RESUMEN
The reaction of mercaptoacetic acid esters with pentachloro-2-nitro-1,3-butadiene provides the appropriate precursors for the synthesis of 2,3,4-trisubstituted benzo[h]quinolines. These heterocycles are easily accessible via a single-step reaction with naphthalen-1-amine or anthracen-1-amine as the precursor. Due to the steric bulk and high electron density ring, the ring closure of benzo[h]quinolines takes place exclusively. Such highly substituted annelated pyridine systems can be modified in subsequent, selective reactions to build up new N-heterocycles with promising microbiological properties. The antibacterial and antiproliferative assays against four mammalian cell lines demonstrate that some of the sulfur-substituted benzo[h]quinoline analogs display potent phenotypic bioactivities in the single-digit micromolar range.
Asunto(s)
Quinolinas , Animales , Quinolinas/farmacología , Antibacterianos , Línea Celular , MamíferosRESUMEN
A Knoevenagel based redox-reaction promoted by intramolecular phosphine sources is presented for the first time. The influence of different diketones, aldehydes, bases and acids was investigated. The effects of different substituents were evaluated based on their electronical influence on the diketone structure. With the obtained results a mechanism is proposed, giving information about transition states formed during the reaction, which can lead to different products. This type of an internal redox transformation with a phosphine oxide moiety remaining in the molecule after the redox reaction represents a new type of reaction.
Asunto(s)
Fosfinas , Catálisis , Cetonas/química , Oxidación-Reducción , Fosfinas/química , EstereoisomerismoRESUMEN
A series of 26 novel 1-(7-chloroquinolin-4-yl)-4-nitro-1H-pyrazoles bearing a dichloromethyl and an amino or thio moiety at C3 and C5 has been prepared in yields up to 72% from the reaction of 1,1-bisazolyl-, 1-azolyl-1-amino-, and 1-thioperchloro-2-nitrobuta-1,3-dienes with 7-chloro-4-hydrazinylquinoline. A new way for the formation of a pyrazole cycle from 3-methyl-2-(2,3,3-trichloro-1-nitroallylidene)oxazolidine (6) is also described. In addition, the antimalarial activity of the synthesized compounds has been evaluated in vitro against the protozoan malaria parasite Plasmodium falciparum. Notably, the 7-chloro-4-(5-(dichloromethyl)-4-nitro-3-(1H-1,2,4-triazol-1-yl)-1H-pyrazol-1-yl)quinoline (3b) and 7-chloro-4-(3-((4-chlorophenyl)thio)-5-(dichloromethyl)-4-nitro-1H-pyrazol-1-yl)quinoline (9e) inhibited the growth of the chloroquine-sensitive Plasmodium falciparum strain 3D7 with EC50 values of 0.2 ± 0.1 µM (85 ng/mL, 200 nM) and 0.2 ± 0.04 µM (100 ng/mL, 200 nM), respectively. Two compounds (3b and 10d) have also been tested for anti-SARS-CoV-2, antibacterial, and cytotoxic activity.
RESUMEN
Substituted nitrogen heterocycles are structural key units in many important pharmaceuticals. A new synthetic approach towards heterocyclic compounds displaying antibacterial activity against Staphylococcus aureus or cytotoxic activity has been developed. The selective synthesis of a series of 64 new N-heterocycles from the three nitrobutadienes 2-nitroperchloro-1,3-butadiene, 4-bromotetrachloro-2-nitro-1,3-butadiene and (Z)-1,1,4-trichloro-2,4-dinitrobuta-1,3-diene proved feasible. Their reactions with N-, O- and S-nucleophiles provide rapid access to push-pull substituted benzoxazolines, benzimidazolines, imidazolidines, thiazolidinones, pyrazoles, pyrimidines, pyridopyrimidines, benzoquinolines, isothiazoles, dihydroisoxazoles, and thiophenes with unique substitution patterns. Antibacterial activities of 64 synthesized compounds were examined. Additionally, seven compounds (thiazolidinone, nitropyrimidine, indole, pyridopyrimidine, and thiophene derivatives) exhibited a significant cytotoxicity with IC50-values from 1.05 to 20.1 µM. In conclusion, it was demonstrated that polyhalonitrobutadienes have an interesting potential as structural backbones for a variety of highly functionalized, pharmaceutically active heterocycles.
Asunto(s)
Butadienos/química , Compuestos Heterocíclicos/química , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/química , Benzoquinonas/síntesis química , Benzoquinonas/química , Benzoxazoles/síntesis química , Benzoxazoles/química , Supervivencia Celular/efectos de los fármacos , Compuestos Heterocíclicos/síntesis química , Imidazolidinas/síntesis química , Imidazolidinas/química , Concentración 50 Inhibidora , Pirazoles/síntesis química , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/química , Tiofenos/síntesis química , Tiofenos/químicaRESUMEN
BACKGROUND: Since malaria parasites highly depend on ribose 5-phosphate for DNA and RNA synthesis and on NADPH as a source of reducing equivalents, the pentose phosphate pathway (PPP) is considered an excellent anti-malarial drug target. In Plasmodium, a bifunctional enzyme named glucose 6-phosphate dehydrogenase 6-phosphogluconolactonase (GluPho) catalyzes the first two steps of the PPP. PfGluPho has been shown to be essential for the growth of blood stage Plasmodium falciparum parasites. METHODS: Plasmodium vivax glucose 6-phosphate dehydrogenase (PvG6PD) was cloned, recombinantly produced in Escherichia coli, purified, and characterized via enzyme kinetics and inhibitor studies. The effects of post-translational cysteine modifications were assessed via western blotting and enzyme activity assays. Genetically encoded probes were employed to study the effects of G6PD inhibitors on the cytosolic redox potential of Plasmodium. RESULTS: Here the recombinant production and characterization of PvG6PD, the C-terminal and NADPH-producing part of PvGluPho, is described. A comparison with PfG6PD (the NADPH-producing part of PfGluPho) indicates that the P. vivax enzyme has higher KM values for the substrate and cofactor. Like the P. falciparum enzyme, PvG6PD is hardly affected by S-glutathionylation and moderately by S-nitrosation. Since there are several naturally occurring variants of PfGluPho, the impact of these mutations on the kinetic properties of the enzyme was analysed. Notably, in contrast to many human G6PD variants, the mutations resulted in only minor changes in enzyme activity. Moreover, nanomolar IC50 values of several compounds were determined on P. vivax G6PD (including ellagic acid, flavellagic acid, and coruleoellagic acid), inhibitors that had been previously characterized on PfGluPho. ML304, a recently developed PfGluPho inhibitor, was verified to also be active on PvG6PD. Using genetically encoded probes, ML304 was confirmed to disturb the cytosolic glutathione-dependent redox potential of P. falciparum blood stage parasites. Finally, a new series of novel small molecules with the potential to inhibit the falciparum and vivax enzymes were synthesized, resulting in two compounds with nanomolar activity. CONCLUSION: The characterization of PvG6PD makes this enzyme accessible to further drug discovery activities. In contrast to naturally occurring G6PD variants in the human host that can alter the kinetic properties of the enzyme and thus the redox homeostasis of the cells, the naturally occurring PfGluPho variants studied here are unlikely to have a major impact on the parasites' redox homeostasis. Several classes of inhibitors have been successfully tested and are presently being followed up.
Asunto(s)
Hidrolasas de Éster Carboxílico/genética , Glucosafosfato Deshidrogenasa/genética , Malaria Vivax/genética , Complejos Multienzimáticos/genética , Proteínas Protozoarias/genética , Hidrolasas de Éster Carboxílico/metabolismo , Clonación Molecular , Citosol/metabolismo , Escherichia coli/metabolismo , Glucosafosfato Deshidrogenasa/antagonistas & inhibidores , Glucosafosfato Deshidrogenasa/metabolismo , Cinética , Malaria Vivax/enzimología , Malaria Vivax/metabolismo , Complejos Multienzimáticos/metabolismo , Oxidación-Reducción , Proteínas Protozoarias/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
DC-SIGN is a cell-surface receptor for several pathogenic threats, such as HIV, Ebola virus, or Mycobacterium tuberculosis. Multiple attempts to develop inhibitors of the underlying carbohydrate-protein interactions have been undertaken in the past fifteen years. Still, drug-like DC-SIGN ligands are sparse, which is most likely due to its hydrophilic, solvent-exposed carbohydrate-binding site. Herein, we report on a parallel fragment screening against DC-SIGN applying SPR and a reporter displacement assay, which complements previous screenings using 19 Fâ NMR spectroscopy and chemical fragment microarrays. Hit validation by SPR and 1 H-15 N HSQC NMR spectroscopy revealed that although no fragment bound in the primary carbohydrate site, five secondary sites are available to harbor drug-like molecules. Building on key interactions of the reported fragment hits, these pockets will be targeted in future approaches to accelerate the development of DC-SIGN inhibitors.
Asunto(s)
Moléculas de Adhesión Celular/química , Lectinas Tipo C/química , Receptores de Superficie Celular/química , Carbohidratos/química , Ligandos , Espectroscopía de Resonancia Magnética/métodos , Reproducibilidad de los Resultados , Resonancia por Plasmón de SuperficieRESUMEN
BACKGROUND: Pathogenic serotypes of Vibrio cholerae cause the life-threatening diarrheal disease cholera. The increasing development of bacterial resistances against the known antibiotics necessitates the search for new antimicrobial compounds and targets for this pathogen. RESULTS: A high-throughput screening assay with a Vibrio cholerae reporter strain constitutively expressing green fluorescent protein (GFP) was developed and applied in the investigation of the growth inhibitory effect of approximately 28,300 structurally diverse natural compounds and synthetic small molecules. Several compounds with activities in the low micromolar concentration range were identified. The most active structure, designated vz0825, displayed a minimal inhibitory concentration (MIC) of 1.6 µM and a minimal bactericidal concentration (MBC) of 3.2 µM against several strains of V. cholerae and was specific for this pathogen. Mutants with reduced sensitivity against vz0825 were generated and whole genome sequencing of 15 pooled mutants was carried out. Comparison with the genome of the wild type strain identified the gene VC_A0531 (GenBank: AE003853.1) as the major site of single nucleotide polymorphisms in the resistant mutants. VC_A0531 is located on the small chromosome of V. cholerae and encodes the osmosensitive K+-channel sensor histidine kinase (KdpD). Nucleotide exchange of the major mutation site in the wild type strain confirmed the sensitive phenotype. CONCLUSION: The reporter strain MO10 pG13 was successfully used for the identification of new antibacterial compounds against V. cholerae. Generation of resistant mutants and whole genome sequencing was carried out to identify the histidine kinase KdpD as a novel antimicrobial target.
Asunto(s)
Antibacterianos/aislamiento & purificación , Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Inhibidores Enzimáticos/aislamiento & purificación , Inhibidores Enzimáticos/farmacología , Vibrio cholerae/efectos de los fármacos , Vibrio cholerae/crecimiento & desarrollo , Proteínas Bacterianas/genética , Análisis Mutacional de ADN , Farmacorresistencia Bacteriana , Genoma Bacteriano , Ensayos Analíticos de Alto Rendimiento , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Mutación , Polimorfismo de Nucleótido Simple , Proteínas Quinasas/genética , Vibrio cholerae/fisiologíaRESUMEN
Nitro-substituted polyhalogenated butadienes are valuable synthetic precursors for polyfunctionalized bioactive heterocyclic compounds. Recently, a new reaction between 2-nitroperchloro-1,3-butadiene and electron-deficient anilines producing the Z stereoisomers of a variety of allylidene arylhydrazines has been reported. Although the formation of a chlorinated nitrile oxide intermediate was proved by trapping it with appropriate alkenes via 1,3-dipolar cycloaddition, the details of the overall mechanism remained unclear. The elucidation of the mechanism is important for a better understanding of polyhalogenated nitrobutadiene chemistry. We proposed six reaction paths for the formation of allylidene arylhydrazine, starting from 2-nitroperchloro-1,3-butadiene and para-nitro aniline, and generated the potential energy profiles with the DFT/B3LYP/6-31+G(d,p) method. To include the solvent effect, single-point energy calculations were carried out at the B3LYP/6-31+G(d,p) level by the polarizable continuum model with tetrahydrofuran, as used in the experimental study. The Gibbs activation energies of the rate-determining steps of each mechanism were defined. Taking into account the downhill nature of the overall potential energy profile, Paths 5 and 6 which proceed via extrusion of p-nitrophenylisocyanate and the formation of chlorinated nitrile oxide were chosen as plausible mechanisms. Results also provide insights into the chemistry of nitrile oxides, oximes, oxazete, and nitroso compounds as well as S(N)Vin reactions.
RESUMEN
The title salt, [Pd(C3H4N2)4]Cl2, was obtained unexpectedly by the reaction of palladium(II) dichloride with equimolar amounts of 1-chloro-1-nitro-2,2,2-tris-(pyrazol-yl)ethane in methanol solution. The Pd(2+) cation is located on an inversion centre and has a square-planar coordination sphere defined by four N atoms of four neutral pyrazole ligands. The average Pd-N distance is 2.000â (2)â Å. The two chloride anions are not coordinating to Pd(2+). They are connected to the complex cations through N-Hâ¯Cl hydrogen bonds. In addition, C-Hâ¯Cl hydrogen bonds are observed, leading to a three-dimensional linkage of cations and anions.
RESUMEN
The reaction of mercaptoacetic acid esters with pentachloro-2-nitro-1,3-butadiene (1) provides an appropriate precursor for the synthesis of special thiazolidin-4-ones. Applying different anilines as the second constituent for the requisite cyclization step, a series of (Z)-2-allylidenethiazolidin-4-ones was obtained in yields up to 81%. Some subsequent reactions have been examined too, such as the formation of perfunctionalized 1H-pyrazoles upon treatment with hydrazine. Thiazolidinones are as well known for their physiological activities as for their application in optoelectronics.
RESUMEN
The nitropolychlorobutadienes 3, 4 are valuable building blocks for various amination and successive heterocyclization products. Nucleophilic substitution reactions of the partially protected, bioactive amines 1, 2 with either vinyl, imidoyl or carbonyl chlorides result in the formation of the enamines 11, 12, 13, 16, 25, the amidine 6, and the amides 20, 21, respectively. In the following, cyclization to the highly functionalized pyrazoles 27, 28, pyrimidine 26 and pyridopyrimidine 24 succeeded. Deprotection of 21, 12 and 28 proved to be only partially feasible.
RESUMEN
A convenient, broadly applicable and durable wood protection was recently published by Kaufmann and Namyslo. This procedure efficiently allows for esterification of wood hydroxyl groups with (1H-benzotriazolyl)-activated functionalized benzoic acids. The result of such wood-modifying reactions is usually monitored by an increase in mass of the wood material (weight percent gain value, WPG) and by infrared spectroscopy (IR). However, diagnostic IR bands suffer from overlap with naturally occurring ester groups, mainly in the hemicellulose part of unmodified wood. In contrast to known NMR spectroscopy approaches that use the non-commonly available solid state techniques, herein we present solution state NMR proof of the covalent attachment of our organic precursors to wood. The finding is based on a time-efficient, non-uniformly sampled (NUS) solution state 1H,13C-HMBC experiment that only needs a tenth of the regular recording time. The appropriate NMR sample of thoroughly dissolved modified wood was prepared by a mild and non-destructive method. The 2D-HMBC shows a specific cross-signal caused by spin-spin coupling over three bonds from the ester carbonyl carbon atom to the α-protons of the esterified wood hydroxyl groups. This specific coupling pathway requires a covalent bonding as a conditio sine qua non. An even more rapid test to monitor the covalent bonding was achieved with an up-to-date diffusion-ordered spectroscopy sequence (Oneshot-DOSY) based on 1H or 19F as the sensitive nucleus. The control experiment in a series of DOSY spectra gave a by far higher D value of (1.22 ± 0.06)â10-10 m2âs-1, which is in accordance with fast diffusion of the "free" and thus rapidly moving small precursor molecule provided as its methyl ester. In the case of a covalent attachment to wood, a significantly smaller D value of (0.12 ± 0.01)â10-10 m2âs-1 was obtained.
RESUMEN
Chemical modification of wood applying benzotriazolyl-activated carboxylic acids has proven to be a versatile method for the durable functionalization of its lignocellulosic biopolymers. Through this process, the material properties of wood can be influenced and specifically optimized. To check the scope and limitations of this modification method, various benzamide derivatives with electron-withdrawing (EWG) or electron-donating (EDG) functional groups in different positions of the aromatic ring were synthesized and applied for covalent modification of Scots pine (Pinus sylvestris L.) sapwood in this study. The bonded amounts of substances (up to 2.20 mmol) were compared with the reactivity constants of the Hammett equation, revealing a significant correlation between the modification efficiency and the theoretical reactivity constants of the corresponding aromatic substitution pattern. The successful covalent attachment of the respective substituted benzamides was proven by attenuated total reflection infrared (ATR-IR) spectroscopy, while the stability of the newly formed ester bond was proven in a standardized leaching test.
RESUMEN
The palladium-catalyzed hydroarylation of N-methyl-substituted tricyclic imides was studied in order to find a new stereoselective access to a series of new exo-aryl(hetaryl)-substituted tricyclic N-methylimides.
Asunto(s)
Imidas/química , Catálisis , Ciclización , Cromatografía de Gases y Espectrometría de Masas , Espectroscopía de Resonancia Magnética , Oxidación-Reducción , Paladio/química , Espectrofotometría InfrarrojaRESUMEN
Timber is constantly exposed to environmental influences under outdoor conditions which limits its lifetime and usability. In order to counteract the damaging processes caused by insects, we have developed a novel and more environmentally friendly method to protect wood materials via covalent modification by organic insecticides. Starting with an important class of synthetic insecticides which are derived from the natural insecticide nicotine, various new carboxylic acid derivatives of imidacloprid were made accessible. These activated neonicotinoids were utilized for the chemical modification of wood hydroxy groups. In contrast to conventional wood preservation methods in which biocides are only physically bound to the surface for a limited time, the covalent fixation of the preservative guarantees a permanent effect against wood pests, demonstrated in standardized biological tests. Additionally, the environmental interaction caused by non-bound neonicotinoids is significantly reduced, since both, a smaller application rate is required and leaching of the active ingredient is prevented. By minimizing the pest infestation, the lifetime of the material increases while preserving the natural appearance of the material.
RESUMEN
The new annulation reaction of trichloronitroethylene with aniline results in the formation of a quinoxalinone-N-oxide derivative. The mechanism of this one-pot annulation reaction between trichloronitroethylene (TCNiE) and anilines has been extensively investigated with B3LYP/6-31+G** methodology. Five different paths (1-5) were proposed and modeled by using this method. These paths were compared in terms of the activation energies of their rate-determining steps and in regard to the experimental findings. Paths 3 and 5, proceeding via four-membered heterocyclic rings, were found to be the most plausible paths with activation energies of 32 and 29 kcal/mol for the rate-determining steps, respectively. The effects of substituent, solvent, temperature, and computational method on these steps were also investigated. The results showed that path 5 is the most plausible mechanism for the annulation reaction of trichloronitroethylene with aniline.
RESUMEN
Nitropolychlorobutadienes are valuable precursors for highly functionalized acyclic or (hetero)cyclic compounds. In this 8th part of our synthetically oriented series we focus on the application of these versatile starting materials in the synthesis of analogs of the heterocyclic insecticides imidacloprid and thiacloprid, and the acyclic counterpart clothianidin. In addition to the main synthetic part, leading to imidazolidines or oxazolidines, further promising types of compounds derived by subsequent chemical modifications, are introduced. Most of the new compounds show high insecticidal activity.
Asunto(s)
Butadienos/química , Insecticidas/química , Butadienos/síntesis química , Guanidinas/síntesis química , Guanidinas/química , Halogenación , Imidazoles/síntesis química , Imidazoles/química , Imidazolidinas/química , Insecticidas/síntesis química , Neonicotinoides , Nitrocompuestos/síntesis química , Nitrocompuestos/química , Oxazoles/química , Piridinas/síntesis química , Piridinas/química , Tiazinas/síntesis química , Tiazinas/química , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
The title compound, [Cu(ClO(4))(2)(C(3)H(4)N(2))(4)], was obtained unexpectedly by the reaction of copper(II) perchlorate hexa-hydrate with equimolar amounts of 1-chloro-1-nitro-2,2,2-tripyrazolylethane in methanol solution. The crystal structure comprises octa-hedrally coordinated Cu(2+) ions, located on an inversion centre, with four pyrazole ligands in the equatorial plane. The average Cu-N distance is 2.000â (1)â Å. Two perchlorate ions are coordinated to copper in trans positions [Cu-O = 2.4163â (11)â Å].
RESUMEN
Palladium-catalyzed hydroarylations and additional domino reactions of aza-bicyclic and tricyclic norbornene derivatives were investigated and a series of new epibatidine analogues were synthesized.