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.

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.

Design, synthesis and identification of novel molecular hybrids based on naphthoquinone aromatic hydrazides as potential trypanocide and leishmanicidal agents.

In pursuit of potential agents to treat Chagas disease and leishmaniasis, we report the design, synthesis, and identification novel naphthoquinone hydrazide-based molecular hybrids. The compounds were subjected to in vitro trypanocide and leishmanicidal activities. N'-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-3,5-dimethoxybenzohydrazide (13) showed the best performance against Trypanosoma cruzi (IC50 1.83 µM) and Leishmania amazonensis (IC50 9.65 µM). 4-Bromo-N'-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)benzohydrazide (16) exhibited leishmanicidal activity (IC50 12.16 µM). Regarding trypanocide activity, compound 13 was low cytotoxic to LLC-MK2 cells (SI = 95.28). Furthermore, through molecular modeling studies, the cysteine proteases cruzain, rhodesain and CPB2.8 were identified as the potential biological targets.

Selenylated Imidazo[1,2-a]pyridine Induces Cell Senescence and Oxidative Stress in Chronic Myeloid Leukemia Cells.

Imidazo[1,2-a]pyridines (IPs) have been studied regarding drug development. The objective of this work was to evaluate the antileukemic capacity of IP derivatives by screening their ability as a pro-oxidant. IP derivatives were synthesized and oral bioavailability and toxicity were analyzed in silico. Redox screening was performed on human Kasumi, KG-1, K562, and Jurkat leukemia cells. The IP derivative and the most responsive leukemic cell were selected for cytotoxicity, cell proliferation, cell senescence, and oxidative stress assays. The predictive toxicity analysis showed a possible effect on the reproductive system, but without mutagenic, carcinogenic, or irritability effects. MRK-107 against K562 cells was the compound that showed the best redox profile. MRK-107 did not induce cell death in K562 and monocyte cells. However, this compound was able to decrease cell proliferation and increase cell senescence after 48 and 72 h. Furthermore, MRK-107 induced oxidative stress in K562 cells after 72 h, increasing lipid peroxidation and decreasing reduced glutathione (GSH) contents. This study demonstrated that MRK-107-induced senescence with the involvement of oxidative stress is a possible mechanism of action, addressing this compound as a potential antitumor drug against chronic myeloid leukemia.

The Thiol-Modifier Effects of Organoselenium Compounds and Their Cytoprotective Actions in Neuronal Cells.

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.

Apoptosis oxidative damage-mediated and antiproliferative effect of selenylated imidazo[1,2-a]pyridines on hepatocellular carcinoma HepG2 cells and in vivo.

Imidazo[1,2-a]pyridines (IP) and organoselenium compounds have been widely exploited in medicinal chemistry due to their pharmacological activities. Hepatocellular carcinoma (HCC) has few treatment options, and unfortunately, the prognosis is poor. Thus, the development of novel therapeutic drugs is urgent. The present study aimed at evaluating the antitumor mechanism of selenylated IP against HepG2 cells and in vivo. The selenylated IP named IP-Se-06 (3-((2-methoxyphenyl)selanyl)-7-methyl-2-phenylimidazol[1,2-a]pyridine) showed high cytotoxicity against HepG2 cells (half-maximal inhibitory concentration [IC50 ] = 0.03 µM) and selectivity for this tumor cell line. At nontoxic concentration, IP-Se-06 decreased the protein levels of Bcl-xL and increased the levels of p53, leading to inhibition of cell proliferation and apoptosis. This compound decreased the level of extracellular signal-regulated kinase 1/2 protein and changed the levels of proteins involved in the drive of the cell cycle, tumor growth, and survival (cyclin B1, cyclin-dependent kinase 2). In addition, IP-Se-06 decreased the number of cells in the S phase. In addition, IP-Se-06 led to increased generation of reactive oxygen species, changed antioxidant defenses, and caused DNA fragmentation. Finally, IP-Se-06 significantly inhibited the growth of Ehrlich ascites tumors in mice, increased survival time, and inhibited angiogenesis. Therefore, IP-Se-06 may be an important compound regarding the development of a therapeutic drug for HCC treatment.

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.

KIO4 -mediated Selective Hydroxymethylation/Methylenation of Imidazo-Heteroarenes: A Greener Approach.

Herein, we report a KIO4 -mediated, sustainable and chemoselective approach for the one-pot C(sp2 )-H bond hydroxymethylation or methylenation of imidazo-heteroarenes with formaldehyde, generated in situ via the oxidative cleavage of ethylene glycol or glycerol (renewable reagents) through the Malaprade reaction. In the presence of ethylene glycol, a series of 3-hydroxymethyl-imidazo-heteroarenes was obtained in good to excellent yields. These compounds are important intermediates to access pharmaceutical drugs, e.g., Zolpidem. Furthermore, by using glycerol, bis(imidazo[1,2-a]pyridin-3-yl)methane derivatives were selectively obtained in good to excellent yields.

Photoinduced, Direct C(sp2 )-H Bond Azo Coupling of Imidazoheteroarenes and Imidazoanilines with Aryl Diazonium Salts Catalyzed by Eosin†Y.

Herein, a greener approach to the eosin Y-Na2 catalyzed, C(sp2 )-H bond azo coupling of imidazoheteroarene with aryl diazonium salts is described, under acid free conditions. This direct photoredox process resulted in the corresponding azo products in good to excellent yields. Besides, this new approach could also be applicable to anilines, which is a poorly reactive substrate by other methods. The main features of this reaction are that it provides high yields and is gram-scalable and applicable to biologically relevant imidazoheteroarenes and -anilines.

Electrochemical synthesis of selenyl-dihydrofurans via anodic selenofunctionalization of allyl-naphthol/phenol derivatives and their anti-Alzheimer activity.

Herein, we report an eco-friendly, electrosynthetic approach for the intramolecular oxyselenylation of allyl-naphthol/phenol derivatives. This reaction proceeds with 0.2 equiv. of nBu4NClO4 as an electrolyte and Pt working electrodes in an undivided cell, resulting in the selenyl-dihydrofurans in good to excellent yields. Furthermore, several of the synthesized products presented a high percentage of acetylcholinesterase (AChE) inhibition, highlighting their potential anti-Alzheimer activity.

Selenylated-oxadiazoles as promising DNA intercalators: Synthesis, electronic structure, DNA interaction and cleavage.

A series of selenylated-oxadiazoles were prepared and their interaction with DNA was investigated. The photophysical studies showed that all the selenylated compounds presented absorption between 270 and 329 nm, assigned to combined n→π* and π→π* transitions, and an intense blue emission (325-380 nm) with quantum yield in the range of Φ F = 0.1-0.4. DFT and TD-DFT calculations were also performed to study the likely geometry and the excited state of these compounds. Electrochemical studies revealed the ionization potential energies (-5.13 to -6.01 eV) and electron affinity energies (-2.25 to -2.83 eV), depending directly on the electronic effect (electron-donating or electron-withdrawing) of the substituent attached to the product. Finally, the UV-Vis DNA interaction experiments indicated that the compounds can interact with the DNA molecule due to intercalation, except for 3g (which interacted via electrostatic interaction). Plasmid cleavage assay presented positive results only for 3f that presented the strongest interaction results. These results made the tested selenylated-oxadiazoles as suitable structures for the development of drugs and the design of structurally-related therapeutics.

Novel selenylated imidazo[1,2-a]pyridines for breast cancer chemotherapy: Inhibition of cell proliferation by Akt-mediated regulation, DNA cleavage and apoptosis.

A novel series of selenylated imidazo[1,2-a]pyridines were designed and synthesized with a view to a promising activity against breast cancer cell. The compounds, 7-methyl-3-(naphthalene-1-ylselanyl)-2-phenylimidazo[1,2-a]pyridine, named IP-Se-05, and 3-((2-methoxyphenyl)selanyl)-7-methyl-2-phenylimidazo[1,2-a]pyridine, named IP-Se-06, showed high cytotoxicity for MCF-7 cells (IC50 = 26.0 µM and 12.5 µM, respectively). Both the compounds inhibited the cell proliferation and caused decrease in the number of cells in the G2/M phase of cell cycle. IP-Se-05 and IP-Se-06 were also evaluated for effects on CT-DNA and DNA of MCF-7 cells. The compounds intercalated into CT-DNA and both treatments caused cleavage of DNA in cells. In addition, the compounds induced cell death by apoptosis. However, the presence of (2-methoxyphenyl) selenyl moiety at the imidazo[1,2-a]pyridine (IP-Se-06) appears to have a better antitumor effect with higher cytotoxicity at a lower concentration and caused less necrosis. Overall, the current study established IP-Se-06 more than IP-Se-05 as a potential prototype compound to be employed as an antiproliferative agent for the treatment of breast cancer.

Direct, Metal-free C(sp2 )-H Chalcogenation of Indoles and Imidazopyridines with Dichalcogenides Catalysed by KIO3.

Herein, we report a greener protocol for the synthesis of 3-Se/S-indoles and imidazo[1,2-a]pyridines through direct C(sp2 )-H bond chalcogenation of heteroarenes with half molar equivalents of different dichalcogenides, using KIO3 as a non-toxic, easy-to-handle catalyst and a stoichiometric amount of glycerol. The reaction features are high yields, based on atom economy, easy performance on gram-scale, metal- and solvent-free conditions as well as applicability to different types of N-heteroarenes.

Rose Bengal catalysed photo-induced selenylation of indoles, imidazoles and arenes: a metal free approach.

In this report, the highly efficient Rose Bengal-catalysed C(sp2)-H selenylation of indoles, imidazoles and arenes was achieved using a half molar equiv. of diorganoyl diselenides. This metal-free, photo-induced protocol resulted in selenylated products in good to excellent yields. The reaction features are high yields, an atom-economic, gram-scalable and metal-free approach, and applicability to different biologically relevant (hetero)arenes.

Copper-Catalyzed Synthesis of Unsymmetrical Diorganyl Chalcogenides (Te/Se/S) from Boronic Acids under Solvent-Free Conditions.

The efficient and mild copper-catalyzed synthesis of unsymmetrical diorganyl chalcogenides under ligand- and solvent-free conditions is described. The cross-coupling reaction was performed using aryl boric acids and 0.5 equiv. of diorganyl dichalcogenides (Te/Se/S) in the presence of 3 mol % of CuI and 3 equiv. of DMSO, under microwave irradiation. This new protocol allowed the preparation of several unsymmetrical diorganyl chalcogenides in good to excellent yields.

Regioselective, Solvent- and Metal-Free Chalcogenation of Imidazo[1,2-a]pyridines by Employing I2 /DMSO as the Catalytic Oxidation System.

Highly efficient molecular-iodine-catalyzed chalcogenations (S and Se) of imidazo[1,2-a]pyridines were achieved by using diorganoyl dichalcogenides under solvent-free conditions. This approach afforded the desired products that had been chalcogenated regioselectively at the C3 position in up to 96 % yield by using DMSO as an oxidant, in the absence of a metal catalyst, and under an inert atmosphere. This mild, green approach allowed the preparation of different types of chalcogenated imidazo[1,2-a]pyridines with structural diversity. Furthermore, the current protocol was also extended to other N-heterocyclic cores.

Synthesis and evaluation of dihydropyrimidinone-derived selenoesters as multi-targeted directed compounds against Alzheimer's disease.

This paper describes the synthesis and evaluation of new dihydropyrimidinone (DHPM)-derived selenoesters as potential multi-targeted agents for the treatment of Alzheimer's disease. A series of DHPM-derived selenoesters were obtained with high structural diversity through a short and modular synthetic route. The antioxidant activity was evaluated by TBARS and iron chelation assays. These compounds were also evaluated as acetylcholinesterase inhibitors (AChEi). The compounds demonstrated good antioxidant activity, since they presented excellent lipid peroxidation inhibition and good iron chelation activity. In addition, they showed acetylcholinesterase inhibition activity and some of them presented activity superior to that of the standard drug galantamine. The in silico predictions showed that the compound 1h may present a good pharmacokinetic profile. Therefore, the series of DHPM-derived selenoesters described herein displayed good potential for the development of antioxidant and anticholinesterasic agents in the search for new multi-targeted therapeutics for the treatment of Alzheimer's disease.

Synthesis and biological evaluation of 2-picolylamide-based diselenides with non-bonded interactions.

In this paper, we report the synthesis and biological evaluation of picolylamide-based diselenides with the aim of developing a new series of diselenides with O···Se non-bonded interactions. The synthesis of diselenides was performed by a simple and efficient synthetic route. All the products were obtained in good yields and their structures were determined by 1H-NMR, 13C-NMR and HRMS. All these new compounds showed promising activities when tested in different antioxidant assays. These amides exhibited strong thiol peroxidase-like (TPx) activity. In fact one of the compounds showed 4.66 times higher potential than the classical standard i.e., diphenyl diselenide. The same compound significantly inhibited iron (Fe)-induced thiobarbituric acid reactive species (TBARS) production in rat's brain homogenate. In addition, the X-ray structure of the most active compound showed non-bonded interaction between the selenium and the oxygen atom that are in close proximity and may be responsible for the increased antioxidant activity. The present study provides evidence about the possible biochemical influence of nonbonding interactions on organochalcogens potency.

Various fractions of Hypericum x moserianum and Hypericum ericoides possess antiglycation, anti-lipid peroxidation, antioxidative activities and non-toxic effects in vitro.

In the present study, two species Hypericum x moserianum and Hypericum ericoides which belong to genus Hypericum were evaluated for their potential antiglycation, antioxidant, anti lipid peroxidation and cytotoxic activities. These species are widely used in folk medicine and to the best of our knowledge there were no previous reports regarding antioxidant, anti-glycation and cytotoxicity studies of these species. Among the crude methanol extracts and fractions of both the species, the ethyl acetate fraction of H. x moserianum exhibited promising antioxidant activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) with IC50 129.084±1.215µg/ml, followed by methanol extract (IC50=232.083 ± 1.215µg/ml) and aqueous fraction (IC50=266.962 ±2.213 µg/ml). The ethyl acetate fraction of H. ericoides exhibited IC50 value of 295.088 ± 2.320 µg/ml. In antiglycation assay, the ethyl acetate fraction of H. x moserianum showed 52.096% inhibition at 500µg/ml. For lipid peroxidation assay, the dichloromethane, aqueous and n-hexane fractions of H. x moserianum showed 67.241, 66.147 and 64.213% inhibition respectively, while aqueous fraction of H. ericoides exhibited 67.404% inhibition at 500µg/ml. In cytotoxicity assay, all fractions of both the species were found to be non-toxic on mouse fibroblast 3T3 cells with IC50 value greater than 30µg/ml as compared to cycloheximide with IC50 value 0.073±0.1µg/ml used as a standard. It was concluded from the study that among the two species, crude methanolic and ethyl acetate fractions were more active regarding the antioxidant, anti-glycation activities while dichloromethane, aqueous and n-hexane fractions possessed anti-lipid peroxidation activity.

Selenium-Containing (Hetero)Aryl Hybrids as Potential Antileishmanial Drug Candidates: In Vitro Screening against L. amazonensis.

Leishmaniasis remains a significant global health concern, with current treatments relying on outdated drugs associated with high toxicity, lengthy administration, elevated costs, and drug resistance. Consequently, the urgent need for safer and more effective therapeutic options in leishmaniasis treatment persists. Previous research has highlighted selenium compounds as promising candidates for innovative leishmaniasis therapy. In light of this, a library of 10 selenium-containing diverse compounds was designed and evaluated in this study. These compounds included selenium-substituted indole, coumarin, chromone, oxadiazole, imidazo[1,2-a]pyridine, Imidazo[2,1-b]thiazole, and oxazole, among others. These compounds were screened against Leishmania amazonensis promastigotes and intracellular amastigotes, and their cytotoxicity was assessed in peritoneal macrophages, NIH/3T3, and J774A.1 cells. Among the tested compounds, MRK-106 and MRK-108 displayed the highest potency against L. amazonensis promastigotes with reduced cytotoxicity. Notably, MRK-106 and MRK-108 exhibited IC50 values of 3.97 µM and 4.23 µM, respectively, and most of the tested compounds showed low cytotoxicity in host cells (CC50 > 200 µM). Also, compounds MRK-107 and MRK-113 showed activity against intracellular amastigotes (IC50 18.31 and 15.93 µM and SI 12.55 and 10.92, respectively). In conclusion, the identified selenium-containing compounds hold potential structures as antileishmanial drug candidates to be further explored in subsequent studies. These findings represent a significant step toward the development of safer and more effective therapies for leishmaniasis, addressing the pressing need for novel and improved treatments.