Thiepin Derivatives Research Articles

Inside Cover Picture

The cover picture shows a facile synthetic methodology towards S‐fused multi‐membered polycyclic heterocycles containing five‐membered thiophene, six‐membered thiopyran, and seven‐membered thiepine. A construction strategy for thermally stable thiepine derivatives is thus established. More details are discussed in the article by Zhou et al. on page 13—20.image

Facile Synthesis of S‐Fused Multi‐Membered Polycyclic Heterocycles: A Construction Strategy towards Thermally Stable Thiepine Derivatives

Comprehensive SummaryS‐fused heterocycles have become popular building blocks to construct functional polycyclic compounds. In contrast to the abundant synthetic methodologies for thiophene‐fused aromatics, the synthesis of S‐heterocycles containing six‐membered thiopyran and seven‐membered thiepine rings is much less reported owing to their unfavorable synthetic protocols and the thermal instabilities. Herein, a series of thiepine‐containing polycyclic S‐heterocycles have been successfully synthesized via different synthetic routes which involve initial construction of sulfur bridges and final ring‐closure reactions. Therefore, the dilithium intermediates are excluded, which facilitates the fusion on the thiepine ring with different S‐heterocycles, including thiophene and thiopyran derivatives. Typically, a S‐fused multi‐membered polycyclic compound simultaneously involving thiophen, thiopyran, and thiepine rings has been successfully prepared. Interestingly, nucleus‐independent chemical shift calculations reveal that the incorporated thiopyran and thiepine rings demonstrate aromatic and nonaromatic characteristics, respectively. Moreover, the thermal stabilities of the thiepine derivatives have been tremendously improved after the fusion on the three vinyl groups in the thiepine unit, which is attributed to the enhancements of the activation energies for the S‐extrusion reactions, as revealed by density functional theory calculations. Therefore, our findings not only provide a facile synthetic methodology for S‐fused multi‐membered polycyclic heterocycles, but also furnish a novel construction strategy towards thermally stable thiepine derivatives.

N‐Heterocyclic Carbene (NHC)‐Catalyzed Intramolecular Stetter Reaction to Access Dibenzo‐fused Seven‐membered Heterocycles

AbstractHerein, we have delineated an NHC‐catalyzed transformation to access dibenzo‐fused seven‐membered heterocyclic compounds via intramolecular Stetter reaction under ambient conditions. A range of dibenzo[b,f]oxepine and dibenzo[b,f]thiepine derivatives have been generated in very good to excellent yields. The 1,4‐dicarbonyl functionality of a representative derivative has undergone further heterocyclization via Paal‐Knorr reaction.

Dengue virus replication inhibition by dibenzothiepin derivatives

The presented research uses both a target-based drug design strategy focused on dengue virus (DENV) helicase, and the repurposing of a known scaffold, the dibenzo[b,e]thiepine moiety, extensively used in antidepressants drugs. A series of dihydrodibenzo[b,e]thiepin derivatives were synthesized and tested at 10 µg/mL in HEK293 cells infected with DENV2. The replication inhibitory effect was average and depends on the chemical structure. The best antiviral effect was recorded for compounds, (E)-(2-methyl-6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)amino butanoate (TM3) and (E)-(2-methyl-6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)amino 3-fluorobenzoate (TM24); the concentrations resulting in a 90% (1 log) inhibiton of viral titers (IC90) being calculated at 10 µM for TM3 and 0.25 µM for TM24. A molecular docking study has been conducted in order to predict the binding affinity of the tested compounds to DENV2 NS3 helicase and also on dopamine D4 receptor and to establish an in silico–in vitro correlation. The results obtained indicate that the antiviral mechanisms are complex and differ significantly depending on the structure. The majority of compounds appear to inhibit only the viral helicase, some of them both helicase and D4 receptors, and in the case of one compound the mechanism is elusive. We also observed that a 2-methyl substitution and S-oxidation on the dibenzo[b,e]thiepin scaffold significantly improves the inhibition of the viral replication.

Consensus-based comparison of chromatographic and computationally estimated lipophilicity of benzothiepino[3,2-c]pyridine derivatives as potential antifungal drugs.

Lipophilicity is one of the essential properties influencing drug absorption, excretion and metabolism. It is used for screening viable drug candidates. Chromatographic behavior of thiepino[3,2-c:6,7-c']dipyridine and 16 benzothiepino[3,2-c]pyridine derivatives as potential antifungal drugs was studied using thin-layer chromatography under typical reversed-phase conditions and two microemulsion chromatographic systems. Seventeen chromatographic and nine in silico lipophilicity measures were estimated. They were compared by classical multivariate approaches: principal component analysis, hierarchical cluster analysis, and ranked and grouped by the non-parametric method-Sum of ranking differences. Two computational and two chromatographic descriptors from the typical reversed-phase conditions using acetone/water mixtures emerged as the best candidates for lipophilicity estimation. The principal component scores related to typical reversed-phase conditions using dioxane/water were ranked as statistically insignificant (the worst). Microemulsion systems were positioned in between, performing worse than in silico estimates. Thiepine derivatives were ranked and grouped by sum of ranking differences, fusing multiple lipophilicity measures. In multicriteria maximization ranking, the compound substituted by phenyl group at position 8 was selected as the most lipophilic one. It is also the most active against Candida albicans. The ranking confirmed that introduction of phenyl core is essential for increasing the lipophilicity of the studied compounds.

Synthesis and anti-Candida activity of novel benzothiepino[3,2-c]pyridine derivatives.

A novel series of thiepine derivatives were synthesized and evaluated as potential antimicrobials. All the synthesized compounds were evaluated for their antimicrobial activities in vitro against the fungi Candida albicans (ATCC 10231), C.parapsilosis (clinical isolate), Gram-negative bacterium Pseudomonas aeruginosa (ATCC 44752), and Gram-positive bacterium Staphylococcus aureus (ATCC 25923). Synthesized compounds showed higher antifungal activity than antibacterial activity, indicating that they could be used as selective antimicrobials. Selected thiepines efficiently inhibited Candida hyphae formation, a trait necessary for their pathogenicity. Thiepine 8-phenyl[1]benzothiepino[3,2-c]pyridine (16) efficiently killed Candida albicans at 15.6μg/mL and showed no embryotoxicity at 75μg/mL. Derivative 8-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl][1]benzothiepino[3,2-c]pyridine (23) caused significant hemolysis and in vitro DNA interaction. The position of the phenyl ring was essential for the antifungal activity, while the electronic effects of the substituents did not significantly influence activity. Results obtained from in vivo embryotoxicity on zebrafish (Danio rerio) encourage further structure optimizations.

Synthesis and antimicrobial activity of azepine and thiepine derivatives

A series of new 5H-pyridobenzazepine and pyridobenzothiepine derivatives was synthesized by Pd-catalyzed formation of C-N and C-S bonds. All synthesized compounds were tested for their in vitro antimicrobial activity. The 5H-pyridobenzazepine derivatives showed better antibacterial and antifungal activity than corresponding 5H-dipyridoazepine analogs. Among the synthesized azepines, derivative 8 displayed potent activity against tested bacteria (MIC = 39-78 ?g/mL), while azepine 12 showed promising antifungal activity (MIC = 156-313 ?g/mL). The synthesized thiepine derivatives exhibited weak antibacterial activity, but showed pronounced antifungal activity.

Conformational properties and chiral separation of dibenzo[b,f]thieno[3,4-d]-fused oxepines and thiepines

The dynamic properties of planar chiral 1-hydroxymethyl-substituted dibenzo[b,f]thieno[3,4-d]-fused oxepine and thiepine derivatives have been investigated by use of variable-temperature nuclear magnetic resonance spectroscopy combined with line-shape analysis, chiral column chromatography, and molecular modelling. NMR data and computational studies revealed the height of the energy barrier for ring inversion in thiepine derivatives was sufficient to enable the existence of a pair of conformational enantiomers at ambient temperature. Their resolution was achieved by chiral column high-performance liquid chromatography (HPLC). The absolute conformation of the enantiomers is proposed. This is the first chromatographic separation of planar chiral enantiomers of [b,d,f]-fused thiepine derivatives.

Synthesis and Antimicrobial Evaluation of Dibenzo[b,e]oxepin-11(6H)-one O-Benzoyloxime Derivatives

A series of dibenzo[b,e]ox(thi)epin-11(6H)-one O-benzoyloximes has been synthesized and structurally elucidated by means of IR, 1H-NMR, 13C-NMR, MS, and elemental analysis. The newly developed compounds were screened at concentrations of 200–25 μg/mL for their antibacterial activity against Gram+ve organisms such as Methicillin-Resistant Staphylococcus Aureus (MRSA), Gram−ve organisms such as Escherichia coli (E. coli), and at the same concentration range for their antifungal activity against fungal strain Aspergillus niger (A. niger) by the cup plate method. Ofloxacin and ketoconazole (10 μg/mL) were used as reference standards for antibacterial and antifungal activity, respectively. The dibenzo[b,e]oxepines 6a–c and 6e–h showed low antimicrobial activity (MIC 125–200 μg/mL) compared to the reference substances, whereas a major improvement (MIC 50–75 μg/mL) was achieved with the synthesis of the corresponding bromomethyl derivative 6d. Moreover, replacement of oxygen by its bioisosteric sulfur led to isomeric dibenzo[b,e]thi-epine derivatives 6g,h which significantly exhibited higher antimicrobial activity (MIC 25–50 μg/mL) against all tested culture strains used in the present study, demonstrating that a change of chemical class from dibenzo[b,e]oxepine to dibenzo[b,e]thiepine significantly improves the antimicrobial activity. Further variation, such as the oxidation of the thiepine sulfur to the corresponding isomeric dibenzo[b,e]thiepine 5,5-dioxide derivative 9, comparatively failed to exhibit high activity (MIC 200 μg/mL) against S. aureus, E. coli or A. niger.

Synthesis and Characterization of New Dibenzo[b, e]Thiepine Derivatives. I

The aim of the present paper was the synthesis and chemical characterization of some original compounds with dibenzo[b,e]thiepine structure. The synthesis of the new compounds was performed in several stages. Thus, by reaction of phtalide with thiophenol potassium salt, we obtained the 2-phenylthiomethyl-benzoic acid. The acid was cyclized with polyphosphoric acid to the desired 6,11-dihydrodibenzo[b,e]thiepin-11(6H)-one, converted afterwards to the corresponding oxime and subsequently to the O-acyloximino-dibenzo[b,e]thiepins by acylation with various substituted benzoic acid chlorides. The oxidation of O-acyloximino-dibenzo[b,e]thiepins with hydrogen peroxide afforded the corresponding sulfones. The new compounds, four O-acyl-oximino-dibenzo[b,e]thiepins, and four O-acyl-oximino-dibenzo[b,e]thiepin-5,5-dioxides, have been characterized by their physical constants (melting point, solubility) and their structures and purity were confirmed by elemental analysis, and spectral analysis (IR, 1H-NMR, 13C-NMR).

ChemInform Abstract: A New Concise Strategy for Synthesis of Dibenzo[b,f]thiepins and Related Fused Symmetrical Thiepin Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A New Concise Strategy for Synthesis of Dibenzo[b,f]thiepins and Related Fused Symmetrical Thiepin Derivatives

A new strategy for preparation of dibenzo[b,f]thiepins and related fused systems in good overall yields is described, featuring ortho-metalation of aromatic or heterocyclic aldehyde acetals followed by treatment with bis(phenylsulfonyl) sulfide for construction of the required bis(aryl)- or bis(heteroaryl) sulfide precursors, which were thereafter subjected to deacetalization, and finally McMurry coupling as the ring-forming step.

ChemInform Abstract: The Place of Dibenzo(b,f)thiepin Derivatives in Medicinal Chemistry: Structures and Activities

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The place of dibenzo[b,f]thiepin derivatives in medicinal chemistry: Structures and activities

The place of dibenzo[<i>b,f</i>]thiepin derivatives in medicinal chemistry: Structures and activities

A new class of calcium antagonists. Synthesis and biological activity of 11-[(.omega.-aminoalkanoyl)amino]-6,6a,7,8,9,10,10a,11-octahydrodibenzo[b,e]thiepin derivatives

A series of 11-[(omega-aminoalkanoyl)amino]-6,6a,7,8,9,10,10a,11- octahydrodibenzo[b,e]thiepin derivatives were prepared and found to be a structurally new class of calcium antagonists. The structure-activity relationship studies indicated that the optimum was (6aR*,10aR*,11R*)-11-[[4-[4-(4-fluorophenyl)-1- piperazinyl]butyryl] amino]-6,6a,7,8,9,10,10a,11-octahydrodibenzo[b,e]thiepin (31,pA2 8.16), which was superior to diltiazem (pA2 7.42) in calcium antagonistic activity. Compound 31 showed antihypertensive activity in anesthetized rats, without a significant effect on the heart rate. It had also antianginal effects in vasopressin-induced ST-depression and methacholine-induced ST-elevation testings in rats. These potencies of 31 were essentially equal to those of diltiazem.

The effect of aromatic substitution on neuroleptic activity in 1-piperazino-3-phenylindans. A comparison based on a new D-2 receptor model with corresponding 10-piperazino-10,11-dihydrodibenzo[b,f]thiepins

The validity of a new dopamine D-2 receptor interaction model based on conformational analysis and least-squares superimposition studies of the indan derivative tefludazine and the thiepin derivative octoclothepin was further tested by comparison of the effect of aromatic substitution on D-2 antagonistic activity in two series of indan and thiepin derivatives. The indan series include new derivatives substituted in the 4-, 7-, 2’- and 3’-position. The substitution effects were largely parallel with one important exception: Only 6-substituted indans have significant neuroleptic activity while both 8- and 7-substituted thiepin derivatives have neuroleptic activity. In indans additional fluorination in the 2’- or 4’-position is demanded to give potent neuroleptic activity, while a 3’-fluoro-substituted derivative was inactive. Fluorination is not necessary in thiepins although 3-fluoro derivatives have a significant prolonged duration of action. Considering the differences in physico-chemical properties, metabolism and pharmacokinetics between the two series, the largely parallel substitution effects support the new D-2 receptor model.

Some further 2-(4-substituted 1-piperazinyl)acetamides derived from 6,11-dihydrodibenzo[b,e]thiepin. Transformations of 6,11-dihydrodibenzo[b,e]thiepin derivatives into anthraquinones, anthrones and anthracenes

Reactions of the secondary amines I and VIII with chloroacetyl chloride gave the 2-chloroacetamides II and IX affording by substitution reactions with 1-methylpiperazine, 2-(1-piperazinyl)ethanol and 3-(1-piperazinyl)propanol in the title compounds III-V and X-XII. The starting amine VIII was prepared from the ketone XIV via XVII and VII. The product of 1,6-addition and the following dehydrogenation XVIII was obtained as a by-product of the reaction of XIV with 1-methyl-4-piperidylmagnesium chloride. Reaction of 2-fluorodibenzo[b,e]thiepin-11(6H)-one (XV) with sodium hydride in dimethylformamide and the following hydrolysis gave 2-fluoroanthraquinone (XXVII). An attempt at trapping the presumed dianion of the type B by treatment with methyl iodide and the following hydrolysis resulted in a mixture of XXVII and the anthracenes XXXI and XXXII. A similar reaction sequence starting from the ketone XIV gave the anthrones XXX and XXXIV, 9-methoxy-10-(methylthio)anthracene (XXXIII) (main product) and anthraquinone (XXVIII). Oxidation of XXXIII with m-chloroperbenzoic acid or hydrogen peroxide gave either the sulfone XXXV or XXXVI.

Base induced skeletal rearrangements via spirocyclic ipso intermediates in dibenzodithiocinium salts

Treatment of 6-methyl-12-oxo-5H,7H-dibenzo[b,g] [1,5]-dithiociniumsalt ( 1a ) with methanolic KOH afforded the ring contracted product ( 2a ), i. e., thiepin derivatives, trans- 2a . (44%) and cis-2a (19%). However, the corresponding deoxodithiociniumsalt ( 1b ) gave an unexpected isomer ( 2b ) with the same thiepin skeleton. These are explained by tandem sigmatropy.

Studies on the Structure-Activity Relationship of Thiepin and Oxepin Derivatives to Antiinflammatory Activities

Studies on the Structure-Activity Relationship of Thiepin and Oxepin Derivatives to Antiinflammatory Activities

Dibenzothiepin derivatives and related compounds. III. Investigation of the reactivity of triphenylmethyl hexachloroantimonate and synthesis of 6,11-dihydrodibenzo(b,e)thiepin-11-ylium hexachloroantimonates (author's transl)

In order to examine the utility of triphenylmethyl hexachloroantimonate (1) for organic synthesis, various kinds of hexachloroantimonates of carbonium ion were prepared by the reaction of 1 with equimolar amount of various kinds of appropriate cyclic compounds. These products were obtained in a simple and stable manner compared to the synthesis of corresponding perchlorates. Experimental studies were also made on the limitation of 1 as an anion (H-, OH-, Cl-, etc.) abstraction reagent, using various kinds of 6, 11-dihydrodibenzo [b, e] thiepin derivatives.