is an emergent fungal pathogen and a global concern, mostly due to its resistance to many currently available antifungal drugs. OBJECTIVE: Thus, in response to this challenge, we evaluated the in vitro activity of potential new drugs, diphenyl diselenide (PhSe)2 and nikkomycin Z (nikZ), alone and in association with currently available antifungals (azoles, echinocandins, and polyenes) against Candida auris. METHODS: Clinical isolates of C. auris were tested in vitro. (PhSe)2 and nikZ activities were tested alone and in combination with amphotericin B, fluconazole, or the echinocandins, micafungin and caspofungin. RESULTS: (PhSe)2 alone was unable to inhibit C. auris, and antagonism or indifferent effects were observed in the combination of this compound with the antifungals tested. NikZ appeared not active alone either, but frequently acted cooperatively with conventional antifungals. CONCLUSION: Our data show that (PhSe)2 appears to not have a good potential to be a candidate in the development of new drugs to treat C. auris, but that nikZ is worthy of further study.
RESUMO
The aim of this study was to evaluate the in vitro antifungal action of a diphenyl diselenide-loaded poly(ε-caprolactone) nanocapsules suspension (NC-1) and incorporate it into a gellan gum hydrogel formulation in order to assess its in vivo efficacy in an animal model of vulvovaginal candidiasis. Nanocapsules suspensions containing the compound (NC-1 â¼ 5 mg/mL) or not (NC-B) were prepared by the interfacial deposition of preformed polymer method. To estimate in vitro antifungal effect, the broth microdilution test was applied. The results showed that NC-1 had equal or lower MIC values when compared to free compound against fifteen Candida strains. Following, the hydrogel was prepared by direct thickening of the nanocapsules suspension by gellan gum addition. The animal model of vulvovaginal candidiasis was induced by infecting female Swiss mice with Candida albicans strains. The animals were topically treated with 20 µL of hydrogels (NC-1 and free compound - 0.1 mg of diphenyl diselenide/once a day for seven days) and then the total fungal burden was assessed after the euthanasia. The results showed that the hydrogels presented pH in the acidic range, compound content close to theoretical value, homogeneous particle distribution with nanometric size, high physicochemical and microbiological stability as well as great bioadhesive property. The nano-based presented superior pharmacological action in comparison to the hydrogel containing non-encapsulated diphenyl diselenide. The results demonstrated that the nanoencapsulation maintained the effective antifungal action of diphenyl diselenide. The nano-based hydrogel formulation may be considered a promising approach against vulvovaginal candidiasis.
Assuntos
Candidíase Vulvovaginal , Nanocápsulas , Animais , Antifúngicos/uso terapêutico , Derivados de Benzeno , Candida , Candidíase Vulvovaginal/tratamento farmacológico , Feminino , Humanos , Hidrogéis/uso terapêutico , Camundongos , Nanocápsulas/uso terapêutico , Compostos Organosselênicos , Polissacarídeos BacterianosRESUMO
Cryptococcus is an encapsulated yeast that causes fungal meningitis, most commonly in HIV patients, with high mortality rates. Thus, the study of new treatment options is relevant. Antifungal activity of organoselenium compounds attributed to their pro-oxidative effect in fungal cells has been shown given that few data regarding its anti-Cryptococcus activity are available, this in vitro study was conducted with 40 clinical isolates of Cryptococcus neoformans. Diphenyl diselenide (DD) alone, and its interaction with amphotericin B or fluconazole, was tested by microdilution and checkerboard assays. All Cryptococcus neoformans were inhibited by DD in concentrations ≤ 32 µg/mL, and fungicidal concentrations were ≤ 64 µg/mL. Advantageous interaction between fluconazole occurred in 40% of the isolates, respectively. This study contributes with data of DD alone and in combination with classical drugs of choice for cryptococcosis treatment. Further studies focused on DD antifungal mechanism of action, and in vivo experiments are necessary.
Assuntos
Derivados de Benzeno , Criptococose , Cryptococcus neoformans , Compostos Organosselênicos , Anfotericina B/farmacologia , Antifúngicos/farmacologia , Derivados de Benzeno/farmacologia , Criptococose/tratamento farmacológico , Cryptococcus neoformans/efeitos dos fármacos , Fluconazol/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Compostos Organosselênicos/farmacologiaRESUMO
Fungal infections are one of the most prevalent diseases in the world and there is a lack of new antifungal drug development for these diseases. We conducted a systematic review of the literature regarding the in vitro antifungal activity of the organoselenium compounds ebselen (Eb) and diphenyl diselenide [(PhSe)2]. A systematic review was carried out based on the search for articles with data concerning Minimal Inhibitory Concentration (MIC) values, indexed in international databases and published until August 2020. A total of 2337 articles were found, and, according to the inclusion and exclusion criteria used, 22 articles were included in the study. Inhibitory activity against 96% (200/208) and 95% (312/328) of the pathogenic fungi tested was described for Eb and [(PhSe)2], respectively. Including in these 536 fungal isolates tested, organoselenium activity was highlighted against Candida spp., Cryptococcus ssp., Trichosporon spp., Aspergillus spp., Fusarium spp., Pythium spp., and Sporothrix spp., with MIC values lower than 64 µg/mL. In conclusion, Eb and [(PhSe)2] have a broad spectrum of in vitro inhibitory antifungal activity. These data added with other pharmacological properties of these organoselenium compounds suggest that both compounds are potential future antifungal drugs. Whether MICs toward the upper end of the ranges described here are compatible with efficacious therapy, and whether they may achieve such end as a result of the favorable non-antimicrobial effects of selenium on the host, requires more in vivo testing.
Fungal infections require the investigation of new drugs. The study is a systematic review of organo-selenium compounds with potential antifungal action. In 22 articles included in this review, in a total of 536 isolates of pathogenic fungi tested, the compounds showed action in more than 90% of them.
Assuntos
Derivados de Benzeno/farmacologia , Fungos/efeitos dos fármacos , Isoindóis/farmacologia , Compostos Organosselênicos/farmacologia , Animais , Antifúngicos/farmacologia , Derivados de Benzeno/química , Sinergismo Farmacológico , Humanos , Isoindóis/química , Testes de Sensibilidade Microbiana , Micoses/tratamento farmacológico , Micoses/microbiologia , Compostos Organosselênicos/químicaRESUMO
Most pharmacological studies concerning the beneficial effects of organoselenium compounds have focused on their ability to mimic glutathione peroxidase (GPx). However, mechanisms other than GPx-like activity might be involved on their biological effects. This study was aimed to investigate and compare the protective effects of two well known [(PhSe)2 and PhSeZnCl] and two newly developed (MRK Picolyl and MRK Ester) organoselenium compounds against oxidative challenge in cultured neuronal HT22 cells. The thiol peroxidase and oxidase activities were performed using the glutathione reductase (GR)-coupled assay. In order to evaluate protective effects of the organoselenium compounds against oxidative challenge in neuronal HT22 cells, experiments based on glutamate-induced oxytosis and SIN-1-mediated peroxynitrite generation were performed. The thiol peroxidase activities of the studied organoselenium compounds were smaller than bovine erythrocytes GPx enzyme. Besides, (PhSe)2 and PhSeZnCl showed higher thiol peroxidase and lower thiol oxidase activities compared to the new compounds. MRK Picolyl and MRK Ester, which showed lower thiol peroxidase activity, showed higher thiol oxidase activity. Both pre- or co-treatment with (PhSe)2, PhSeZnCl, MRK Picolyl and MRK Ester protected HT22 cells against glutamate-induced cytotoxicity. (PhSe)2 and MRK Picolyl significantly prevented peroxinitrite-induced dihydrorhodamine oxidation, but this effect was observed only when HT22 were pre-treated with these compounds. The treatment with (PhSe)2 increased the protein expression of antioxidant defences (Prx3, CAT and GCLC) in HT22 cells. Taking together, our results suggest that the biological effects elicited by these compounds are not directly related to their GPx-mimetic and thiol oxidase activities, but might be linked to the up-regulation of endogenous antioxidant defences trough their thiol-modifier effects.
Assuntos
Antioxidantes/farmacologia , Neurônios/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Catalase/metabolismo , Bovinos , Linhagem Celular , Glutamato-Cisteína Ligase/metabolismo , Glutationa Peroxidase/metabolismo , Proteínas de Homeodomínio/metabolismo , CamundongosRESUMO
Diphenyl diselenide [(PhSe)2] is a pleiotropic pharmacological agent, but it has low aqueous solubility. The nanoencapsulation of (PhSe)2 allowed the preparation of an aqueous formulation as well as potentiated its in vitro antitumor effect and the effectiveness in a preclinical model of glioblastoma when administered by the intragastric route. Thus, aiming at maximizing the therapeutic potential of (PhSe)2, the present study designed a pegylated-formulation intending to intravenous administration of the (PhSe)2 as a new approach for glioma therapy. The poly(Æ-caprolactone) nanocapsules containing (PhSe)2 were physically coated with polyethyleneglycol (PEG) using the preformed polymer interfacial deposition technique and evaluated through physicochemical, morphological, spectroscopic, and thermal characteristics. Hemocompatibility was determined by the in vitro hemolysis test and cytotoxicity assays were performed in astrocytes and glioma C6 cells (10-100 µM). The pegylated-nanocapsules had an average diameter of 218 ± 25 nm, polydispersity index of 0.164 ± 0.046, zeta potential of - 8.1 ± 1.6 mV, pH 6.0 ± 0.09, (PhSe)2 content of 102.00 ± 3.57%, and encapsulation efficiency around 98%. Besides, the (PhSe)2 pegylated-nanocapsules were spherical, presented absence of chemical interaction among the constituents, and showed higher thermal stability than the non-encapsulated materials. PEG-coated nanocapsules did not cause hemolytic effect while formulations without PEG induced a hemolysis rate above 10%. Moreover, pegylated-nanocapsules had superior in vitro antiglioma effect in comparison to free compound (IC50: 24.10 µM and 74.83 µM, respectively). Therefore, the (PhSe)2-loaded pegylated-nanocapsule suspensions can be considered a hemocompatible formulation for the glioma treatment by the intravenous route.
Assuntos
Antineoplásicos/administração & dosagem , Derivados de Benzeno/administração & dosagem , Materiais Biocompatíveis , Glioma/tratamento farmacológico , Nanocápsulas/química , Compostos Organosselênicos/administração & dosagem , Polietilenoglicóis/química , Animais , Antineoplásicos/química , Astrócitos/efeitos dos fármacos , Derivados de Benzeno/química , Compostos Organosselênicos/química , SolubilidadeRESUMO
Previous findings showed that the nanoencapsulation of diphenyl diselenide [(PhSe)2], an organoselenium compound, provided superior biological effects and lower toxicological potential than its free form in vitro. However, few studies reported the behavioral and biochemical effects of this nanocapsules formulation in vivo. Zebrafish (Danio rerio) has emerged as a useful animal model to determine the pharmacological and toxicological effects of nanoparticles. Here, we evaluated the behavioral and brain oxidative effects after zebrafish exposure to (PhSe)2-loaded nanocapsules. Formulations were prepared by interfacial deposition of preformed polymer method and later tested at concentrations ranging from 0.1 to 2.0 µM. Both locomotor and exploratory activities were assessed in the novel tank diving test. Moreover, brain oxidative status was determined by measuring thiobarbituric acid-reactive substance levels, glutathione peroxidase, glutathione redutase and glutathione S-transferase activities. (PhSe)2-loaded nanocapsules showed no alteration on travelled distance, immobility, and erratic swimming, suggesting the absence of behavioral impairments. Interestingly, the higher concentration tested had anxiolytic-like effects, since animals spent more time in the top area and showed a decreased thigmotaxis behavior. Biochemical analysis demonstrated that the concentrations used in this study did not affect oxidative stress-related parameters in brain samples, reinforcing the low toxicological potential of the formulation. In conclusion, the exposure to (PhSe)2-loaded nanocapsules caused no locomotor impairments as well as did not modify the oxidative status of zebrafish brain, indicating that this formulation is probably non-toxic and promising for future pharmacological studies.
Assuntos
Derivados de Benzeno/administração & dosagem , Derivados de Benzeno/farmacologia , Encéfalo/efeitos dos fármacos , Nanocápsulas/administração & dosagem , Compostos Organosselênicos/administração & dosagem , Compostos Organosselênicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Polímeros/administração & dosagem , Peixe-Zebra/metabolismo , Animais , Encéfalo/metabolismo , Feminino , MasculinoRESUMO
This study evaluated the in vitro susceptibility of Trichosporon asahii strains to diphenyl diselenide (DPDS) and ebselen (EBS) alone and in combination with amphotericin B (AMB), fluconazole (FCZ), itraconazole (ITZ) and caspofungin (CAS) using the microdilution method. EBS showed in vitro activity against T asahii strains with minimal inhibitory concentration (MIC) ranged from 0.25 to 8.0 µg/mL. For DPDS, the MIC ranged from 8.0 to 64 µg/mL. The combinations demonstrating the greatest synergism rate against fluconazole-resistant T asahii strains were the following: CAS + DPDS (96.67%), AMB + DPDS (93.33%), FCZ + DPDS (86.67%) and ITZ + DPDS (83.33%). The combinations AMB + DPDS and AMB + EBS exhibited the highest synergism rate against the fluconazole-susceptible (FS) T asahii strains (90%). Antagonism was observed in the following combinations: FCZ + EBS (80%) and FCZ + DPDS (13.33%) against the FS strains, and ITZ + EBS (20%) against the FR strains. Our findings suggest that the antimicrobial activity of DPDS and EBS against T. asahii and its use as an adjuvant therapy with antifungal agents warrant in vivo experimental investigation.
Assuntos
Antifúngicos/farmacologia , Azóis/farmacologia , Derivados de Benzeno/farmacologia , Agonismo de Drogas , Sinergismo Farmacológico , Compostos Organosselênicos/farmacologia , Trichosporon/efeitos dos fármacos , Isoindóis , Testes de Sensibilidade MicrobianaRESUMO
We describe here a simple method for the synthesis of 6-arylselanylpurines with antioxidant and anticholinesterase activities, and memory improvement effect. This class of compounds was synthesized in good yields by a reaction of 6-chloropurine with diaryl diselenides using NaBH4 as reducing agent and PEG-400 as solvent. Furthermore, the synthesized compounds were evaluated for their in vitro antioxidant and acetylcholinesterase (AChE) inhibitor activities. The best AChE inhibitor was assessed on the in vivo memory improvement. Our results demonstrated that the 6-((4-chlorophenyl)selanyl)-9H-purine and 6-(p-tolylselanyl)-9H-purine presented in vitro antioxidant effect. In addition, 6-((4-fluorophenyl)selanyl)-9H-purine inhibited the AChE activity and improved memory, being a promising therapeutic agent for the treatment of Alzheimer's disease.
Assuntos
Acetilcolinesterase/metabolismo , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Memória/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Purinas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Animais , Antioxidantes/administração & dosagem , Antioxidantes/química , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/síntese química , Relação Dose-Resposta a Droga , Masculino , Camundongos , Estrutura Molecular , Compostos Organosselênicos/administração & dosagem , Compostos Organosselênicos/síntese química , Purinas/administração & dosagem , Purinas/química , Relação Estrutura-AtividadeRESUMO
The use of sonochemistry is described in the organocatalytic enamine-azide [3 + 2] cycloaddition between 1,3-diketones and aryl azidophenyl selenides. These sonochemically promoted reactions were found to be amenable to a range of 1,3-diketones or aryl azidophenyl selenides, providing an efficient access to new ((arylselanyl)phenyl-1H-1,2,3-triazol-4-yl)ketones in good to excellent yields and short reaction times. In addition, this protocol was extended to ß-keto esters, ß-keto amides and α-cyano ketones. Selanyltriazoyl carboxylates, carboxamides and carbonitriles were synthesized in high yields at short times of reaction under very mild reaction conditions.
RESUMO
Acquired immunodeficiency syndrome (AIDS) is a worldwide disease characterized by impairments of immune function. AIDS can be associated with oxidative stress (OS) that can be linked to selenium (Se) deficiency. Se is fundamental for the synthesis of selenoproteins, such as glutathione peroxidase and thioredoxin reductase. These enzymes catalyze the decomposition of reactive oxygen species and contribute to maintain equilibrium in cell redox status. Literature data indicate that organoselenium compounds, such as ebselen and diphenyl diselenide, have antioxidant properties in vitro and in vivo models associated with OS. Nevertheless, selenocompounds can also react and oxidize thiols groups, inducing toxicity in mammals. Here, we tested the potential cytotoxic and genotoxic properties of six analogs of the prototypal anti-HIV drug azidothymidine (AZT) containing Se (5'-Se-(phenyl)zidovudine; 5'-Se-(1,3,5-trimethylphenyl)zidovudine; 5'-Se-(1-naphtyl)zidovudine; 5'-Se-(4-chlorophenyl)zidovudine) (C4); 5'-Se-(4-methylphenyl)zidovudine (C5); and 5'-(4-methylbenzoselenoate)zidovudine). C5 increased the rate of dithiothreitol oxidation (thiol oxidase activity) and C2-C4 and C6 (at 100 µM) increased DNA damage index (DI) in human leukocytes. Moreover, C5 (200 µM) decreased human leukocyte viability to about 50%. Taken together, these results indicated the low in vitro toxicity in human leukocytes of some Se-containing analogs of AZT.
Assuntos
Fármacos Anti-HIV/toxicidade , Leucócitos/efeitos dos fármacos , Compostos Organosselênicos/toxicidade , Zidovudina/análogos & derivados , Zidovudina/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ensaio Cometa , Dano ao DNA , HumanosRESUMO
RATIONALE: (Octylseleno)-xylofuranoside (OSX) is an organoselenium compound from the class of alkylseleno carbohydrates possessing a C8 alkyl chain. Members of this class of organoselenium compounds have promising pharmacological activities, among them are antioxidant and acute antidepressant-like activities with the involvement of monoaminergic system, as previously presented by our research group. OBJECTIVE: The objective of the study was to investigate the possible involvement of cellular signalling pathways in the antidepressant-like effect caused by OSX (0.01 mg/kg, oral route (p.o.) by gavage) in the tail suspension test (TST) in mice. METHODS: Mice were treated by intracerebroventricular (i.c.v.) injection either with vehicle or with H-89 (1 µg/site i.c.v., an inhibitor of protein kinase A-PKA), KN-62 (1 µg/site i.c.v., an inhibitor of Ca2+/calmodulin-dependent protein kinase II-CAMKII), chelerythrine (1 µg/site i.c.v., an inhibitor of protein kinase C-PKC) or PD098059 (5 µg/site i.c.v., an inhibitor of extracellular-regulated protein kinase 1/2-ERK1/2). Fifteen minutes after, vehicle or OSX was injected, and 30 min later, the TST and open field tests (OFT) were carried out. RESULTS: The antidepressant-like effect of orally administered OSX was blocked by treatment of the mice with H-89, KN-62, chelerythrine and PD098059; all inhibitors of signalling proteins involved with neurotrophic signalling pathways. The number of crossings in the OFT was not altered by treatment with OSX and/or signalling antagonists. CONCLUSIONS: The results demonstrated that OSX showed an antidepressant-like effect in the TST in mice through the activation of protein kinases PKA, PKC, CAMKII and ERK1/2 that are involved in intracellular signalling pathways.
Assuntos
Antidepressivos/farmacologia , Glicosídeos/farmacologia , Compostos Organosselênicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Animais , Antidepressivos/uso terapêutico , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Glicosídeos/uso terapêutico , Elevação dos Membros Posteriores/métodos , Isoquinolinas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Compostos Organosselênicos/uso terapêutico , Proteína Quinase C/metabolismo , Sulfonamidas/farmacologiaRESUMO
The antioxidant potential of organoselenium compounds has been extensively investigated because oxidative stress is a hallmark of a variety of human diseases. In this study, we report the influence of substituent groups on the antioxidant activity of (R)-Se-aryl thiazolidine-4-carboselenoate (Se-PTC) in several in vitro assays. The amino group in the thiazolidine ring affects the antioxidant activity of the compound. Our data revealed that Se-PTC a had higher radical scavenging efficiency in the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS(+)) assays compared to other compounds. In the ferric ion reducing antioxidant power (FRAP) assay, Se-PTC a exhibited ferric-reducing ability at concentrations as low as 5µM. However, this effect was diminished when the amino group was protected with carbamate (Se-PTC d). In the nitric oxide scavenging assay, Se-PTC c presented better NO-scavenging than Se-PTC b. However, Se-PTC a and d did not prevent NO formation at any of the tested concentrations. Se-PTC c decreased the sodium nitroprussate-induced lipid peroxidation in the cortex and hippocampus of mice. In summary, we demonstrate that Se-PTC is a promising antioxidant compound and that the compound's activity is influenced by the amino group and by the characteristics of the arylselenium substituents. Thus, these compounds may be used as synthetic antioxidants that provide protection against oxidative diseases.
Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Tiazolidinas/química , Tiazolidinas/farmacologia , Animais , Benzotiazóis/química , Benzotiazóis/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Picratos/química , Picratos/farmacologia , Relação Estrutura-Atividade , Ácidos Sulfônicos/química , Ácidos Sulfônicos/farmacologiaRESUMO
We evaluated the potential neuroprotective effect of 1-100 µM of four organoselenium compounds: diphenyl diselenide, 3’3-ditri-fluoromethyldiphenyl diselenide, p-methoxy-diphenyl diselenide, and p-chloro-diphenyl diselenide, against methylmercury-induced mitochondrial dysfunction and oxidative stress in mitochondrial-enriched fractions from adult Swiss mouse brain. Methylmercury (10-100 µM) significantly decreased mitochondrial activity, assessed by MTT reduction assay, in a dose-dependent manner, which occurred in parallel with increased glutathione oxidation, hydroperoxide formation (xylenol orange assay) and lipid peroxidation end-products (thiobarbituric acid reactive substances, TBARS). The co-incubation with diphenyl diselenide (100 µM) completely prevented the disruption of mitochondrial activity as well as the increase in TBARS levels caused by methylmercury. The compound 3’3-ditrifluoromethyldiphenyl diselenide provided a partial but significant protection against methylmercury-induced mitochondrial dysfunction (45.4 ± 5.8 percent inhibition of the methylmercury effect). Diphenyl diselenide showed a higher thiol peroxidase activity compared to the other three compounds. Catalase blocked methylmercury-induced TBARS, pointing to hydrogen peroxide as a vector during methylmercury toxicity in this model. This result also suggests that thiol peroxidase activity of organoselenium compounds accounts for their protective actions against methylmercury-induced oxidative stress. Our results show that diphenyl diselenide and potentially other organoselenium compounds may represent important molecules in the search for an improved therapy against the deleterious effects of methylmercury as well as other mercury compounds.