Synthesis and mechanistic study of 2-(trifluoromethyl)-10H-phenoselenazine from double cross coupling reaction.

Phenoselenazines are nitrogen and selenium-based heterocyclic compounds that have important biological activities. However, their preparation methods are scarce and difficult to handle. The synthesis of a phenoselenazine from a simple and robust CuO nanoparticle catalyzed methodology, using bis-aniline-diselenide and 1,2-dihalobenzenes under microwave irradiation. Also, the double-cross-coupling reaction mechanism for C-Se and C-N bond formation, including the observation of a reaction intermediate by mass spectrometry have been studied.

KIO3-catalyzed selective oxidation of thiols to disulfides in water under ambient conditions.

Herein, we report a KIO3-catalyzed oxidative coupling of thiols to their corresponding disulfides in water, in a short time and at ambient temperature. The reaction has a broad scope and exhibits good functional group tolerance, resulting in the desired products in excellent yields. This approach allows the reuse of the reaction system in multiple cycles and scale-up. Furthermore, the current protocol demonstrates compatibility for in situ generation of disulfides and post application in C(sp2)-H bond sulfenylation.

3-Halochromones Through Oxidative α-Halogenation of Enaminones and its Photophysical Investigation: Another Case of Photo-induced Partially Aromatised Intramolecular Charge Transfer?

A versatile synthesis strategy for fluorescent 3-halo-4H-chromen-4-one derivatives is reported. The method involves the oxidative α-halogenation of enaminones performed by an efficient and sustainable oxidation system. The use of Oxone® in combination with KCl, KBr, or KI enables the preparation of 3-chloro-, 3-bromo-, or 3-iodo-4H-chromen-4-one in good to excellent yields, with great functional group tolerance where the protocol is amenable to gram-scale synthesis. The analysis of the photophysical properties of the presented 4H-chromen-4-one showed absorption in the UV region and fluorescence emission in the violet-to-cyan region with a relatively large Stokes shift. In solution, all compounds present a dual fluorescence emission, regardless of the solvent, assigned to a partially aromatised intramolecular charge transfer mechanism, considering the presence of a pseudo-aromatic ring in the chromone scaffold and the absence of the influence of substituent electronic features in optical behaviour.

Inhibitory effects against SARSCoV-2 main protease (Mpro) of biflavonoids and benzophenones from the fruit of Platonia insignis.

The SARS-CoV-2 mutation and the limitation of the approved drug against COVID-19 are still a challenge in many country healthcare systems and need to be affronted despite the set of vaccines to prevent this viral infection. To contribute to the identification of new antiviral agents, the present study focused on natural products from an edible fruit with potential inhibitory effects against the SARS-CoV-2 main protease (Mpro). First, LC-ESIMS analysis of Platonia insignis fruits was performed and showed the presence of biflavonoids and benzophenones in the seed and pulp, respectively. Then, maceration and chromatographic purification led to the identification of two triglycerides (1 and 2) alongside chamaejasmine (3) and volkensiflavone (4) from the seed and isogarcinol (5) and cycloxanthochymol (6), from the pulp. Compounds 1-6 after evaluating their inhibitory against Mpro, displayed from no to significant activity. Compound 5 was the most potent with an IC50 value of 0.72 µM and was more active than the positive control, Ebselen (IC50 of 3.4 µM). It displayed weak and no cytotoxicity against THP-1 (CC50 of 116.2 µM) and Vero cell lines, respectively. Other active compounds showed no cytotoxicity against THP-1. and Vero cell lines. Molecular docking studies revealed interactions in the catalytic pocket between compound 5 and amino acid residues that composed the catalytic dyads (His 41 and Cyst 145).

Green Approach for the Synthesis of Chalcogenyl- 2,3-dihydrobenzofuran Derivatives Through Allyl-phenols/ Naphthols and Their Potential as MAO-B Inhibitors.

This work presents the design, synthesis, and MAO-B inhibitor activity of a series of chalcogenyl-2,3-dihydrobenzofurans derivatives. Using solvent- and metal-free methodology, a series of chalcogen-containing dihydrobenzofurans 7-9 was obtained with yields ranging from 40% to 99%, using an I2 /DMSO catalytic system. All compounds were fully structurally characterized using 1 H and 13 C NMR analysis, and the unprecedented compounds were additionally analyzed using high-resolution mass spectrometry (HRMS). In addition, the mechanistic proposal that iodide is the most likely species to act in the transfer of protons along the reaction path was studied through theoretical calculations. Finally, the compounds 7b-e, 8a-e, and 9a showed great promise as inhibitors against MAO-B activity.

Catalyst- and metal-free C(sp2)-H bond selenylation of (N-hetero)-arenes using diselenides and trichloroisocyanuric acid at room temperature.

In this paper, we report an eco-friendly approach for the C(sp2)-H bond selenylation of imidazopyridines and other N-heteroarenes as well as simple arenes at ambient temperature. This new protocol consists of the reaction between (N-hetero)-arenes and the diorganyl-diselenides and trichloroisocyanuric acid (TCCA)-ethanol reagent system. In a short reaction time, the desired selenylated products were obtained regioselectively in good yields, with tolerance for a wide range of functional groups.

Inhibitory effects of 190 compounds against SARS-CoV-2 Mpr o protein: Molecular docking interactions.

COVID-19 has caused many deaths since the first outbreak in 2019. The burden on healthcare systems around the world has been reduced by the success of vaccines. However, population adherence and the occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are still challenging tasks to be affronted. In addition, the newly approved drug presents some limitations in terms of side effects and drug interference, highlighting the importance of searching for new antiviral agents against SARS-CoV-2. The SARS-CoV-2 main protease (Mpr o ) represents a versatile target to search for new drug candidates due to its essential role in proteolytic activities responsible for the virus replication. In this work, a series of 190 compounds, composed of 27 natural ones and 163 synthetic compounds, were screened in vitro for their inhibitory effects against SARS-CoV-2 Mpro . Twenty-five compounds inhibited Mpro with inhibitory constant values (Ki ) between 23.2 and 241 µM. Among them, a thiosemicarbazone derivative was the most active compound. Molecular docking studies using Protein Data Bank ID 5RG1, 5RG2, and 5RG3 crystal structures of Mpro revealed important interactions identified as hydrophobic, hydrogen bonding and steric interactions with amino acid residues in the active site cavity. Overall, our findings indicate the described thiosemicarbazones as good candidates to be further explored to develop antiviral leads against SARS-CoV-2. Moreover, the studies showed the importance of careful evaluation of test results to detect and exclude false-positive findings.

Citrinin as a potential anti-cancer therapy: A comprehensive review.

Citrinin (CIT) is a polyketide-derived mycotoxin, which is produced by many fungal strains belonging to the gerena Monascus, Aspergillus, and Penicillium. It has been postulated that mycotoxins have several toxic mechanisms and are potentially used as antineoplastic agents. Therefore, the present study carried out a systematic review, including articles from 1978 to 2022, by collecting evidence in experimental studies of CIT antiplorifactive activity in cancer. The Data indicate that CIT intervenes in important mediators and cell signaling pathways, including MAPKs, ERK1/2, JNK, Bcl-2, BAX, caspases 3,6,7 and 9, p53, p21, PARP cleavage, MDA, reactive oxygen species (ROS) and antioxidant defenses (SOD, CAT, GST and GPX). These factors demonstrate the potential antitumor drug CIT in inducing cell death, reducing DNA repair capacity and inducing cytotoxic and genotoxic effects in cancer cells.

Studies of Cytotoxicity Effects, SARS-CoV-2 Main Protease Inhibition, and in Silico Interactions of Synthetic Chalcones.

SARS-CoV-2 main protease (Mpro ) plays an essential role in proteolysis cleavage that promotes coronavirus replication. Thus, attenuating the activity of this enzyme represents a strategy to develop antiviral agents. We report inhibitory effects against Mpro of 40 synthetic chalcones, and cytotoxicity activities, hemolysis, and in silico interactions of active compounds. Seven of them bearing a (E)-3-(furan-2-yl)-1-arylprop-2-en-1-one skeleton (10, 28, and 35-39) showed enzyme inhibition with IC50 ranging from 13.76 and 36.13 µM. Except for 35 and 36, other active compounds were not cytotoxic up to 150 µM against THP-1 and Vero cell lines. Compounds 10, and 35-39 showed no hemolysis while 28 was weakly hemotoxic at 150 µM. Moreover, molecular docking showed interactions between compound 10 and Mpro (PDBID 5RG2 and 5RG3) with proximity to cys145 and His41, suggesting a covalent binding. Products of the reaction between chalcones and cyclohexanethiol indicated that this binding could be a Michael addition type.

Selenium-Derivative Compounds: A Review of New Perspectives in the Treatment of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is one of the most prevalent types of dementia, affecting millions of older people worldwide. AD is stimulating efforts to develop novel molecules targeting its main features associated with a decrease in acetylcholine levels, an increase in oxidative stress and depositions of amyloid-ß (Aß) and tau protein. In this regard, selenium-containing compounds have been demonstrated as potential multi-targeted compounds in the treatment of AD. These compounds are known for their antioxidant and anticholinesterase properties, causing a decrease in Aß aggregation. OBJECTIVE: In this review, we approach structure-activity relationships of each compound, associating the decrease of ROS activity, an increase of tau-like activity and inhibition of AChE with a decrease in the self-aggregation of Aß. METHODS: We also verify that the molecular descriptors apol, nHBAcc and MlogP may be related to optimized pharmacokinetic properties for anti-AD drugs. RESULTS: In our analysis, few selenium-derived compounds presented similar molecular features to FDA-approved drugs. CONCLUSION: We suggest that unknown selenium-derived molecules with apol, nHBAcc and MlogP like FDA-approved drugs may be better successes with optimized pharmacokinetic properties in future studies in AD.

Versatile Electrochemical Synthesis of Selenylbenzo[b]Furan Derivatives Through the Cyclization of 2-Alkynylphenols.

We report an electrochemical oxidative intramolecular cyclization reaction between 2-alkynylphenol derivatives and different diselenides species to generate a wide variety of substituted-benzo[b]furans. Driven by the galvanostatic electrolysis assembled in an undivided cell, it provided efficient transformation into oxidant-, base-, and metal-free conditions in an open system at room temperature. With satisfactory functional group compatibility, the products were obtained in good to excellent yields.

Novel trypanocidal thiophen-chalcone cruzain inhibitors: structure- and ligand-based studies.

Background: Chagas disease is a neglected tropical disease that affects millions of people worldwide and for which no effective treatment is available. Materials & methods: 17 chalcones were synthesized, for which the inhibition of cruzain and trypanocidal activity were investigated. Results: Chalcone C8 showed the highest cruzain inhibitory (IC50 = 0.536 µm) and trypanocidal activity (IC50 = 0.990 µm). Molecular docking studies showed interactions involving Asp161 and the thiophen group interacting with the S2 subsite. Furthermore, quantitative structure-activity relationship (q2 = 0.786; r2 = 0.953) and density functional theory studies were carried out, and a correlation between the lowest unoccupied molecular orbital surface and trypanocidal activity was observed. Conclusion: These results demonstrate that these chalcones are worthwhile hits to be further optimized in Chagas disease drug discovery programs.

IP-Se-06, a Selenylated Imidazo[1,2-a]pyridine, Modulates Intracellular Redox State and Causes Akt/mTOR/HIF-1α and MAPK Signaling Inhibition, Promoting Antiproliferative Effect and Apoptosis in Glioblastoma Cells.

Glioblastoma multiforme (GBM) is a notably lethal brain tumor associated with high proliferation rate and therapeutic resistance, while currently effective treatment options are still lacking. Imidazo[1,2-a]pyridine derivatives and organoselenium compounds are largely used in medicinal chemistry and drug development. This study is aimed at further investigating the antitumor mechanism of IP-Se-06 (3-((2-methoxyphenyl)selanyl)-7-methyl-2-phenylimidazol[1,2-a]pyridine), a selenylated imidazo[1,2-a]pyridine derivative in glioblastoma cells. IP-Se-06 exhibited high cytotoxicity against A172 cells (IC50 = 1.8 µM) and selectivity for this glioblastoma cell. The IP-Se-06 compound has pharmacological properties verified in its ADMET profile, especially related to blood-brain barrier (BBB) permeability. At low concentration (1 µM), IP-Se-06 induced intracellular redox state modulation with depletion of TrxR and GSH levels as well as inhibition of NRF2 protein. IP-Se-06 also decreased mitochondrial membrane potential, induced cytochrome c release, and chromatin condensation. Furthermore, IP-Se-06 induced apoptosis by decreasing levels of Bcl-xL while increasing levels of γ-H2AX and p53 proteins. Treatment with IP-Se-06 induced cell cycle arrest and showed antiproliferative effect by inhibition of Akt/mTOR/HIF-1α and ERK 1/2 signaling pathways. In addition, IP-Se-06 displayed significant inhibition of p38 MAPK and p-p38, leading to inhibition of inflammasome complex proteins (NLRP3 and caspase-1) in glioblastoma cells. These collective findings demonstrated that IP-Se-06 is a bioactive molecule that can be considered a candidate for the development of a novel drug for glioblastoma treatment.

"Green Is the Color": An Update on Ecofriendly Aspects of Organoselenium Chemistry.

Organoselenium compounds have been successfully applied in biological, medicinal and material sciences, as well as a powerful tool for modern organic synthesis, attracting the attention of the scientific community. This great success is mainly due to the breaking of paradigm demonstrated by innumerous works, that the selenium compounds were toxic and would have a potential impact on the environment. In this update review, we highlight the relevance of these compounds in several fields of research as well as the possibility to synthesize them through more environmentally sustainable methodologies, involving catalytic processes, flow chemistry, electrosynthesis, as well as by the use of alternative energy sources, including mechanochemical, photochemistry, sonochemical and microwave irradiation.

A Novel Diselenide-Probucol-Analogue Protects Against Methylmercury-Induced Toxicity in HT22 Cells by Upregulating Peroxide Detoxification Systems: a Comparison with Diphenyl Diselenide.

Methylmercury (MeHg) is a ubiquitous environmental neurotoxicant whose mechanisms of action involve oxidation of endogenous nucleophilic groups (mainly thiols and selenols), depletion of antioxidant defenses, and disruption of neurotransmitter homeostasis. Diphenyl diselenide-(PhSe)2-a model diaryl diselenide, has been reported to display significant protective effects against MeHg-induced neurotoxicity under both in vitro and in vivo experimental conditions. In this study, we compared the protective effects of (PhSe)2 with those of RC513 (4,4'-diselanediylbis(2,6-di-tert-butylphenol), a novel diselenide-probucol-analog) against MeHg-induced toxicity in the neuronal (hippocampal) cell line HT22. Although both (PhSe)2 and RC513 significantly mitigated MeHg- and tert-butylhydroperoxide (t-BuOOH)-cytotoxicity, the probucol analog exhibited superior protective effects, which were observed earlier and at lower concentrations compared to (PhSe)2. RC513 treatment (at either 0.5 µM or 2 µM) significantly increased glutathione peroxidase (GPx) activity, which has been reported to counteract MeHg-toxicity. (PhSe)2 was also able to increase GPx activity, but only at 2 µM. Although both compounds increased the Gpx1 transcripts at 6 h after treatments, only RC513 was able to increase mRNA levels of Prx2, Prx3, Prx5, and Txn2, which are also involved in peroxide detoxification. RC513 (at 2 µM) significantly increased GPx-1 protein expression in HT22 cells, although (PhSe)2 displayed a minor (nonsignificant) effect in this parameter. In agreement, RC513 induced a faster and superior capability to cope with exogenously-added peroxide (t-BuOOH). In summary, when compared to the prototypical organic diaryl diselenide [(PhSe)2], RC513 displayed superior protective properties against MeHg-toxicity in vitro; this was paralleled by a more pronounced upregulation of defenses related to detoxification of peroxides, which are well-known MeHg-derived intermediate oxidant species.

Docking and molecular dynamics predicted B-DNA and dihydropyrimidinone selenoesters interactions elucidating antiproliferative effects on breast adenocarcinoma cells.

Dihydropyrimidinones have demonstrated different biological activities including anticancer properties. Cytotoxic potential and antiproliferative potential of new dihydropyrimidinone-derived selenoesters (Se-DHPM) compounds were assessed in vitro against the breast adenocarcinoma cells (MCF-7). Among the eight Se-DHPM compounds tested just 49A and 49F were the most cytotoxic for MCF-7 and the most selective for the non-tumor strain (McCoy) and reduced cell viability in a time- and concentration-dependent manner. Compounds 49A and 49F increased the rate of cell death due to apoptosis and necrosis comparatively to the control, however only the 49F showed antiproliferative potential, reducing the number of colonies formed. In the molecular assay 49A interacts with CT-DNA and caused hyperchromism while 49F caused a hypochromic effect. The intercalation test revealed that the two compounds caused destabilization in the CT-DNA molecule. This effect was evidenced by the loss of fluorescence when the compounds competed and caused the displacement of propidium iodide. Simulations (docking and molecular dynamics) using B-DNA brought a greater understanding of ligand-B-DNA interactions. Furthermore, they predicted that the compounds act as minor groove ligands that are stabilized through hydrogen bonds and hydrophobic interactions. However, the form of interaction foreseen for 49A was more energetically favorable and had more stable hydrogen bonds during the simulation time. Despite some violations foreseen in the ADMET for 49F, the set of other results point to this Se-DHPM as a promising leader compound with anti-tumor potential for breast cancer.Communicated by Ramaswamy H. Sarma.

It takes two to tango: synthesis of cytotoxic quinones containing two redox active centers with potential antitumor activity.

We report the synthesis of 47 new quinone-based derivatives via click chemistry and their subsequent evaluation against cancer cell lines and the control L929 murine fibroblast cell line. These compounds combine two redox centers, such as an ortho-quinone/para-quinone or quinones/selenium with the 1,2,3-triazole nucleus. Several of these compounds present IC50 values below 0.5 µM in cancer cell lines with significantly lower cytotoxicity in the control cell line L929 and good selectivity index. Hence, our study confirms the use of a complete and very diverse range of quinone compounds with potential application against certain cancer cell lines.

Catalytic Antioxidant Activity of Bis-Aniline-Derived Diselenides as GPx Mimics.

Herein, we describe a simple and efficient route to access aniline-derived diselenides and evaluate their antioxidant/GPx-mimetic properties. The diselenides were obtained in good yields via ipso-substitution/reduction from the readily available 2-nitroaromatic halides (Cl, Br, I). These diselenides present GPx-mimetic properties, showing better antioxidant activity than the standard GPx-mimetic compounds, ebselen and diphenyl diselenide. DFT analysis demonstrated that the electronic properties of the substituents determine the charge delocalization and the partial charge on selenium, which correlate with the catalytic performances. The amino group concurs in the stabilization of the selenolate intermediate through a hydrogen bond with the selenium.

Light-Mediated Seleno-Functionalization of Organic Molecules: Recent Advances.

Organoselenium compounds constitute an important class of substances with applications in the biological, medicinal and material sciences as well as in modern organic synthesis, attracting considerable attention from the scientific community. Therefore, the construction of the C-Se bond via facile, efficient and sustainable strategies to access complex scaffolds from simple substrates are an appealing and hot topic. Visible light can be regarded as an alternative source of energy and is associated with environmentally-friendly processes. Recently, the use of visible-light mediated seleno-functionalization has emerged as an ideal and powerful route to obtain high-value selenylated products, with diminished cost and waste. This approach, involving photo-excited substrates/catalyst and single-electron transfer (SET) between substrates in the presence of visible light has been successfully used in the versatile and direct insertion of organoselenium moieties in activated and unactivated C(sp3 )-H, C(sp2 )-H, C(sp)-H bonds as well as C-heteroatom bonds. In most cases, ease of operation and accessibility of the light source (LEDs or commercial CFL bulbs) makes this approach more attractive and sustainable than the traditional strategies.

Electrohalogenation of organic compounds.

Herein, we present an overview of recent advances in the electrochemical halogenation of organic compounds. Halogen-containing compounds are essential building blocks for post-functionalization in academic research and in different industrial sectors, notably pharmaceutical companies. One of the main advantages of using electrosynthesis is its environmentally-friendly characteristics. Electrosynthesis is recognized as a methodology that can fulfill different criteria of the green chemistry concept and constitutes a promising tool in the development of new procedures in organic synthesis. In this review we target sp, sp2 and sp3 carbon fluorination, chlorination, bromination and iodination reactions using electrolysis as a redox medium. Mechanistic insights and substrate reactivity are also discussed.