Indole System Research Articles

Synthesis of symetrical near-infrared dyes containing benzo[c,d]indole system

Five symmetrical near infrared dyes having different linker between the two heterocycles were synthesized by condensation of N-alkylbenzo[c,d]indolium salts with either squaric acid or imine. All synthesized dyes showed strong absorbance in the near-infrared region of 850-1015 nm and can be used as nucleic acid detection or fluorescent labeling agents for proteins. Three of the dyes 21, 22 and 25 containing functionalized N-substituents (ester group) can be further modified or covalently attached to target. The structures of these cyanine dyes where characterized by virtue of NMR, UV, MALDI and Elemental analysis.Keywords: Synthesis, cyanine, Polymethine dyes, Near-IR dyes, Absorption, Chromophore.

Innovative Synthesis and Anti-Microbial Activity Study of Innovative Mannich Bases Containing 2- Phenoxy-1, 3, 2-Dioxa Phospholanes and Indole Systems

In the present study, synthesis, characterization, antimicrobial activity on some novel pyrazolone derivatives has been taken up. The primary amines were diazotized with sodium nitrite and HCl mixture at 0-5 0 C which were further coupled with ethyl acetoacetic ester to afford phenyl diazonium acetoacetic esters (II). Condensation of 4-substituted aryl hydrazono acetoacetic ester, 4-hydrazinylbenzenamine in the presence of catalytic amount of DMF under microwave irradiation afforded (4Z)-4-(2-substituted aryl hydrazono)-1-(4-aminophenyl)-3-methyl-1H-pyrazol-5(4H)-one (III). Subjecting (III) to anhydrous K 2 CO 3 in DMF for 8 hours afforded 2-{4-[(4Z)-4-(2-substituted aryl hydrazono)-4, 5-dihydro-3-methyl-5-oxopyrazol-1-yl] phenyl amino} acetate( IV) which was further reacted with hydrazine hydrate to afford 2-{4-[(4Z)-4-(2-substituted aryl hydrazono)-4, 5-dihydro3-methyl-5-oxopyrazol-1-yl] phenylamino} acetohydrazide (V). Reaction of (V) and Isatin (VI b) in DMF afforded (4Z)-2-(4-((15Z)-4-(2-phenylhydrazono)-4,5-dihydro-3-methyl-5 oxopyrazol-1-yl) phenylamino)-N’-(2-oxoindolin-3-ylidene)acetohydrazide (VII). Compound (VII) was subsequently subjected to Mannich reaction with cyclic secondary amines (piperidine/morpholine/N-methyl piperidine) in the presence of formaldehyde in DMF to afford (4Z)-2-(4-((15Z)-4-(2-substituted aryl hydrazono)-4,5-dihydro-3-methyl-5-oxopyrazol-1-yl)phenylamino)-N’-(2-oxo-1-((piperidin-1-yl)methyl) indolin-3-ylidene)acetohydrazide (VIII) which was characterized by I.R, 1HNMR and Mass data. The anti-bacterial activity of synthesized compounds was studied by the disc diffusion method against pathogenic bacteria and fungi.

Total Synthesis of the Marine Natural Product Hemiasterlin by Organocatalyzed α‐Hydrazination

An efficient synthesis of the potently cytotoxic marine peptide hemiasterlin is presented. The tetramethyltryptophan moiety is assembled by tert-prenylation of indole, followed by the high-yielding organocatalyzed α-hydrazination of a sterically congested aldehyde with excellent enantioselectivity. 2-Bromo-N-ethylpyridinium tetrafluoroborate (BEP)-mediated peptide coupling completes the synthesis, being the first approach that does not employ chiral auxiliaries. A novel phenonium-type rearrangement of the indole system occurred when subjecting dihydroxylated 3-tert-prenylindole to Mitsunobu conditions.

Synthesis and antimicrobial activity of novel fused [1,2,4]triazino[5,6-b]indole derivatives

Synthesis of new fused systems of triazino[5,6-b]indole starting with preparation of 3-amino[1,2,4]-triazino[5,6-b]indole 1 by reaction of isatin with 2-aminoguanidinium carbonate in boiling acetic acid is presented [1]. Intermediate compound 1 reacted with aldehyde, ethyl chloroformate, triethyl orthoformate, and ninhydrine and gave new heterotetracyclic nitrogen systems, such as 3-(N 2-guanidinylimino)indole-2(1H)-one 2, 3-(N-ethoxycarbonylamino)-4H-[1,2,4]triazino[5,6-b]indole 3, 3-(N-ethoxymethyleneamino)-4H-[1,2,4]-triazino[5,6-b]indole 4, 3-(hydrazinothiocarbonylamino)-4H-[1,2,4]triazino[5,6-b]indole 5, respectively. N-(1,3-dioxoindene-2-ylidene)-4H-[1,2,4]triazino[5,6-b]indol-3-amine 6 was synthesized by reaction of compound 1 with aldehyde, ethyl chloroformate, triethyl orthoformate, and ninhydrine. New fused indole systems, pyrimido[2′,1′:3,4][1,2,4]triazino[5,6-b]indol-3(4H)-one 8, 9, 11, 12 and 1H-imidazo[2′,1′:3,4][1,2,4]triazino-[5,6-b]indol-2(3H)-one 10, were synthesized in the reaction of the intermediate 1 with bifunctional compounds. Structures of the products were elucidated from their elemental analysis and spectral data (IR, 1H and 13C NMR and mass spectra). Antimicrobial activity of some synthesized compounds was tested.

Synthesis, structure, and properties of luminescent diazaborole and indole systems

Thiophenes and phenylacetylenes, decorated with 1-methylindol-2-yl, 1,3,2-benzodiazaborol-2-yl, 1,3,2-diazaborol-2-yl, or 1,3,2-diazaborolidinyl groups at one end and dimesitylborolyl or CN substituents at the opposite end of the molecules, were synthesized. Upon UV irradiation, these push-pull systems in THF solution gave rise to bright-blue emission with Stokes shifts ranging from 4100 to 9300 cm–1 and quantum efficiencies up to 0.99. Thereby intramolecular charge transfer took place from the HOMO of the indolyl or borolyl fluorophores to the LUMO, mainly centered on the electron-withdrawing cyano or dimesitylboranyl group.

Solid-liquid equilibria of indole binary systems

Solid-liquid equilibrium temperatures, obtained using a differential scanning calorimetry (DSC) technique, are reported for indole(1)+n-C20(2), or +n-C24(2), or +n-C50(2) systems. Values of the eutectic heat and of the heat of melting needed to determine the final composition of the eutectic points on the basis of the Tamman plots are also given. At x1>x1eu (eutectic mole fraction), the mixtures with n-C20, or n-C24 show positive deviations from the Raoult́s law, which reveal the existence of indole-indole interactions in that range of concentration. At x1<x1eu, the systems show an ideal behaviour. The mixture with n-C50 is characterized by negative deviations from the Raoult’s law due to the very different size of the mixture components. Systems formed by indole and n-alkane, aromatic compound or alkyl-naphthalene have been investigated by means of the DISQUAC model. The interaction parameters for the aliphatic/amine contacts in the studied mixtures are reported. DISQUAC improves results from the ideal solubility model.

The Biosynthesis of the Indolic Acid Moiety from the Antibiotic Nosiheptide

Nosiheptide (NOS) is a highly modified thiopeptide natural product produced by Streptomyces actuosus that belongs to a unique class of thiazole‐containing peptide antibiotics. Recent studies have shown that NOS is as an effective antibacterial agent against a number of pathogenic bacteria, such as methicillin resistant Staphylococcus aureus, penicillin‐resistant Streptococcus pneumoniae, and vancomycin‐resistant enterococci. One key structural feature of NOS essential for its antibacterial properties is an indolic acid ring system characteristic of e‐series thiopeptides. The indolic acid moiety is derived from the amino acid tryptophan. In the first step of the proposed pathway, catalyzed by NosL, tryptophan is converted into 3‐methyl indolic acid (MIA). The remaining steps and enzymes involved in the formation and installation of MIA into the NOS core have not yet been definitively determined, but are believed to be catalyzed by the action of four enzymes: NosI, NosJ, NosK, and NosN. The research herein uses isothermal titration calorimetry (ITC), high‐pressure liquid chromatography (HPLC), mass spectrometry, and bioinformatics to delineate the exact roles of each of the enzymes in the biosynthesis of the indolic acid moiety. We show that NosJ is an acyl carrier protein that is post‐translationally modified with a 4′‐phosphopantetheine group, and that NosI catalyzes the ATP‐dependent adenylation of MIA. Upon incubation of NosI with ATP and MIA in the presence of NosJ, we observe transfer of MIA to NosJ. We believe that NosK then catalyzes the transfer of MIA from NosJ to the side‐chain of a cysteinyl residue of NOS. NosN, annotated as a radical S‐adenosylmethionine (SAM) methylase, subsequently attaches a C1 unit—suggested to be a methyl group—to C4 of the indolic acid moiety and then connects the C1 unit to Glu 43 of the macrocyclic core, completing the synthesis of NOS. We are particularly interested in understanding how NosN carries out this reaction. Preliminary ITC experiments show that two SAM molecules bind to the enzyme simultaneously. We suggest that one SAM molecule is converted into a 5′‐deoxyadenosyl 5′‐radical that initiates a novel methylation reaction by abstracting a hydrogen atom from the methyl moiety of the second SAM molecule. These studies shed new light on novel mechanisms for methylating unactivated carbon centers.Support or Funding InformationThis work was supported by NIH (GM103268), the President's Undergraduate Research Fund (Penn State), and the Rodney Erickson Discovery Grant (Penn State).

Exploration of Ring‐Closing Enyne Metathesis for the Synthesis of ­Azonino[5,4‐b]indoles

AbstractThe use of the ring‐closing enyne metathesis (RCEYM) as a methodology for the synthesis of the azonino[5,4‐b]indole system, featuring the tricyclic substructure of the alkaloids cleavamine and quebrachamine, has been explored. Three series of enyne substrates were studied for their compatibility with the RCEYM reaction. In addition to the usual substrates bearing either a terminal or an internal alkyne, for the first time enynes with an alkynyl halide moiety were also considered. Although the metathesis cyclization allowed for assembly of the azoninoindole nucleus in all three series, an effective catalytic cycle was only noted for internal alkyne substrates. On the basis of the experimental results, the “yne‐then‐ene” pathway seems to be the mechanism at play in these reactions.

Concise approach to pyrrolizino[1,2-b]indoles from indole-derived donor–acceptor cyclopropanes

A direct approach to previously unexplored pyrrolizidino[1,2-b]indole system from indole-derived donor–acceptor cyclopropanes based on a sequence of three synthetic steps was developed.

Crystal and mol-ecular structure of aflatrem.

The crystal structure of the title compound, C32H39NO4, confirms the absolute configuration of the seven chiral centres in the mol­ecule. The molecule has a 1,1-dimethylprop-2-enyl substituent on the indole nucleus and this nucleus shares one edge with the five-membered ring which is, in turn, connected to a sequence of three edge-shared fused rings. The skeleton is completed by the 7,7-trimethyl-6,8-dioxabi­cyclo­[3.2.1]oct-3-en-2-one group connected to the terminal cyclohexene ring. The two cyclohexane rings adopt chair and half-chair conformations, while in the dioxabi­cyclo­[3.2.1]oct-3-en-2-one unit, the six-membered ring has a half-chair conformation. The indole system of the mol­ecule exhibits a tilt of 2.02 (1)° between its two rings. In the crystal, O—H⋯O hydrogen bonds connect mol­ecules into chains along [010]. Weak N—H⋯π inter­actions connect these chains, forming sheets parallel to (10-1).

Host–guest complexation in the β-glycyrrhizic acid–2,8-dimethyl-5-[2´-(6″-methylpyridin-3″-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole system

Electronic, IR, and NMR spectroscopy methods were used to study the interaction in the β-glycyrrhizic acid (GA)–2,8-dimethyl-5-[2´-(6″-methylpyridin-3″-yl)ethyl]-2,3,4,5-tetra-hydro-1H-pyrido[4,3-b]indole (Dim) system in an alcoholic medium. The complete assignment of signals in the 1H and 13C NMR spectra of Dim and GA in CD3OD was made for the individual components and for thier mixtures at different ratios. These data suggest the formation of a host–guest complex in this system. It is hypothesized that associates of GA molecules interact with Dim through Δ12,13–carbonyl group conjugated bonds in the triterpene moiety of GA that interact with the aromatic systems of the indole and pyridine moieties of Dim, as well as via an acid-base mechanism involving mainly the carboxy groups of glucuronic acid residues in the carbohydrate part of GA and the nitrogen atom of the tetrahydropyridine ring of Dim.

Unraveling the Biosynthesis of Dimethyl Indolic Acid, A Key Moiety of the Antibacterial Nosiheptide

Nosiheptide (NOS) belongs to a unique class of thiazole‐containing peptide antibiotics that display formidable activity against a number of pathogenic bacteria. Such bacteria include methicillin resistant Staphylococcus aureus, penicillin‐resistant Streptococcus pneumoniae, and vancomycin‐resistant enterococci. One key structural feature of NOS is an indolic acid ring system. The indolic acid moiety is derived from tryptophan via the action of at least four enzymes. In the first step of the proposed pathway, which is catalyzed by NosL, tryptophan is converted into 3‐methyl indolic acid (MIA). The remaining steps and enzymes involved in formation and installation of MIA into the NOS core have not been definitively determined, but are believed to be catalyzed by the sequential action of NosI, NosK, and NosN. The research described herein is focused on elucidating the mechanism by which the indolic acid moiety is formed and installed with the immediate goal of characterizing NosI, NosK, and NosN and the reactions they catalyze. Additionally through bioinformatic analyses, a protein in the nos operon, NosJ, has a sequence similarity to acyl carrier proteins. We believe that this protein carries the product of NosI to either NosK or NosN.

ChemInform Abstract: An Aluminum Triflate‐Catalyzed Intramolecular Reaction Sequence Toward Concise Construction of the Tetrahydropyrido[1,2‐a]indol‐6‐one Skeleton.

AbstractAlthough the transformation succeeds efficiently for indole system the reaction fails for pyrroles.

Searching for indole derivatives as potential mushroom tyrosinase inhibitors

Tyrosinase is a copper-containing enzyme widely distributed in nature, involved in the biosynthesis of melanin whose role is to protect the skin from ultraviolet damage. A great interest has been shown on the melanin involvement in malignant melanoma and other carcinogenetic processes. These phenomena have encouraged the research of tyrosinase inhibitors useful in therapeutic field as well as in foods and cosmetics to prevent browning. The idea was to screen our “in house” database to select suitable lead compounds for the discovery of potential drug-inhibiting enzyme. The obtained biological results demonstrated that compounds containing 4-fluorobenzyl moiety at N − 1 position of indole system showed the best activity. In addition, the role of the portion linked to the carbonyl group at C − 3 was discussed. A Lineweaver–Burk kinetic analysis of the most active indoles, CHI 1043 and derivative 4, showed a mixed-type inhibition in the presence of l-3,4-dihydroxyphenylalanine (l-DOPA) as substrate.

ChemInform Abstract: Tandem Reactions via Barton Esters with Intermolecular Addition and Vinyl Radical Substitution onto Indole.

A one-pot initiator-free Barton ester decomposition with tandem radical addition onto alkyl propiolates or phenylacetylene with aromatic substitution of the resultant vinyl radical allows convenient access to new 9-substituted 6,7-dihydropyrido[1,2-a]indoles. Propyl radical cyclizations compete when forming the expanded 7,8-dihydro-6H-azepino[1,2-a]indole system. 2-Thiopyridinyl S-radical is incorporated into aromatic adducts when using unsubstituted indole-1-alkanoic acid precursors. X-ray crystallography on substitution products allows selectivity of the radical addition onto less reactive internal alkynes to be determined.

Racemosin C, a novel minor bisindole alkaloid with protein tyrosine phosphatase-1B inhibitory activity from the green alga Caulerpa racemosa

A novel minor bisindole alkaloid, racemosin C (1), characterized by a naturally unprecedented 8-hydroxy-2,4,6-cyclooctatrienone ring fused with two indole systems, was isolated from the green alga Caulerpa racemosa, together with one known related metabolite, caulersin (2). The structure of 1 was elucidated on the basis of extensive spectroscopic analysis, and by comparison with the data of related known compounds. A plausible biosynthetic pathway of 1 was proposed. Compounds 1 and 2 exhibited significant PTP1B inhibitory activity with IC50 values of 5.86 ± 0.57 and 7.14 ± 1.00 μM, respectively, compared with the positive control oleanolic acid (IC50 = 3.03 ± 0.20 μM). On the basis of the data obtained, the Caulerpa bisindole alkaloids may be considered as a new class of PTP1B inhibitors.

ChemInform Abstract: Intramolecular Cycloaddition Reactions of Furo[3,4‐b]indoles for Alkaloid Synthesis.

Model studies dealing with the Cu(II)- or Rh(II)-catalyzed carbenoid cyclization/cycloaddition cascade of several α-diazo indolo amido esters have been carried out as an approach to the alkaloid scandine. The Cu(II)-catalyzed reaction of an α-diazo indolo diester that contains a tethered oxa-pentenyl side chain was found to give rise to a reactive benzo[c]furan which undergoes a subsequent [4 + 2]-cycloaddition across the tethered π-bond. The reaction proceeds by the initial generation of a copper carbenoid intermediate which cyclizes onto the adjacent carbonyl group to give a reactive benzo[c]furan which in certain cases can be isolated. Disappointingly, the analogous reaction with the related amido indolo ester failed to take place, even when the tethered π-bond contained an electron-withdrawing carbomethoxy group. It would seem that the geometric requirements for the intramolecular cycloaddition of the furo[3,4-b]indole system with the tethered π-bond imposes distinct restrictions upon the bond angles ...

Trimethylaluminium‐Mediated Reaction of Primary Carboxamides with Amines and Indoles: A Convenient Synthesis of Amidines and Indole‐3‐acylimines

AbstractA simple, convenient and general method, exhibiting good functional group tolerance, is described for the synthesis of N‐ and N,N‐disubstituted amidines by the reaction of primary carboxamides with amines mediated by trimethylaluminium (AlMe3). Subsequent reaction of the indole systems with primary carboxamides in the presence of AlMe3 gives exclusively the C‐3 substituted imine product.

Synthesis of substituted 3-indolylimines and indole-3-carboxaldehydes by rhodium(II)-catalyzed annulation.

An efficient Cu/Rh-catalyzed method is proposed for the synthesis of 3-indolylimines from N-propargylanilines through Rh(II)-catalyzed denitrogenative annulation of N-sulfonyl-1,2,3-triazoles. Further combined with hydrolysis or reduction, a one-pot method is developed to enable the direct incorporation of an imine, aldehyde, or amine group into an indole system from an alkyne. A variety of substituted 3-indolylimines, indole-3-carboxaldehydes, and 3-Indolylmethanamines are synthesized in good yields.

Natural vs synthetic auxin: Studies on the interactions between plant hormones and biological membrane lipids

Analysis of the interactions between two representatives of plant hormones: synthetic (1-naphthaleneacetic acid, NAA) as well as natural (indole-3-acetic acid, IAA) and phospholipids occurring in biological membrane of both plant and animal cells was the subject of present studies. The aim of undertaken experiments was to elucidate the problem of direct influence of these plant growth regulators on phosphatidylcholines (PCs) and phosphatidylethanolamines (PEs) in monolayers at the air/water solution interface. The studied phospholipids differ not only as regards the structure of polar head-groups but also in the length of hydrophobic chains as well as their saturation degree. These differences result also in the main properties and functions of these phospholipids in biomembranes. The analysis of the results was based on the characteristics of the surface pressure (π) – area (A) isotherms registered for monolayers spread on the subphase containing plant hormone and as a reference on the surface of pure water. Moreover, as a complementary technique, Brewster angle microscopy was applied for the direct visualization of the investigated surface films. The obtained results revealed that auxins effectively influence phospholipids monolayers, regardless of the lipid structure, at the concentration of 10−4M. It was found that for this concentration, the influence of auxins was visibly larger in the case of PCs as compared to PEs. On the other hand, in the case of auxins solution of ≤10−5M, the observed trend was opposite. Generally, our studies showed that the natural plant hormone (IAA) interacts with the investigated lipid monolayers stronger than its synthetic derivative (NAA). The reason of these differences connects with the steric properties of both auxins; namely, the naphthalene ring of NAA molecule occupies larger space than the indole system of IAA. Therefore molecules of the latter compound penetrate easier into the region of phospholipids׳ polar head-groups. Moreover, the NH group of the indole moiety is capable of hydrogen bond formation with the acceptor groups in the polar fragment of lipid molecules. We proved also that among the investigated phospholipids, the highest susceptibility toward auxin influence show these lipids, for which during compression, surface film increases the degree of condensation.