Diaryl Sulfide Research Articles

Gold-Catalyzed [3,3]-Sigmatropic Rearrangement of ortho-Alkynyl-S,S-diarylsulfilimines.

Highly functionalized 5H-pyrrolo[2,3-b]pyrazine cores, carrying a diaryl sulfide moiety at the C-7 position, were obtained from a gold-catalyzed reaction using easily accessible ortho-alkynyl-substituted S,S-diarylsulfilimines as intramolecular nitrene transfer reagents for the first time. The reaction proceeds under mild conditions, providing excellent yields while tolerating a large variety of different substitution patterns. We provide experimental evidence for an intramolecular reaction mechanism, likely including an unprecedented gold-catalyzed amino sulfonium [3,3]-sigmatropic rearrangement.

I2/DMSO-Promoted Synthesis of Diaryl Sulfide- and Selenide-Embedded Arylhydrazones

Functionalization and derivatization of arylhydrazones are important in pharmaceutical, medicinal, material, and coordination chemistry. In this regard, a facile I2/DMSO-promoted cross-dehydrogenative coupling (CDC) for direct sulfenylation and selenylation of arylhydrazones has been accomplished utilizing arylthiols/arylselenols at 80 °C. This method provides a metal-free benign route for the synthesis of a variety of arylhydrazones embedded with diverse diaryl sulfide and selenide moieties in good to excellent yield. In this reaction, molecular I2 acts as a catalyst, and DMSO is utilized as a mild oxidant as well as solvent to produce several sulfenyl and selenyl arylhydrazones through a CDC-mediated catalytic cycle.

Metal- and Solvent-Free Cascade Reaction for the Synthesis of Amino Pyrazole Thioether Derivatives.

We developed an iodine-mediated cascade strategy to synthesize amino pyrazole thioether derivatives (11) in the absence of metals as well as solvents. The present approach provides amino pyrazole thioethers in a highly selective manner without the formation of diaryl sulfide and sulfenyl-enaminonitrile with broad substrate scope. The reactivity of nine sulfenylation sources and synthetic applications of the synthesized compounds have been demonstrated. Thus, the overall iodine-mediated multicomponent reaction (MCR) is more economically feasible, efficient, and environmentally benign.

Diaryl Sulfide Derivatives as Potential Iron Corrosion Inhibitors: A Computational Study.

The present work aimed to assess six diaryl sulfide derivatives as potential corrosion inhibitors. These derivatives were compared with dapsone (4,4′-diaminodiphenyl sulfone), a common leprosy antibiotic that has been shown to resist the corrosion of mild steel in acidic media with a corrosion efficiency exceeding 90%. Since all the studied compounds possess a common molecular backbone (diphenyl sulfide), dapsone was taken as the reference compound to evaluate the efficiency of the remainder. In this respect, two structural factors were examined, namely, (i) the effect of replacement of the S-atom of diaryl sulfide by SO or SO2 group, (ii) the effect of the introduction of an electron-withdrawing or an electron-donating group in the aryl moiety. Two computational chemical approaches were used to achieve the objectives: the density functional theory (DFT) and the Monto Carlo (MC) simulation. First, B3LYP/6-311+G(d,p) model chemistry was employed to calculate quantum chemical descriptors of the studied molecules and their geometric and electronic structures. Additionally, the mode of adsorption of the tested molecules was investigated using MC simulation. In general, the adsorption process was favorable for molecules with a lower dipole moment. Based on the adsorption energy results, five diaryl sulfide derivatives are expected to act as better corrosion inhibitors than dapsone.

A review on the latest progress of C‐S cross‐coupling in diaryl sulfide synthesis: Update from 2012 to 2021

Diaryl sulfides are a highly valuable class of sulfur‐containing compounds presented in numerous drugs with a broad range of therapeutic activities and are also employed as precursors to other higher oxidation state sulfur‐containing compounds with important bioactivities. Thus, the development of efficient approaches for C−S bond formation is essential in synthetic and medicinal chemistry. Many efforts have been made in constructing C−S bonds via various protocols. This review highlights the current strategies emphasizing metal‐catalyzed reactions (MRC), metal‐free approaches, photocatalysis reactions, and MCR's from 2012 onwards.

Diverse diaryl sulfide synthesis through consecutive aryne reactions.

An efficient method to synthesize diaryl sulfides with structural diversity is disclosed. Demethylative hydrothiolation of aryne intermediates generated from o-iodoaryl triflates with methylthio-substituted o-silylaryl triflates and further aryne reactions afford diverse diaryl sulfides.

Synthesis of diaryl sulfides based on copper-doped OMS-2

We describe a practical protocol for efficiently preparing diaryl sulfide compounds using Cu–OMS-2 as the catalyst. Cu–OMS-2 originates from manganese oxide octahedral molecular sieves modified with copper ions and catalyzes the C–S coupling reaction of substituted thiophenols and aryl halides. This protocol has the advantages of environmental friendliness, simple operation, high yields, good tolerance of functional groups, and the Cu–OMS-2 catalytic material can be recycled several times.

Structure-guided approach to identify a novel class of anti-leishmaniasis diaryl sulfide compounds targeting the trypanothione metabolism.

Leishmania protozoans are the causative agent of leishmaniasis, a neglected tropical disease consisting of three major clinical forms: visceral leishmaniasis (VL), cutaneous leishmaniasis, and mucocutaneous leishmaniasis. VL is caused by Leishmania donovani in East Africa and the Indian subcontinent and by Leishmania infantum in Europe, North Africa, and Latin America, and causes an estimated 60,000 deaths per year. Trypanothione reductase (TR) is considered to be one of the best targets to find new drugs against leishmaniasis. This enzyme is fundamental for parasite survival in the human host since it reduces trypanothione, a molecule used by the tryparedoxin/tryparedoxin peroxidase system of Leishmania to neutralize the hydrogen peroxide produced by host macrophages during infection. Recently, we solved the X-ray structure of TR in complex with the diaryl sulfide compound RDS 777 (6-(sec-butoxy)-2-((3-chlorophenyl)thio)pyrimidin-4-amine), which impairs the parasite defense against the reactive oxygen species by inhibiting TR with high efficiency. The compound binds to the catalytic site and engages in hydrogen bonds the residues more involved in the catalysis, namely Glu466', Cys57 and Cys52, thereby inhibiting the trypanothione binding. On the basis of the RDS 777-TR complex, we synthesized structurally related diaryl sulfide analogs as TR inhibitors able to compete for trypanothione binding to the enzyme and to kill the promastigote in the micromolar range. One of the most active among these compounds (RDS 562) was able to reduce the trypanothione concentration in cell of about 33% via TR inhibition. RDS 562 inhibits selectively Leishmania TR, while it does not inhibit the human homolog glutathione reductase.

Latent Radical Cleavage of α-Allenylic C–O Bonds: Potassium Persulfate Mediated Thiolation of Allenylphosphine Oxides

A novel potassium persulfate (K2S2O8) mediated thiolation of allenylphosphine oxides with diaryl sulfides is disclosed. Mechanistic studies indicate that K2S2O8 homolyzes the diaryl sulfide to produce a thiyl radical (PhS•), which is followed by C–O bond cleavage of the allenylphosphine oxide under metal-free conditions, affording novel S,P-bifunctionalized butadienes in moderate to excellent yields.

Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives

The study presented here aimed at identifying a new class of compounds acting against Leishmania parasites, the causative agent of Leishmaniasis. For this purpose, the thioether derivatives of our in-house library have been evaluated in whole-cell screening assays in order to determine their in vitro activity against Leishmania protozoan. Among them, promising results have been achieved with compound RDS 777 (6-(sec-butoxy)-2-((3-chlorophenyl)thio)pyrimidin-4-amine) (IC50 = 29.43 µM), which is able to impair the mechanism of the parasite defence against the reactive oxygen species by inhibiting the trypanothione reductase (TR) with high efficiency (Ki 0.25 ± 0.18 µM). The X-ray structure of L. infantum TR in complex with RDS 777 disclosed the mechanism of action of this compound that binds to the catalytic site and engages in hydrogen bonds the residues more involved in the catalysis, namely Glu466', Cys57 and Cys52, thereby inhibiting the trypanothione binding and avoiding its reduction.

Metal-free C-H thioarylation of arenes using sulfoxides: a direct, general diaryl sulfide synthesis.

Metal-free C-H thioarylation of arenes and heteroarenes using methyl sulfoxides constitutes a general protocol for the synthesis of high value diaryl sulfides. The coupling of arenes and heteroarenes with in situ activated sulfoxides is regioselective, uses readily available starting materials, is operationally simple, and tolerates a wide range of functional groups.

DFT studies on the mechanism of palladium catalyzed arylthiolation of unactive arene to diaryl sulfide

The cleavage of S–N bond prefers to take place via concerted σ-bond metathesis rather than oxidative addition proposed in experiment.

Diaryl sulfide analogs of combretastatin A-4: Toxicogenetic, immunomodulatory and apoptotic evaluations and prospects for use as a new chemotherapeutic drug.

Combretastatin A-4 exhibits efficient anti-cancer potential in human tumors, including multidrug-resistant tumors. We evaluated the mutagenic, apoptotic and immunomodulatory potential of two diaryl sulfide analogs of combretastatin A-4, 1,2,3-trimethoxy-5-([4-methoxy-3-nitrophenyl]thio)benzene (analog 1) and 1,2,3-trimethoxy-5-([3-amino-4-methoxyphenyl]thio)benzene (analog 2), as well as their association with the anti-tumor agent cyclophosphamide, in Swiss mice. Such evaluation was achieved using the comet assay, peripheral blood micronucleus test, splenic phagocytosis assay, and apoptosis assay. Both analogs were found to be genotoxic, mutagenic and to induce apoptosis. They also increased splenic phagocytosis, although this increase was more pronounced for analog 2. When combined with cyclophosphamide, analog 1 enhanced the mutagenic and apoptotic effects of this anti-tumor agent. In contrast, analog 2 did not enhance the effects of cyclophosphamide and prevented apoptosis at lower doses. These data suggest that analog 1 could be an adjuvant chemotherapeutic agent and possibly improve the anti-neoplastic effect of cyclophosphamide. Additionally, this compound could be a candidate chemotherapeutic agent and/or an adjuvant for use in combined anti-cancer therapy.

Synthesis and coordination modes of metals with diaryl sulfides and its derivatives. Mini review

Metal–organic coordination compounds containing sulfur functionality have attracted much attention because of their intriguing architectures and applications. In this review, the synthesis of different coordination modes, structural features and applications of complexes derived from diaryl sulfide have been discussed in the absence or presence of other donor groups.

Fluorinated Diaryl Sulfides

Diaryl sulfides also known as diphenyl sulfides, phenylthiobenzylamines, and biphenylthiols are a class of compounds with phenylthiophenyl scaffold that have been validated as biomarkers to label the brain serotonin transporter (SERT), in vivo. The development of those synthetic and non-natural compounds started more than a decade ago when the observation that 5-chloro-((2-((dimethylamino)methyl)phenyl)thio)benzene-methanol hydrochloride also called 403U76 inhibited the serotonin and norepinephrine uptake into rat brain synaptosomes, led to the preparation of few derivatives based on 403U76 chemical structure. The new class of compounds, called the diaryl sulfide family, was investigated as biomarkers for the brain SERT. The promising data demonstrated by the carbon-11 labeled diaryl sulfides led to the translation of few of them into humans and the further evaluation of the phenylthiophenyl core structure by developing some fluorinated derivatives. This review will mainly focus on the fluorinated diaryl sulfides as fluorine-containing tracers validated to image the human brain SERT using positron emission tomography.

11C and 18F PET radioligands for the serotonin transporter (SERT)

The serotonin transporter (SERT) has been implicated in a variety of neuropsychiatric disorders including depression, anxiety, and suicide, and is the target of the selective serotonin reuptake inhibitor (SSRI) class of antidepressants. The availability of SERT-specific positron emission tomography (PET) radioligands will allow the SERT to be studied noninvasively in living subjects through PET imaging of the SERT and occupancy studies of SSRIs. Numerous diaryl sulfide and tropane derivatives have been developed and radiolabeled with (11) C or (18) F for imaging the SERT with PET.

Microwave-assisted Ullmann-Buchwald C-S bond formation using a copper(I) catalyst and trans-cyclohexane-1,2-diol as ligand

Microwave irradiation of a thiophenol or alkyl thiol (1 equiv.) and an aryl halide (1 equiv.) in 2propanol at 120 °C for three hours in the presence of K2CO3 (2 equiv.) as base using copper(I) iodide as catalyst (5 mol%) and trans-cyclohexane-1,2-diol (2 equiv.) as ligand provides a rapid and convenient method for C−S bond formation. The process is most efficient using thiophenol and aryl iodide precursors, both of which may contain electron-donating and electronwithdrawing groups, to give the corresponding diaryl sulfide in good to excellent yield.

Synthesis of exo-Olefin Terminated Polyisobutylene by Sulfide/Base Quenching of Living Polyisobutylene

exo-Olefin (methyl vinylidene)-terminated polyisobutylene (PIB) was synthesized in one pot by quenching TiCl4-catalyzed living PIB with a dialkyl (or) diaryl sulfide at −60 to −40 °C, followed by a...

Synthesis, Inhibition Potency, Binding Mode, and Antiprotozoal Activities of Fluorescent Inhibitors of Trypanothione Reductase Based on Mepacrine‐Conjugated Diaryl Sulfide Scaffolds

Trypanothione reductase (TR) is a flavoenzyme unique to trypanosomatid parasites and a target for lead discovery programs. Various inhibitor scaffolds have emerged in the past, exhibiting moderate affinity for the parasite enzyme. Herein we show that the combination of two structural motifs of known TR inhibitors - diaryl sulfides and mepacrine - enables the simultaneous addressing of two hydrophobic patches in the active site. The binding efficacy of these conjugates is enhanced over that of the respective parent inhibitors. They show K(ic) values for the parasite enzyme down to 0.9+/-0.1 microm and exhibit high selectivity for TR over human glutathione reductase (GR). Despite their considerable molecular mass and in some cases permanent positive charges, in vitro studies revealed IC(50) values in the low micromolar to sub-micromolar range against Trypanosoma brucei rhodesiense and Trypanosoma cruzi, as well as the malaria parasite Plasmodium falciparum, which lack trypanothione metabolism. The inhibitors exhibit strong fluorescence due to their aminoacridine moiety. This feature allows visualization of the drugs in the parasite where high accumulation was observed by fluorescence microscopy even after short exposure times.

Inside Cover: Synthesis, Inhibition Potency, Binding Mode, and Antiprotozoal Activities of Fluorescent Inhibitors of Trypanothione Reductase Based on Mepacrine‐Conjugated Diaryl Sulfide Scaffolds (ChemMedChem 12/2009)

Inside Cover: Synthesis, Inhibition Potency, Binding Mode, and Antiprotozoal Activities of Fluorescent Inhibitors of Trypanothione Reductase Based on Mepacrine‐Conjugated Diaryl Sulfide Scaffolds (ChemMedChem 12/2009)