Dentifrícios branqueadores contendo Blue covarine: revisão de literatura / Bleaching dentifrices containing "Blue covarine" literature review

Introdução: O efeito branqueador dos dentifrícios contendo Blue covarine é fundamentado no seu mecanismo de ação, caracterizado pela sua deposição na superfície dentária, alterando a percepção da cor. Objetivo: Revisar a literatura e buscar evidência científica sobre o efeito branqueador do Blue Covarine em tecidos mineralizados e materiais restauradores estéticos. Materiais e métodos: Para a revisão da literatura foram feitas buscas nas bases de dados PubMed, LILACS, BBO, SciELO e MEDLINE para identificar estudos clínicos e laboratoriais que avaliassem a ação branqueadora do agente óptico Blue covarine. Como estratégia de busca foram utilizados os descritores "Blue covarine", "Blue covarine e pasta de dentes", "Blue covarine and toothpaste", "Blue covarine e dentifrícios", "Blue covarine and dentifrices", "Blue covarine e dentifrícios branqueadores", "Blue covarine and whitening dentifrices", "Blue covarine e dentifrícios clareadores", "Blue covarine and bleaching dentifrices", "Blue covarine e pasta de dentes branqueadoras", "Blue covarine and whitening toothpaste", "Blue covarine e pasta de dentes clareadoras", "Blue covarine and bleaching toothpaste". Resultados: Dois pesquisadores selecionaram e analisaram criticamente 31 artigos, sendo 2 revisões da literatura, 4 estudos clínicos e 25 estudos laboratoriais. Divergências quanto ao desenho de estudo, métodos, amostra, critérios clínicos e parâmetros laboratoriais foram observados, além de conflitos de interesse. Conclusão: O Blue Covarine presente nos dentifrícios branqueadores parece ser efetivo na promoção do branqueamento dentário apenas quando associado aos agentes abrasivos presentes nas formulações, evidenciando que ensaios clínicos e laboratoriais, com metodologias semelhantes, são necessários para se obter evidência científica conclusiva sobre o efeito deste agente branqueador.(AU)

Introduction: The whitening effect of dentifrices containing Blue Covarine is based on its mechanism of action, characterized by its deposition on the tooth surface, altering the perception of color. Objective: To review the literature and seek scientific evidence on the whitening effect of Blue Covarine on mineralized tissues and aesthetic restorative materials. Materials and methods: For the literature review, searches were carried out in the PubMed, LILACS, BBO, SciELO and MEDLINE databases, in order to identify clinical and laboratory studies that evaluated the whitening action of the optical agent Blue Covarine. As a search strategy, the descriptors "Blue Covarine", "Blue Covarine and toothpaste", "Blue Covarine and dentifrices", "Blue Covarine and whitening dentifrices", "Blue Covarine and bleaching dentifrices", "Blue Covarine and whitening toothpaste", "Blue Covarine and bleaching toothpaste". Results: Two researchers selected and critically analyzed 31 articles, including 2 literature reviews, 4 clinical studies and 25 laboratory studies. Differences in study design, methods, sample, clinical criteria and laboratory parameters were observed, in addition to conflicts of interest. Conclusion: Blue Covarine present in whitening dentifrices seems to be effective in promoting dental whitening only when associated with abrasive agents present in the formulations, showing that clinical and laboratory tests, with similar methodologies, are necessary to obtain conclusive scientific evidence on the effect of this bleaching agent.(AU)

Synthesis of 2-(2-(4-thioxo-3H-1,2-dithiole-5-yl) phenoxy)ethyl)isoindole-1,3-thione, a novel hydrogen sulfide-releasing phthalimide hybrid, and evaluation of its activity in models of inflammatory pain.

Hydrogen sulfide (H2S) is a gaseous mediator that modulates several physiological and pathological processes. Phthalimide analogues, substances that have the phthalimide ring in the structure, belong to the group of thalidomide analogues. Both H2S donors and phthalimide analogues exhibit activities in models of inflammation and pain. As molecular hybridization is an important strategy aiming to develop drugs with a better pharmacological profile, in the present study we synthesized a novel H2S-releasing phthalimide hybrid, 2-(2-(4-thioxo-3H-1,2-dithiole-5-yl) phenoxy)ethyl)isoindole-1,3-thione (PTD-H2S), and evaluated its activity in models of inflammatory pain in mice. Per os (p.o.) administration of PTD-H2S (125 or 250 mg/kg) reduced mechanical allodynia induced by carrageenan and lipopolysaccharide. Intraperitoneal (i.p.) administration of PTD-H2S (25 mg/kg), but not equimolar doses of its precursors 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (14.2 mg/kg) and 2-phthalimidethanol (12 mg/kg), reduced mechanical allodynia induced by lipopolysaccharide. The antiallodynic effect induced by PTD-H2S (25 mg/kg, i.p.) was more sustained than that induced by the H2S donor NaHS (8 mg/kg, i.p.). Previous administration of hydroxocobalamin (300 mg/kg, i.p.) or glibenclamide (40 mg/kg, p.o.) attenuated PTD-H2S antiallodynic activity. In conclusion, we synthesized a novel H2S-releasing phthalimide hybrid and demonstrated its activity in models of inflammatory pain. PTD-H2S activity may be due to H2S release and activation of ATP-sensitive potassium channels. The demonstration of PTD-H2S activity in models of pain stimulates further studies aiming to evaluate H2S-releasing phthalimide hybrids as candidates for analgesic drugs.

Melanosomal targeting via caveolin-1 dependent endocytosis mediates ZN(II) phthalocyanine phototoxic action in melanoma cells.

Melanosomes have been considered crucial targets in melanoma treatments. In this study we explored the role of melanosomes in photodynamic therapy (PDT), employing the synthetic Zn(II) phthalocyanine Pc13, a potent photosensitizer that promotes melanoma cell death after irradiation. Phototoxic action is mediated by reactive oxygen species increase. The internalization mechanism of Pc13 and its consequent subcellular localization were evaluated in melanotic B16-F0 cells. Pharmacological inhibitors of dynamin or caveolae, but not of clathrin, decreased Pc13 cellular uptake and phototoxicity. Similar results were obtained when cells over-expressed dominant negative mutants of dynamin-2 and caveolin-1, indicating that Pc13 is internalized by caveolae-mediated endocytosis. Confocal microscopy analysis revealed that Pc13 targets melanosomes and damage of these structures after irradiation was demonstrated by transmission electron microscopy. Treatment of pigmented B16-F0 and WM35 melanoma cells with the melanin synthesis inhibitor phenylthiourea for 48 h led to cell depigmentation and enhanced cell death after irradiation, whereas a 3-h period of inhibition did not modify melanin content but produced a marked reduction of Pc13 phototoxicity, together with a decrease of oxidative melanin synthesis intermediates. In contrast, the effect of Pc13 in amelanotic A375 cells was not altered by phenylthiourea treatment. These results provide evidence that melanosomes have a dual role in the efficacy of PDT. While melanin antagonizes the phototoxic action of Pc13, the release of cytotoxic synthetic intermediates to cytosol after irradiation and melanosome damage is conducive to the phototoxic response. Based on these findings, we demonstrate that melanosome-targeted PDT could be an effective approach for melanoma treatment.

Target selectivity of cholesterol-phosphatidylcholine liposome loaded with phthalocyanine for breast cancer diagnosis and treatment by photodynamic therapy.

This study investigated the ability of cholesterol-phosphatidylcholine liposomes loaded with chloride aluminum phthalocyanine (CL-AlClPc) to discriminate between healthy (MCF-10A) and neoplastic (MCF-7 and MDA-MB-231) breast cells for breast cancer diagnosis and treatment by photodynamic therapy (PDT) using a new drug delivery system consisting of CL-AlClPc. When PDT treatment was applied at an energy fluence of 700 mJ/cm², CL-AlClPc was more cytotoxic to neoplastic cells than to healthy breast cells because CL-AlClPc was better internalized by the tumor cells. An even higher fluorescence signal is expected for neoplastic cells during clinical treatment than for healthy cells, which will be useful for precise and targeted tumor cell detection. CL-AlClPc also facilitated better drug distribution and targeting of essential organelles inside the cells. This selectivity is critical for future in vivo diagnosis and treatment; it prevents side effects because it prioritizes tumor cells and tissues instead of healthy ones. The CL-AlClPc system designed herein had a small size (150 nm), low zeta potential (-6 mV), low polydispersity (0.16), high encapsulation rate efficiency (82.83%), and high shelf stability (12 months).

A high-performance electrochemical sensor based on a mesoporous silica/titania material and cobalt(II) phthalocyanine for sensitive pentachlorophenol determination.

The synthesis and characterization of a novel titania/silica hybrid xerogel subsequently modified with 4-methylpyridine (4-Pic), named TiSi4Pic+Cl- is reported. The physicochemical, structural and thermal properties of TiSi4Pic+Cl- were characterized using several techniques. Anchoring cobalt(II) phthalocyanine (CoTsPc) in TiSi4Pic+Cl- showed greater electroanalytical sensitivity over other sensors built with these materials. A novel electroanalytical method was developed to quantify the noxious biocide pentachlorophenol (PCP) for environmental monitoring. The peak current intensity increased linearly with the analyte concentration in the range between 0.99 and 4.21 µmol L-1, based on the oxidation process (at + 0.81 V, vs. Ag/AgCl) of differential pulse voltammetry (DPV). The estimated limit of detection (LOD) was 29 nmol L-1. Recovery tests in environmental samples showed a PCP concentration of 2.05 ± 0.03 µmol L-1 (n = 3). The method was statistically validated by comparing the PCP concentrations with those obtained by molecular absorption spectrometry and high-performance liquid chromatography-diode array detection (HPLC-DAD). At a 95% confidence level, no difference between the results was found, therefore confirming the excellent accuracy of the proposed method.

Thiopyridinium phthalocyanine for improved photodynamic efficiency against pathogenic fungi.

The emergence of opportunistic pathogens and the selection of resistant strains have created a grim scenario for conventional antimicrobials. Consequently, there is an ongoing search for alternative techniques to control these microorganisms. One such technique is antimicrobial photodynamic therapy (aPDT), which combines photosensitizers, light, and molecular oxygen to produce reactive oxygen species and kill the target pathogen. Here, the in vitro susceptibilities of three fungal pathogens, namely Candida albicans, Aspergillus nidulans, and Colletotrichum abscissum to aPDT with zinc(II) phthalocyanine (ZnPc) derivative complexes were investigated. Three ZnPc bearing thiopyridinium substituents were synthesized and characterized by several spectroscopic techniques. The Q-band showed sensitivity to the substituent with high absorptivity coefficient in the 680-720 nm region. Derivatization and position of the rings with thiopyridinium units led to high antifungal efficiency of the cationic phthalocyanines, which could be correlated with singlet oxygen quantum yield, subcellular localization, and cellular uptake. The minimum inhibitory concentrations (MIC) of the investigated ZnPc-R complexes against the studied microorganisms were 2.5 µM (C. albicans) and 5 µM (A. nidulans and C. abscissum). One ZnPc derivative achieved complete photokilling of C. albicans and, furthermore, yielded low MIC values when used against the tolerant plant-pathogen C. abscissum. Our results show that chemical modification is an important step in producing better photosensitizers for aPDT against fungal pathogens.

Pharmaceutical nanotechnology applied to phthalocyanines for the promotion of antimicrobial photodynamic therapy: A literature review.

Phthalocyanines are photosensitizers activated by light at a specific wavelength in the presence of oxygen and act through the production of Reactive Oxygen Species, which simultaneously attack several biomolecular targets in the pathogen agent and, therefore, have multiple and variable action sites. This nonspecific action site bypasses conventional resistance mechanisms. Antimicrobial Photodynamic Therapy (aPDT) is safe, easy to implement and, unlike conventional agents, may have a wide activity spectrum of photoantimicrobials. This work is a systematic review of the literature based on nanocarriers containing phthalocyanines in aPDT against bacteria, fungi, viruses, and protozoa. The search was performed in two different databases (MEDLINE/PubMed and Web of Science) between 2011 and May 2021. Nanocarriers often improve the action or are equivalent to free drugs, but their use allows substituting the organic solvent in the case of hydrophobic phthalocyanines, allowing for a safer application of aPDT with the possibility of prolonged release. In the case of hydrophilic phthalocyanines, they would allow for nonspecific site delivery with a possibility of cellular internalization. A single infectious lesion can have multiple microorganisms, and PDT with phthalocyanines is an interesting treatment given its ample spectrum of action. It is possible to highlight the upconversion nanosystems, which allow for the activation of phthalocyanine in deeper tissues by using longer wavelengths, as a system that has not yet been studied, but which could provide treatment solutions. The use of nanocarriers containing phthalocyanines requires more study to establish the use of aPDT in humans.

Synthesis, characterization, and evaluation of chloroaluminium phthalocyanine incorporated in poly(ε-caprolactone) nanoparticles for photodynamic therapy.

BACKGROUND: The use of nanotechnology has been widely used in biomedical science, including orthopedic implants, tissue engineering, cancer therapy and drug elution from nanoparticle systems, such as poly-caprolactone (PCL) nanoparticles, which stand out mainly for their biocompatibility, being considered as effective carriers for photosensitizing drugs (PS) in photodynamic therapy (PDT) protocols. METHODS: This manuscript describes the synthesis and characterization of PCL nanoparticles for controlled release of the drug chloro-aluminum phthalocyanine (ClAlPc) as a photosensitizer for application in PDT. The PCL-ClAlPc nanoparticles were developed by the nanoprecipitation process. The structure and morphology of the nanoparticles were studied with scanning electron microscopy (SEM) and with Fourier transform infrared (FTIR). The size of nanomaterials was studied using the Dynamic Light Scattering (DLS) method. Photophysical and photochemical characterizations were performed. Subsequently, photobiological studies were also used to characterize the system. RESULTS: The nanoparticles had an average diameter of 384.7 ± 138.6 nm and a polydispersity index of 0.153. SEM analysis revealed that the system formed a spherical shape typical of these delivery systems. Charging efficiency was 82.1% ± 1.2%. The phthalocyanine-loaded PCL nanoparticles maintained their photophysical behavior after encapsulation. Cell viability was determined after the dark toxicity test, and it was possible to observe that there was no evidence of toxicity in the dark, for all concentrations tested. The assay also revealed that adenocarcinoma cells treated with free ClAlPc and in the nanoformulation showed 100% cell death when subjected to PDT protocols. The intracellular location of the photosensitizer indicated a high potential for accumulation in the cytoplasm and nucleus. CONCLUSIONS: From the photophysical, photochemical and photobiological analyzes obtained, it was possible to observe that the development of PCL nanoparticles encapsulated with ClAlPc, by the nanoprecipitation method was adequate and that the in vivo release study is efficient to reduce the release rate and attenuate the burst of PS loaded on PCL nanoparticles. The results reinforce that the use of this system as drug delivery systems is useful in PDT protocols.

Interactions of Co, Cu, and non-metal phthalocyanines with external structures of SARS-CoV-2 using docking and molecular dynamics.

The new coronavirus, SARS-CoV-2, caused the COVID-19 pandemic, characterized by its high rate of contamination, propagation capacity, and lethality rate. In this work, we approach the use of phthalocyanines as an inhibitor of SARS-CoV-2, as they present several interactive properties of the phthalocyanines (Pc) of Cobalt (CoPc), Copper (CuPc) and without a metal group (NoPc) can interact with SARS-CoV-2, showing potential be used as filtering by adsorption on paints on walls, masks, clothes, and air conditioning filters. Molecular modeling techniques through Molecular Docking and Molecular Dynamics were used, where the target was the external structures of the virus, but specifically the envelope protein, main protease, and Spike glycoprotein proteases. Using the g_MM-GBSA module and with it, the molecular docking studies show that the ligands have interaction characteristics capable of adsorbing the structures. Molecular dynamics provided information on the root-mean-square deviation of the atomic positions provided values between 1 and 2.5. The generalized Born implicit solvation model, Gibbs free energy, and solvent accessible surface area approach were used. Among the results obtained through molecular dynamics, it was noticed that interactions occur since Pc could bind to residues of the active site of macromolecules, demonstrating good interactions; in particular with CoPc. Molecular couplings and free energy showed that S-gly active site residues interacted strongly with phthalocyanines with values ​​of - 182.443 kJ/mol (CoPc), 158.954 kJ/mol (CuPc), and - 129.963 kJ/mol (NoPc). The interactions of Pc's with SARS-CoV-2 may predict some promising candidates for antagonists to the virus, which if confirmed through experimental approaches, may contribute to resolving the global crisis of the COVID-19 pandemic.

Photodynamic therapy mediated by nanoparticles Aluminum Chloro Phthalocyanine in oral squamous carcinoma cells.

The aim of this study is to investigate the antineoplastic potential of photodynamic therapy (PDT) mediated by an aluminum-phthalocyanine chloride nanoemulsion (AlPc-NE), against an oral squamous cell carcinoma (OSCC) cell line in vitro. Both OSCC (SCC9) and A431 cell lines were studied in vitro. Four study groups were used: Group 1 (phosphate-buffered saline [PBS]), Group 2 (PBS + 28.3 J/cm2 irradiation), Group 3 (AlPc-NE alone), and Group 4 (AlPc-NE + 28.3 J/cm2 irradiation). To test the effect of PDT with AlPc-NE, cell viability, migration, and cell death assays were performed. Moreover, the expressions of Ki-67 and TP53 were evaluated using immunoassays. The results showed that PDT mediated by all AlPc-NE concentrations evaluated (i.e., 0.7, 0.35, and 0.17 nM AlPc) significantly reduced the viability of SCC9 cells. Migration and cell death assays also revealed that PDT with AlPc-NE significantly reduced the rate of migration and increased cell death compared to the control groups. In addition, it was found that PDT with AlPc-NE reduced Ki-67 and mutated TP53 immunoexpression. PDT with AlPc-NE is effective in reducing the viability and migration of SCC9. Moreover, PDT with AlPc-NE nanoemulsions reduces the cell proliferation and expression of mutant TP53.

Evolution of Phthalocyanine Structures as Photodynamic Agents for Bacteria Inactivation.

Phthalocyanine derivatives have been proposed as photosensitizers for the treatment of several microbial infections. In this review, the progress in the structures of phthalocyanines was analyzed, considering that these compounds can easily functionalize and can form complexes with various metal ions. In this sense, different substituents were used to increase the interaction with the microorganisms, improving their photodynamic inactivation. Furthermore, these photosensitizers absorb strongly at phototherapeutic window, emit red fluorescence, and efficiently produce the formation of reactive oxygen species. Subsequently, the influence of binding, bacteria types, cell density, washing effect, and media on photoinactivation was remarked to elimination of microbes. Finally, photokilling of bacterial biofilm by phthalocyanines and the mechanism of action were discussed. Therefore, this review brings together the main features of phthalocyanines as antimicrobial phototherapeutic agents.

Beneficial effects of a mouthwash containing an antiviral phthalocyanine derivative on the length of hospital stay for COVID-19: randomised trial.

The risk of contamination and dissemination by SARS-CoV-2 has a strong link with nasal, oral and pharyngeal cavities. Recently, our research group observed the promising performance of an anionic phthalocyanine derivative (APD) used in a mouthwash protocol without photoexcitation; this protocol improved the general clinical condition of patients infected with SARS-CoV-2. The present two-arm study evaluated in vitro the antiviral activity and cytotoxicity of APD. Additionally, a triple-blind randomized controlled trial was conducted with 41 hospitalized patients who tested positive for COVID-19. All the included patients received World Health Organization standard care hospital treatment (non-intensive care) plus active mouthwash (experimental group AM/n = 20) or nonactive mouthwash (control group NAM/n = 21). The adjunct mouthwash intervention protocol used in both groups consisted one-minute gargling/rinsing / 5 times/day until hospital discharge. Groups were compared considering age, number of comorbidities, duration of symptoms prior admission and length of hospital stay (LOS). The associations between group and sex, age range, presence of comorbidities, admission to Intensive care unit (ICU) and death were also evaluated. The in vitro evaluation demonstrated that APD compound was highly effective for reduction of SARS-CoV-2 viral load in the 1.0 mg/mL (99.96%) to 0.125 mg/mL (92.65%) range without causing cytotoxicity. Regarding the clinical trial, the median LOS of the AM group was significantly shortened (4 days) compared with that of the NAM group (7 days) (p = 0.0314). Additionally, gargling/rinsing with APD was very helpful in reducing the severity of symptoms (no ICU care was needed) compared to not gargling/rinsing with APD (28.6% of the patients in the NAM group needed ICU care, and 50% of this ICU subgroup passed way, p = 0.0207). This study indicated that the mechanical action of the protocol involving mouthwash containing a compound with antiviral effects against SARS-CoV-2 may reduce the symptoms of the patients and the spread of infection. The use of APD in a mouthwash as an adjuvant the hospital COVID-19 treatment presented no contraindication and reduced the hospital stay period.Trial registration: The clinical study was registered at REBEC-Brazilian Clinical Trial Register (RBR-58ftdj).

The Labile Iron Pool Reacts Rapidly and Catalytically with Peroxynitrite.

While investigating peroxynitrite-dependent oxidation in murine RAW 264.7 macrophage cells, we observed that removal of the Labile Iron Pool (LIP) by chelation increases the intracellular oxidation of the fluorescent indicator H2DCF, so we concluded that the LIP reacts with peroxynitrite and decreases the yield of peroxynitrite-derived oxidants. This was a paradigm-shifting finding in LIP biochemistry and raised many questions. In this follow-up study, we address fundamental properties of the interaction between the LIP and peroxynitrite by using the same cellular model and fluorescence methodology. We have identified that the reaction between the LIP and peroxynitrite has catalytic characteristics, and we have estimated that the rate constant of the reaction is in the range of 106 to 107 M-1s-1. Together, these observations suggest that the LIP represents a constitutive peroxynitrite reductase system in RAW 264.7 cells.

Development of Novel Isoindolone-Based Compounds against Trypanosoma brucei rhodesiense.

This study identified the isoindolone ring as a scaffold for novel agents against Trypanosoma brucei rhodesiense and explored the structure-activity relationships of various aromatic ring substitutions. The compounds were evaluated in an integrated in vitro screen. Eight compounds exhibited selective activity against T. b. rhodesiense (IC50 <2.2 µm) with no detectable side activity against T. cruzi and Leishmania infantum. Compound 20 showed low nanomolar potency against T. b. rhodesiense (IC50 =40 nm) and no toxicity against MRC-5 and PMM cell lines and may be regarded as a new lead template for agents against T. b. rhodesiense. The isoindolone-based compounds have the potential to progress into lead optimization in view of their highly selective in vitro potency, absence of cytotoxicity and acceptable metabolic stability. However, the solubility of the compounds represents a limiting factor that should be addressed to improve the physicochemical properties that are required to proceed further in the development of in vivo-active derivatives.

Photochemical and photophysical properties of tetracarboxylic acid phthalocyanines from glycolic and lactic acids in homogeneous and micro heterogeneous media.

Glycolic acid and lactic acid substituted zinc phthalocyanines were studied concerning their photophysical and photochemical properties in eight organic solvents (homogeneous medium) and in aqueous media with the presence of CTAB and PVP 360 surfactants. Solvent effects were investigated according to several physical solvent parameters, including studies that used more than one parameter at a time, such as the ET(30) scale and the Lippet-Mataga equation. Computational studies were realized and was found in good agreement with experimental data indicating J-type dimers' formation through hydrogen bonds, which may not affect the spectroscopic properties. Fluorescence lifetimes were recorded using a time-correlated single-photon counting setup (TCSPC) technique. The direct method (analyzing the phosphorescence decay curves of singlet oxygen at 1270 nm) was employed to study singlet oxygen quantum yields. Phthalocyanine macrocycle with lactic acid substituent showed better solvation arrangement than the glycolic derivative, which can be explained based on the presence of the methyl group bonded to the chain. The water solvation of Pc's in the presence of cationic surfactant (CTAB) and biocompatible polymer PVP 360 increses the importance of this study for appliance in photodynamic therapy (PDT).

Efficacy of Ebselen Against Invasive Aspergillosis in a Murine Model.

Invasive aspergillosis is one of the major causes of morbidity and mortality among invasive fungal infections. The search for new antifungal drugs becomes imperative when existing drugs are not able to efficiently treat these infections. Ebselen, is an organoselenium compound, already successfully approved in clinical trials as a repositioned drug for the treatment of bipolar disorder and prevention of noise-induced hearing loss. In this study, we aimed to reposition ebselen for the treatment of invasive aspergillosis by showing ebselen effectiveness in a murine model. For this, BALB/c mice were immunosuppressed and infected systemically with Aspergillus fumigatus. Animals were divided and treated with ebselen, voriconazole, or drug-free control, for four days. The kidneys were used for CFU count and, histopathological and cytokine analysis. Ebselen was able to significantly reduce the fungal burden in the kidneys of infected mice with efficacy comparable with voriconazole treatment as both had reductions to the same extent. The absence of hyphae and intact kidney tissue structure observed in the histopathological sections analyzed from treated groups corroborate with the downregulation of IL-6 and TNF. In summary, this study brings for the first time in vivo evidence of ebselen efficacy against invasive aspergillosis. Despite these promising results, more animal studies are warranted to evaluate the potential role of ebselen as an alternative option for the management of invasive aspergillosis in humans.

Amphiphilic tricationic Zn(II)phthalocyanine provides effective photodynamic action to eradicate broad-spectrum microorganisms.

A novel tricationic Zn(II)phthalocyanine derivative, (NCH3)3ZnPc3+, was synthesized by ring expansion reaction of boron(III) [2,9(10),16(17)-trinitrosubphthalocyaninato]chloride. First, the reaction of this subphthalocyanine with 2,3-naphthalenedicarbonitrile and Zn(CH3COO)2 catalyzed by 8-diazabicyclo[5.4.0]undec-7-ene was used to obtain the A3B-type nitrophthalocyanine. After reduction of nitro groups with Na2S and exhaustive methylation of amino groups, (NCH3)3ZnPc3+ was formed in good yields. In addition, the tetracationic analog (NCH3)4ZnPc4+ was synthesized to compare their properties. The absorption and fluorescence spectra showed the Q-bands and the red emission, respectively, which are characteristic of the Zn(II)phthalocyanine derivatives in N,N-dimethylformamide. Furthermore, photodynamic activity sensitized by these compounds was studied in the presence of different molecular probes to sense the formation of reactive oxygen species. (NCH3)3ZnPc3+ efficiently produced singlet molecular oxygen and also it sensitized the formation of superoxide anion radical in the presence of NADH, while the photodynamic activity of (NCH3)4ZnPc4+ was very poor, possibly due to the partial formation of aggregates. Furthermore, the decomposition of L-tryptophan induced by (NCH3)3ZnPc3+ was mainly mediated by a type II mechanism. Antimicrobial photodynamic inactivation sensitized by these phthalocyanines was evaluated in Staphylococcus aureus, Escherichia coli, and Candida albicans, as representative microbial cells. In cell suspensions, (NCH3)3ZnPc3+ was rapidly bound to microbial cells, showing bioimages with red fluorescence emission. After 5 min of irradiation with visible light, (NCH3)3ZnPc3+ was able to completely eliminate S. aureus, E. coli and C. albicans, using 1.0, 2.5 and 5.0 µM phthalocyanine, respectively. In contrast, a low photoinactivation activity was found with (NCH3)4ZnPc4+ as a photosensitizer. Therefore, the amphiphilic tricationic phthalocyanine (NCH3)3ZnPc3+ is a promising photosensitizing structure for application as a broad-spectrum antimicrobial phototherapeutic agent.

In silico Studies on the Interaction between Mpro and PLpro From SARS-CoV-2 and Ebselen, its Metabolites and Derivatives.

The COVID-19 pandemic caused by the SARS-CoV-2 has mobilized scientific attention in search of a treatment. The cysteine-proteases, main protease (Mpro) and papain-like protease (PLpro) are important targets for antiviral drugs. In this work, we simulate the interactions between the Mpro and PLpro with Ebselen, its metabolites and derivatives with the aim of finding molecules that can potentially inhibit these enzymes. The docking data demonstrate that there are two main interactions between the thiol (-SH) group of Cys (from the protease active sites) and the electrophilic centers of the organoselenium molecules, i. e. the interaction with the carbonyl group (O=C… SH) and the interaction with the Se moiety (Se… SH). Both interactions may lead to an adduct formation and enzyme inhibition. Density Functional Theory (DFT) calculations with Ebselen indicate that the energetics of the thiol nucleophilic attack is more favorable on Se than on the carbonyl group, which is in accordance with experimental data (Jin et al. Nature, 2020, 582, 289-293). Therefore, organoselenium molecules should be further explored as inhibitors of the SARS-CoV-2 proteases. Furthermore, we suggest that some metabolites of Ebselen (e. g. Ebselen diselenide and methylebselenoxide) and derivatives ethaselen and ebsulfur should be tested in vitro as inhibitors of virus replication and its proteases.

Toxicology and pharmacology of synthetic organoselenium compounds: an update.

Here, we addressed the pharmacology and toxicology of synthetic organoselenium compounds and some naturally occurring organoselenium amino acids. The use of selenium as a tool in organic synthesis and as a pharmacological agent goes back to the middle of the nineteenth and the beginning of the twentieth centuries. The rediscovery of ebselen and its investigation in clinical trials have motivated the search for new organoselenium molecules with pharmacological properties. Although ebselen and diselenides have some overlapping pharmacological properties, their molecular targets are not identical. However, they have similar anti-inflammatory and antioxidant activities, possibly, via activation of transcription factors, regulating the expression of antioxidant genes. In short, our knowledge about the pharmacological properties of simple organoselenium compounds is still elusive. However, contrary to our early expectations that they could imitate selenoproteins, organoselenium compounds seem to have non-specific modulatory activation of antioxidant pathways and specific inhibitory effects in some thiol-containing proteins. The thiol-oxidizing properties of organoselenium compounds are considered the molecular basis of their chronic toxicity; however, the acute use of organoselenium compounds as inhibitors of specific thiol-containing enzymes can be of therapeutic significance. In summary, the outcomes of the clinical trials of ebselen as a mimetic of lithium or as an inhibitor of SARS-CoV-2 proteases will be important to the field of organoselenium synthesis. The development of computational techniques that could predict rational modifications in the structure of organoselenium compounds to increase their specificity is required to construct a library of thiol-modifying agents with selectivity toward specific target proteins.

Copolymer-nanocapsules of zinc phenyl-thio-phthalocyanine and amphotericin-B in association with antimicrobial photodynamic therapy (A-PDT) applications against Candida albicans yeasts.

Antimicrobial Photodynamic Therapy (A-PDT) is a modern and non-invasive therapeutic modality. Nanostructures like the polymeric nanocapsules (NC) has proved to be a system that has enormous potential to improve current antimicrobial therapeutic practice. NC of Zinc phenyl-thio-phthalocyanine and Amphotericin B association (NC/ZnS4Pc + AMB) built with poly(lactide-co-glycolide) (PLGA) 50:50 using the preformed polymer interfacial deposition method were developed at a 0.05 mg mL- 1 theoretical concentration to improve antifungal activity with two actives association and assistance from PDTa. It showed an average particle diameter of 253.8 ±â€¯17.3, an average polydispersity index of 0.36 ±â€¯0.01, and a negative Zeta potential average of -31.03 ±â€¯5.54 for 158 days. UV-vis absorption and emission spectroscopy analyses did not show changes in photophysical properties in the steady-state of NC/ZnS4Pc + AMB counterparts free ZnS4Pc. The encapsulation percentage of actives was 89.24 % and 7.40 % for ZnS4Pc and AMB, respectively. Cell viability assay using NIH/3T3 ATCC® CRL-1658 ™ cells line showed no cytotoxicity for the concentrations tested. The photodynamic activity assay using NC/ZnS4Pc + AMB diluted showed fungal toxicity against Candida albicans yeast with energetic fluences of 12 J.cm-2 and 25 J.cm-2 by a decrease in cell viability. The MFC assay demonstrated a fungistatic activity for the conditions employed in the PDTa assay. The results show that NC/ZnS4Pc + AMB is a promising nanomaterial for antimicrobial inactivation using PDT.