RESUMEN
A facile and direct intramolecular indolinone-quinolone rearrangement was developed for the synthesis of quinolino[3,4-b]quinoxalin-6-ones from spiro[indoline-3,2'-quinoxaline]-2,3'-diones, which are readily available with use of isatines, malononitrile, and 1,2-phenylenediamines under quite mild conditions. This efficient approach provides excellent yields and could potentially be used for the construction of a diverse library of quinolino[3,4-b]quinoxalin-6-ones for high-throughput screening in medicinal chemistry. The reaction mechanism is explored by extensive DFT calculations.
RESUMEN
Herein, we report a polyphosphoric acid (PPA)-mediated divergent metal-free operation to access a diverse collection of 3-(indol-2-yl)quinoxalin-2-ones and 4-(benzimidazol-2-yl)-3-methylcinnolines in moderate to excellent overall yields. The described process involves two distinct, and competing rearrangements of 3-(methyl(2-phenylhydrazono)methyl)quinoxalin-2-ones, namely [3,3]-sigmatropic Fischer rearrangement with the formation of an indole ring to produce 3-(indol-2-yl)-quinoxalin-2-ones, and Mamedov rearrangement with simultaneous construction of benzimidazole and cinnoline rings to form the new biheterocyclic systemâ4-(benzimidazol-2-yl)-3-methylcinnolines. The reaction mechanism of both rearrangement channels is explored by extensive dispersion-corrected DFT calculations. It is partcularly remarkable that when 3-(aryl(2-phenylhydrazono)methyl)quinoxalin-2-ones is used, instead of 3-(methyl(2-phenylhydrazono)methyl)quinoxalin-2-ones, reactions proceed regioselectively with the formation of only rearrangement productsâ4-(benzimidazol-2-yl)-3-arylcinnolines with high yields. This operationally simple protocol enables a rapid access to these scaffolds and is compatible with a wide scope of starting materials. In addition, the new rearrangement found features a promising approach for the design of unique compound libraries for drug design and discovery programs.
RESUMEN
A new process has been developed for the bromine-promoted sequential (sp2)C = (sp2)C bond functionalization of (E)-3-styrylquinoxalin-2(1H)-ones and furo[b]annulation via the 5-exo-cyclization in dimethyl sulfoxide (DMSO). The reaction represents a novel strategy for the synthesis of 2-aryl-3-(methylthio)furo[2,3-b]quinoxalines and involves 3-(1,2-dibromo-2-arylethyl)quinoxalin-2(1H)-ones and 2-arylfuro[2,3-b]quinoxalines as key intermediates. Furthermore, DMSO was converted to dimethyl sulfide in situ, which served as the methylthiolation reagent in the reaction. This protocol constitutes an efficient and convenient method for the annulation and methylthiolation of (E)-3-styrylquinoxalin-2(1H)-ones bearing a wide range of functional groups in high yields at room temperature.
RESUMEN
A mild, efficient electrochemical approach to the site-selective direct C-H amidation of benzene and its derivatives with acetonitrile and benzonitrile has been developed. It has been shown that joint electrochemical oxidation of various arenes in the presence of a copper salt as a catalyst and nitriles leads to the formation of N-phenylacetamide from benzene and N-benzylacetamides from benzyl derivatives (up to 78% yield). A favorable feature of the process is mild conditions (room temperature, ambient pressure, no strong oxidants) that meet the criteria of green chemistry.
RESUMEN
The nanotechnological approach is an innovative strategy of high potential to achieve reactivation of organophosphorus-inhibited acetylcholinesterase in central nervous system. It was previously shown that pralidoxime chloride-loaded solid lipid nanoparticles (2-PAM-SLNs) are able to protect the brain against pesticide (paraoxon) central toxicity. In the present work, we increased brain AChE reactivation efficacy by PEGylation of 2-PAM-SLNs using PEG-lipid N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine, sodium salt) (DSPE-PEG2000) as a surface-modifier of SLNs. To perform pharmacokinetic study, a simple, sensitive (LLOQ 1.0 ng/mL) high-performance liquid chromatography tandem mass spectrometry with atmospheric pressure chemical ionization by multiple reaction monitoring mode (HPLC-APCI-MS) was developed. The method was compared to mass spectrometry with electrospray ionization. The method was validated for linearity, accuracy, precision, extraction recovery, matrix effect and stability. Acetophenone oxime was used as the internal standard for the quantification of 2-PAM in rat plasma and brain tissue after intravenous administration. 2-PAM-DSPE-PEG2000-SLNs of mean size about 80 nm (PDI = 0.26), zeta-potential of -55 mV and of high in vitro stability, prolonged the elimination phase of 2-PAM from the bloodstream more than 3 times compared to free 2-PAM. An increase in reactivation of POX-inhibited human brain acetylcholinesterase up to 36.08 ± 4.3 % after intravenous administration of 2-PAM-DSPE-PEG2000-SLNs (dose of 2-PAM is 5 mg/kg) was achieved. The result is one of the first examples where this level of brain acetylcholinesterase reactivation was achieved. Thus, the implementation of different approaches for targeting and modifying nanoparticles' surface gives hope for improving the antidotal treatment of organophosphorus poisoning by marketed reactivators.
Asunto(s)
Antídotos/administración & dosificación , Inhibidores de la Colinesterasa/toxicidad , Reactivadores de la Colinesterasa/administración & dosificación , Nanopartículas/administración & dosificación , Compuestos de Pralidoxima/administración & dosificación , Acetilcolinesterasa/metabolismo , Animales , Antídotos/química , Antídotos/farmacocinética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Reactivadores de la Colinesterasa/sangre , Reactivadores de la Colinesterasa/química , Reactivadores de la Colinesterasa/farmacocinética , Liberación de Fármacos , Femenino , Humanos , Lípidos/administración & dosificación , Lípidos/química , Lípidos/farmacocinética , Masculino , Nanopartículas/química , Compuestos Organofosforados/toxicidad , Polietilenglicoles/administración & dosificación , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Compuestos de Pralidoxima/sangre , Compuestos de Pralidoxima/química , Compuestos de Pralidoxima/farmacocinética , Ratas Wistar , Propiedades de SuperficieRESUMEN
Achieving high thermal stability and control of supramolecular organization of functional dyes in sensors and nonlinear optics remains a demanding task. This study was aimed at the evaluation of thermal behavior and Langmuir monolayer characteristics of topologically varied nitrothiacalixarene multichromophores and phenol monomers. A nitration/azo coupling alkylation synthetic route towards partially O-substituted nitrothiacalixarenes and 4-nitrophenylazo-thiacalixarenes was proposed and realized. Nuclear magnetic resonance (NMR) spectroscopy and X-ray diffractometry of disubstituted nitrothiacalix[4]arene revealed a rare 1,2-alternate conformation. A synchronous thermal analysis indicated higher decomposition temperatures of nitrothiacalixarene macrocycles as compared with monomers. Through surface pressure/potential-molecular area measurements, nitrothiacalixarenes were shown to form Langmuir monolayers at the air-water interface and, through atomic force microscopy (AFM) technique, Langmuir-Blodgett (LB) films on solid substrates. Reflection-absorption spectroscopy of monolayers and electronic absorption spectroscopy of LB films of nitrothiacalixarenes recorded a red-shifted band (290 nm) with a transition from chloroform, indicative of solvatochromism. Additionally, shoulder band at 360 nm was attributed to aggregation and supported by gas-phase density functional theory (DFT) calculations and dynamic light scattering (DLS) analysis in chloroform-methanol solvent in the case of monoalkylated calixarene 3. Excellent thermal stability and monolayer formation of nitrothiacalixarenes suggest their potential as functional dyes.
Asunto(s)
Membranas Artificiales , Fenoles/química , Adsorción , Conformación MolecularRESUMEN
Hydroxyethyl bearing gemini surfactants, alkanediyl-α,ω-bis(N-hexadecyl-N-2-hydroxyethyl-N-methylammonium bromide), 16-s-16(OH), were used to augment phosphatidylcholine based liposomes to achieve higher stability and enhanced cellular uptake and penetration. The developed liposomes were loaded with rhodamine B, doxorubicin hydrochloride, pralidoxime chloride to investigate release properties, cytotoxicity in vitro, as well as ability to cross the blood-brain barrier. At molar ratio of 35:1 (lipid:surfactant) the formulation was found to be of low toxicity, stable for two months, and able to deliver rhodamine B beyond the blood-brain barrier in rats. In vivo, pharmacokinetics of free and formulated 2-PAM in plasma and brain were evaluated, liposomal 2-PAM was found to reactivate 27% of brain acetylcholinesterase, which is, to our knowledge, the first example of such high degree of reactivation after intravenous administration of liposomal drug.
Asunto(s)
Sistemas de Liberación de Medicamentos , Liposomas , Animales , Cationes , Doxorrubicina , Ratas , TensoactivosRESUMEN
A new imidazolium amphiphilic calix[4]arene with terminal acetylene fragments in the polar region was synthesized according to a two step scheme including regioselective chloromethylation of distal di-O-butyl calix[4]arene and subsequent interaction with 1-(hex-5-yn-1-yl)-1H-imidazole. The aggregation properties (CAC, the size and zeta potential of aggregates) of alkynyl calix[4]arene as well as of previously synthesized azidopropyl calix[4]arene and their 1 : 1 mixture were disclosed. Macrocycles with azide and alkyne fragments in the polar region were covalently cross-linked under CuAAC conditions in water. Successful cross-linking of molecules has been proven by IR spectroscopy and MALDI-TOF spectrometry. The obtained polymeric particles were studied both in solution and the solid state and the presence of submicron (â¼200 nm) and micron (â¼1-5 µm) particles with the prevalence of the latter was found. The average molecular weight of the polymer according to the static light scattering data was found to be 639 ± 44 kDa. The obtained polymeric imidazolium-triazole particles were tested as a support for Pd(OAc)2 in the Mizoroki-Heck reaction carried out in both organic and water media. In both solvents (especially in water) the addition of imidazolium-triazole particles to Pd(OAc)2 increased the conversion of 4-iodanisole. It was found that the ratio between the products (1,1 and 1,2-substituted ethylenes) changes drastically on going from DMF to water from 1 : 5 to 1 : 40 when using supported Pd(OAc)2.
RESUMEN
A novel and efficient protocol for the synthesis of diversely substituted 2,2'-bibenzimidazoles from the reaction of 3-cyanoquinoxalin-2(1H)-ones with 1,2-diaminobenzenes has been developed, which proceeds through sequential nucleophilic addition and electrophilic substitution followed by a Mamedov rearrangement. The synthetic utility of this strategy was illustrated by the concise, one-pot synthesis of 5,5'-bi(2,2'-bibenzimidazoles) and aza-analogues of 2,2'-bibenzimidazole.
RESUMEN
The new efficient synthesis of biologically important 3-hydroxy-4-arylquinolin-2-ones through the Darzens condensation (epoxidation) of dichloroacetanilides with aromatic aldehydes followed by one-pot dechlorative epoxide-arene cyclization is described. This methodology has been utilized for the synthesis of naturally occurring viridicatol, a fungal metabolite isolated from the penicillium species.
RESUMEN
A novel approach for brain protection against poisoning by organophosphorus agents is developed based on the combination treatment of dual delivery of two oximes. Pralidoxime chloride (2-PAM) and a novel reactivator, 6-(5-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)pentyl)-3-hydroxy picolinaldehyde oxime (3-HPA), have been loaded in solid-lipid nanoparticles (SLNs) to offer distinct release profile and systemic half-life for both oximes. To increase the therapeutic time window of both oximes, SLNs with two different compartments were designed to load each respective drug. Oxime-loaded SLNs of hydrodynamic diameter between 100 and 160â¯nm and negative zeta potential (-30 to -25â¯mV) were stable for a period of 10â¯months at 4⯰C. SLNs displayed longer circulation time in the bloodstream compared to free 3-HPA and free 2-PAM. Oxime-loaded SLNs were suitable for intravenous (iv) administration. Paraoxon-poisoned rats (0.8â¯×â¯LD50) were treated with 3-HPA-loaded SLNs and 2-PAM+3-HPA-loaded SLNs at the dose of 3-HPA and 2-PAM of 5â¯mg/kg. Brain AChE reactivation up to 30% was slowly achieved in 5â¯h after administration of 3-HPA-SLNs. For combination therapy with two oximes, a time-dependent additivity and increased reactivation up to 35% were observed.
Asunto(s)
Encéfalo/efectos de los fármacos , Inhibidores de la Colinesterasa/toxicidad , Nanopartículas/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Oximas/administración & dosificación , Paraoxon/toxicidad , Acetilcolinesterasa/metabolismo , Animales , Encéfalo/metabolismo , Sinergismo Farmacológico , Femenino , Lípidos/administración & dosificación , Masculino , Oximas/sangre , Oximas/farmacocinética , Ratas WistarRESUMEN
Late stage diversification of calix[4]arenes and thiacalix[4]arenes with heterocycles remains a significant synthetic challenge and hampers further exploitation of the scaffolds. Here we describe the development of a short and facile synthetic route to conformationally diverse novel calix[4]arene and thiacalix[4]arene ynones using a palladium cross coupling approach (5% Pd(ii) + 10% Cu(i)) with benzoyl chloride. Their successful conversion to heterocycles to afford pyrazoles was demonstrated through treatment with hydrazine. Functionalisation is calixarene conformation and linker independent enabling access to a library of structures.
RESUMEN
Solid lipid nanoparticles (SLNs) are among the most promising nanocarriers to target the blood-brain barrier (BBB) for drug delivery to the central nervous system (CNS). Encapsulation of the acetylcholinesterase reactivator, pralidoxime chloride (2-PAM), in SLNs appears to be a suitable strategy for protection against poisoning by organophosphorus agents (OPs) and postexposure treatment. 2-PAM-loaded SLNs were developed for brain targeting and delivery via intravenous (iv) administration. 2-PAM-SLNs displayed a high 2-PAM encapsulation efficiency (â¼90%) and loading capacity (maximum 30.8 ± 1%). Drug-loaded particles had a mean hydrodynamic diameter close to 100 nm and high negative zeta potential (-54 to -15 mV). These properties contribute to improve long-term stability of 2-PAM-SLNs when stored both at room temperature (22 °C) and at 4 °C, as well as to longer circulation time in the bloodstream compared to free 2-PAM. Paraoxon-poisoned rats (2 × LD50) were treated with 2-PAM-loaded SLNs at a dose of 2-PAM of 5 mg/kg. 2-PAM-SLNs reactivated 15% of brain AChE activity. Our results confirm the potential use of SLNs loaded with positively charged oximes as a medical countermeasure both for protection against OPs poisoning and for postexposure treatment.
Asunto(s)
Nanopartículas , Animales , Encéfalo , Reactivadores de la Colinesterasa , Lípidos , Paraoxon , Compuestos de Pralidoxima , RatasRESUMEN
A series of diverse binuclear and mononuclear cyclometalated palladium(ii) complexes of different structure was investigated by electrochemical techniques combined with density functional theory (DFT) calculations. The studies including cyclic and differential pulse voltammetry, X-ray structure analysis and quantum chemical calculations revealed a regularity of the complexes oxidation potential on the metal-metal distance in the complexes: the larger Pd-Pd distance, the higher oxidation potentials. The reduction potentials feature unusually high negative values while no correlation depending on the structure could be observed. These results are in a good agreement with the electron density distribution in the complexes. Additionally, ESR data obtained for the complexes upon oxidation is reported.
RESUMEN
The present work describes a new method to sense cholinesterase-catalyzed hydrolysis of acetylcholine (ACh) through a luminescence response of the hexarhenium cluster complex [{Re6S8}(OH)6](4-). A proton released from acetylcholinesterase (AChE)- or butyrylcholinesterase (BuChE)-catalyzed hydrolysis of ACh results in time-resolved sensitization of cluster-centered luminescence. The sensitization results from protonation of apical hydroxo-groups of the cluster complex. The protonation is affected by a counter ion effect. Thus, optimal conditions for adequate sensing of acetic acid produced by ACh hydrolysis are highlighted. Time-resolved luminescence and pH measurements under conditions of AChE-catalyzed hydrolysis of ACh show a good correlation between the cluster-centered luminescence and pH-induced inhibition of AChE. The inhibition is not significant within the first two minutes of ACh hydrolysis. Thus, the luminescence response measured within two minutes is dependent on both substrate and enzyme concentrations, which fits with AChE and BuChE kinetics. The usability of cluster-centered luminescence for monitoring the concentration-dependent inhibition of AChE with irreversible inhibitors is demonstrated, using a carbamylating agent, pyridostigmine bromide, as a model.
RESUMEN
A series of novel triphenylphosphonium (TPP) cations of the diterpenoid isosteviol (1, 16-oxo-ent-beyeran-19-oic acid) have been synthesized and evaluated in an in vivo phenotypic sea urchin embryo assay for antimitotic activity. The TPP moiety was applied as a carrier to provide selective accumulation of a connected compound into mitochondria. When applied to fertilized eggs, the targeted isosteviol TPP conjugates induced mitotic arrest with the formation of aberrant multipolar mitotic spindles, whereas both isosteviol and the methyltriphenylphosphonium cation were inactive. The structure-activity relationship study revealed the essential role of the TPP group for the realization of the isosteviol effect, while the chemical structure and the length of the linker only slightly influenced the antimitotic potency. The results obtained using the sea urchin embryo model suggested that TPP conjugates of isosteviol induced mitotic spindle defects and mitotic arrest presumably by affecting mitochondrial DNA. Since targeting mitochondria is considered as an encouraging strategy for cancer therapy, TPP-isosteviol conjugates may represent promising candidates for further design as anticancer agents.
Asunto(s)
Antimitóticos/síntesis química , Antimitóticos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Diterpenos de Tipo Kaurano/química , Diterpenos de Tipo Kaurano/farmacología , Compuestos Organofosforados/síntesis química , Compuestos Organofosforados/farmacología , Erizos de Mar/efectos de los fármacos , Animales , Antimitóticos/química , Antineoplásicos/química , Cationes/química , Modelos Animales de Enfermedad , Diterpenos/química , Diterpenos de Tipo Kaurano/síntesis química , Humanos , Mar Mediterráneo , Mitocondrias/efectos de los fármacos , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Compuestos Organofosforados/química , Relación Estructura-ActividadRESUMEN
New water-soluble p-tert-butylthiacalix[4]arenes containing peptide and quaternary ammonium fragments in cone and 1,3-alternate conformations were synthesized and characterized. The interaction of the macrocycles with DNA was studied by UV-spectroscopy, DLS and TEM. It was shown that the interaction of the self-associates based on p-tert-butylthiacalix[4]arenes tetrasubstituted at the lower rim with glycine and quaternary ammonium fragments in cone and 1,3-alternate conformations with DNA led to the formation of particles of about 99-192 nm in size.
Asunto(s)
ADN/metabolismo , Fragmentos de Péptidos/síntesis química , Fragmentos de Péptidos/metabolismo , Fenoles/síntesis química , Fenoles/metabolismo , Tensoactivos/síntesis química , Tensoactivos/metabolismo , ADN/química , Modelos Moleculares , Conformación Molecular , Tamaño de la Partícula , Fragmentos de Péptidos/química , Fenoles/química , Compuestos de Amonio Cuaternario/síntesis química , Compuestos de Amonio Cuaternario/química , Compuestos de Amonio Cuaternario/metabolismo , Tensoactivos/químicaRESUMEN
The reaction of 3-benzoylquinoxalin-2(1H)-ones with enamines (generated in situ from ammonium acetate and the corresponding methylaryl(hetaryl)ketones) proceeds smoothly to give the corresponding substituted 1-(pyrrolyl)benzimidazolone derivatives in moderate yields through the novel rearrangement of 3-benzoylquinoxalin-2(1H)-ones involving a dual cleavage of the C3âN4 and C2-C3 bonds under mild conditions.
Asunto(s)
Acetatos/química , Aminas/química , Bencimidazoles/química , Bencimidazoles/síntesis química , Cetonas/química , Quinoxalinas/química , Catálisis , Estructura Molecular , EstereoisomerismoRESUMEN
A synthetically useful protocol has been developed for the preparation of highly functionalized N-pyrrolylbenzimidazol-2-ones. The reaction of variously substituted 3-aroyl- and 3-alkanoylquinoxalin-2(1H)-ones with commercially available enamines in acetic acid results in a rapid rearrangement and formation of N-pyrrolylbenzimidazol-2-ones in modest to excellent yields. The key step of the rearrangement involves the novel ring contraction of 3-aroyl- and 3-alkanoylquinoxalin-2(1H)-ones with enamines. In this case, the atom of carbon which is displaced from the pyrazine ring of quinoxalin-2(1H)-one becomes the fourth carbon atom of the newly formed pyrrole ring. The method is applicable for the aza analogues of quinoxalin-2(1H)-ones.