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1.
Nanoscale ; 12(25): 13757-13770, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32573587

RESUMO

New lipid-based nanomaterials and multi-target directed ligands (MTDLs) based on sterically hindered phenol, containing a quaternary ammonium moiety (SHP-s-R, with s = 2,3) of varying hydrophobicity (R = CH2Ph and CnH2n+1, with n = 8, 10, 12, 16), have been prepared as potential drugs against Alzheimer's disease (AD). SHP-s-R are inhibitors of human cholinesterases with antioxidant properties. The inhibitory potency of SHP-s-R and selectivity ratio of cholinesterase inhibition were found to significantly depend on the length of the methylene spacer (s) and alkyl chain length. The compound SHP-2-16 showed the best IC50 for human AChE and the highest selectivity, being 30-fold more potent than for human BChE. Molecular modeling of SHP-2-16 binding to human AChE suggests that this compound is a dual binding site inhibitor that interacts with both the peripheral anionic site and catalytic active site. The relationship between self-assembly parameters (CMC, solubilization capacity, aggregation number), antioxidant activity and a toxicological parameter (hemolytic action on human red blood cells) was investigated. Two sterically hindered phenols (SHP-2-Bn and SHP-2-R) were loaded into L-α-phosphatidylcholine (PC) nanoparticles by varying the SHP alkyl chain length. For the brain AChE inhibition assay, PC/SHP-2-Bn/SHP-2-16 nanoparticles were administered to rats intranasally at a dose of 8 mg kg-1. The Morris water maze experiment showed that scopolamine-induced AD-like dementia in rats treated with PC/SHP-2-Bn/SHP-2-16 nanoparticles was significantly reduced. This is the first example of cationic SHP-phospholipid nanoparticles for inhibition of brain cholinesterases realized by the use of intranasal administration. This route has promising potential for the treatment of AD.

2.
J Org Chem ; 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32588636

RESUMO

New three-component domino reactions providing divergent approaches to multifunctionalized pyrroles with different substitution patterns, have been established (47 examples). In this work a new rearrangement of quinoxalinones with the participation of in situ generated 2-en-1-imine moiety of the substituent at C-3 makes it possible to construct two new heterocyclic systems, namely a benzimidazolone and a pyrrole, simultaneously under one-pot reaction conditions. The reaction is easy to perform simply by mixing three common reactants in an appropriate alcohol solution in the presence of acetic acid with heating. Secondary amines or primary alcohols as the third component of the reaction, along with quinoxalin-3(4H)-ones and malononitrile, not only initiate the rearrangement, but also are responsible for the nature of substituents at position 5 of the pyrrole ring in the newly formed new biheterocyclic system. The reaction proceeds smoothly and can be finished within seven hours, which makes work-up convenient to give up to 97% chemical yields.

3.
J Org Chem ; 84(21): 13572-13581, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31549510

RESUMO

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.

4.
Inorg Chem ; 58(12): 7698-7704, 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31144500

RESUMO

A series of novel charged disilver(I) complexes with pyridyl-containing phospholanes was synthesized. These complexes were characterized using a range of spectroscopic techniques and single-crystal and powder X-ray diffraction. The complexes demonstrate solid-state near-infrared (NIR) luminescence (765-902 nm) that is unique for dinuclear AgI complexes. Combined spectroscopic/quantum chemical analysis suggests that the NIR luminescence of complexes 4-6 in the solid state is mainly due to crystal packing effects.

5.
Colloids Surf B Biointerfaces ; 178: 317-328, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30884347

RESUMO

Multi-targeted approaches for inhibition of сervical cancer cells in vitro were developed by implementing two different strategies and drug combination for creation of new therapeutic target agents and for nanotechnological-enhancement of intracellular delivery. New 2-benzimidazolylquinoxalines derivatives were synthesized and characterized by combining two different pharmacophores - benzimidazole and quinoxaline rings directly bonded in their structures. Spectrophotometric technique for determination of content of compounds in various media was developed to evaluate their solubility in water and micellar solutions of surfactants. The bioavailability of poorly water-soluble 2-benzimidazolylquinoxalines was improved by PEGylated liposomes as antitumor drug delivery carriers. 2-benzimidazolylquinoxalines-loaded PEGylated liposomes, with size close to 100 nm and negative zeta potential ranging from -13 mV to -27 mV, were time-stable at room temperature. The design of liposomal formulations for improving cellular uptake and in vitro antitumor efficacy was performed by modification of liposome surface with the new arginine surfactant. The cell viability of 2-benzimidazolylquinoxalines-loaded arginine liposomes on human cancer M-Hela cells was 16% at the concentration 0.15 mg/ml. Moreover, these liposomes showed a lower toxicity (40%) against normal human Gang liver cells both at the lowest and highest tested concentrations.


Assuntos
Arginina/química , Sistemas de Liberação de Medicamentos/métodos , Lipossomos/química , Quinoxalinas/química , Células HeLa , Humanos , Tensoativos/química
6.
J Org Chem ; 83(21): 13132-13145, 2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30272451

RESUMO

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.

7.
J Control Release ; 290: 102-111, 2018 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-30308259

RESUMO

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 160 nm and negative zeta potential (-30 to -25 mV) were stable for a period of 10 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 (0.8 × 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 5 mg/kg. Brain AChE reactivation up to 30% was slowly achieved in 5 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.


Assuntos
Encéfalo/efeitos dos fármacos , Inibidores da Colinesterase/toxicidade , Nanopartículas/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Oximas/administração & dosagem , Paraoxon/toxicidade , Acetilcolinesterase/metabolismo , Animais , Encéfalo/metabolismo , Sinergismo Farmacológico , Feminino , Lipídeos/administração & dosagem , Masculino , Oximas/sangue , Oximas/farmacocinética , Ratos Wistar
8.
Colloids Surf B Biointerfaces ; 171: 358-367, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30059851

RESUMO

New mixed cationic liposomes based on L-α-phosphatidylcholine and dihexadecylmethylhydroxyethylammonium bromide (DHDHAB) were designed to overcome the BBB crossing by using the intranasal route. Synthesis and self-assembly of DHDHAB were performed. A low critical association concentration (0.01 mM), good solubilization properties toward hydrophobic dye Orange OT and antimicrobial activity against gram-positive bacteria Staphylococcus aureus (MIC=7.8 µg mL-1) and Bacillus cereus (MIC=7.8 µg mL-1), low hemolytic activities against human red blood cells (less than 10%) were achieved. Conditions for preparation of cationic vesicles and mixed liposomes with excellent colloidal stability at room temperature were determined. The intranasal administration of rhodamine B-loaded cationic liposomes was shown to increase bioavailability into the brain in comparison to the intravenous injection. The cholinesterase reactivator, 2-PAM, was used as model drug for the loading in cationic liposomes. 2-PAM-loaded cationic liposomes displayed high encapsulation efficiency (∼ 90%) and hydrodynamic diameter close to 100 nm. Intranasally administered 2-PAM-loaded cationic liposomes were effective against paraoxon-induced acetylcholinesterase inhibition in the brain. 2-PAM-loaded liposomes reactivated 12 ± 1% of brain acetylcholinesterase. This promising result opens the possibility to use marketed positively charged oximes in medical countermeasures against organophosphorus poisoning for reactivation of central acetylcholinesterase by implementing a non-invasive approach, via the "nose-brain" pathway.


Assuntos
Antibacterianos/farmacologia , Encéfalo/efeitos dos fármacos , Reativadores da Colinesterase/farmacologia , Sistemas de Liberação de Medicamentos , Compostos de Pralidoxima/farmacologia , Compostos de Amônio Quaternário/farmacologia , Acetilcolinesterase/metabolismo , Administração Intranasal , Antibacterianos/administração & dosagem , Antibacterianos/síntese química , Antibacterianos/química , Bacillus cereus/efeitos dos fármacos , Encéfalo/metabolismo , Cátions/química , Reativadores da Colinesterase/administração & dosagem , Reativadores da Colinesterase/química , Lipossomos/química , Paraoxon/antagonistas & inibidores , Paraoxon/farmacologia , Tamanho da Partícula , Compostos de Pralidoxima/administração & dosagem , Compostos de Pralidoxima/química , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/química , Rodaminas/administração & dosagem , Rodaminas/química , Staphylococcus aureus/efeitos dos fármacos , Propriedades de Superfície
9.
ACS Appl Mater Interfaces ; 10(17): 14948-14955, 2018 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-29652477

RESUMO

The present work for the first time introduces nanosensors for luminescent monitoring of acetylcholinesterase (AChE)-catalyzed hydrolysis of endogenous acetylcholine (ACh) released in neuromuscular junctions of isolated muscles. The sensing function results from the quenching of Tb(III)-centered luminescence due to proton-induced degradation of luminescent Tb(III) complexes doped into silica nanoparticles (SNs, 23 nm), when acetic acid is produced from the enzymatic hydrolysis of ACh. The targeting of the silica nanoparticles by α-bungarotoxin was used for selective staining of the synaptic space in the isolated muscles by the nanosensors. The targeting procedure was optimized for the high sensing sensitivity. The measuring of the Tb(III)-centered luminescence intensity of the targeted SNs by fluorescent microscopy enables us to sense a release of endogenous ACh in neuromuscular junctions of the isolated muscles under their stimulation by a high-frequency train (20 Hz, for 3 min). The ability of the targeted SNs to sense an inhibiting effect of paraoxon on enzymatic activity of AChE in ex vivo conditions provides a way of mimicking external stimuli effects on enzymatic processes in the isolated muscles.

10.
Dalton Trans ; 46(25): 8146-8156, 2017 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-28607987

RESUMO

The interplay of NMR experiments and DFT calculations of NMR parameters is a reliable method for determining the relative configurations of pentacoordinate chiral spirophosphoranes bearing two six- or five-membered rings at the phosphorus atom in solution. The major product of the Betti based derivatives corresponds to the isomers with both substituents at chiral carbons being opposite to the P-H proton. The next populated product corresponds to the isomer with different chiralities at carbons. The least populated isomer is one with both substituents being at the same side of the heterocycle as the P-H bond.

11.
Mater Sci Eng C Mater Biol Appl ; 76: 551-558, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28482563

RESUMO

The work introduces Tb(III)-centered luminescence of amino-modified silica nanoparticles doped with Tb(III) complexes for cellular imaging. For these purposes water-in-oil procedure was optimized for synthesis of 20 and 35nm luminescent nanoparticles with amino-groups embedded on the surface. The obtained results indicate an impact of the nanoparticle size in decoration, aggregation behavior and luminescent properties of the nanoparticles in protein-based buffer solutions. Formation of a protein-based corona on the nanoparticles surface was revealed through the effect of the nanoparticles on helical superstructure of BSA. This effect is evident from CD spectral data, while no any size impact on the adsorption of BSA onto aminomodified silica surface was observed. Cellular uptake of the nanoparticles studied by confocal and TEM microscopy methods indicates greater cellular uptake for the smaller nanoparticles. Cytotoxicity of the nanoparticles was found to agree well with their cellular uptake behavior, which in turn was found to be greater for the smaller nanoparticles.


Assuntos
Nanopartículas Metálicas , Luminescência , Dióxido de Silício , Água
12.
ACS Appl Mater Interfaces ; 9(20): 16922-16932, 2017 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-28504886

RESUMO

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 (∼90%) 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.


Assuntos
Nanopartículas , Animais , Encéfalo , Reativadores da Colinesterase , Lipídeos , Paraoxon , Compostos de Pralidoxima , Ratos
13.
Beilstein J Nanotechnol ; 8: 313-324, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28243570

RESUMO

Over the last decade isoindigo derivatives have attracted much attention due to their high potential in pharmacy and in the chemistry of materials. In addition, isoindigo derivatives can be modified to form supramolecular structures with tunable morphologies for the use in drug delivery. Amphiphilic long-chain dialkylated isoindigos have the ability to form stable solid nanoparticles via a simple nanoprecipitation technique. Their self-assembly was investigated using tensiometry, dynamic light scattering, spectrophotometry, and fluorometry. The critical association concentrations and aggregate sizes were measured. The hydrophilic-lipophilic balance of alkylated isoindigo derivatives strongly influences aggregate morphology. In the case of short-chain dialkylated isoindigo derivatives, supramolecular polymers of 200 to 700 nm were formed. For long-chain dialkylated isoindigo derivatives, micellar aggregates of 100 to 200 nm were observed. Using micellar surfactant water-soluble forms of monosubstituted 1-hexadecylisoindigo as well as 1,1'-dimethylisoindigo were prepared for the first time. The formation of mixed micellar structures of different types in micellar anionic surfactant solutions (sodium dodecyl sulfate) was determined. These findings are of practical importance and are of potential interest for the design of drug delivery systems and new nanomaterials.

14.
Dalton Trans ; 46(1): 165-177, 2016 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-27901542

RESUMO

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.

15.
Analyst ; 141(13): 4204-10, 2016 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-27169678

RESUMO

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.

16.
Artigo em Inglês | MEDLINE | ID: mdl-28955154

RESUMO

A new reaction of elemental phosphorus (P4) with elemental sulfur and 1,3-propylene glycol in the presence of different amines has been investigated. Ammonium salts of O,O'- alkylenedithiophosphoric acids have been observed as main products of the reaction. Octathiotetraphosphetane ammonium salts were formed as minor products. The reaction is characterized by a complete conversion of white phosphorus and is not accompanied by the release of hydrogen sulfide. The crystal structure features's of diethylammonium salt of O,O'-propylenedithiophosphoric acid were determined using single crystal X-ray diffraction. Piperidinium salt of octathiotetraphosphetane in DMSO and DMF solutions possess significant antifungal activity against Candida albicans.

17.
Dalton Trans ; 45(5): 2053-9, 2016 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-26407302

RESUMO

In solution, nickel phosphanido hydride complexes ([NiH{P(Ar)(H)}(dtbpe)], Ar = Dmp, Mes*) undergo a degenerate intramolecular exchange, with the Ni-H and P-H hydrogens and both halves of the dtbpe moiety interchanging. This intramolecular rearrangement was shown to occur in three steps: first, the hydride proton migrates to phosphorus, then the P-Aryl moiety rotates around the P-Ni bond, and finally the back migration of one proton to Ni completes the process. Both migration and rotation were determined to be characterized by high barriers (on the NMR time scale) and to depend on the type of aryl group at the terminal phosphorus. Compared to that observed for the Ni complexes, the same isomeric preference, but with a slower rate of intramolecular rearrangement, is predicted for the corresponding Pt complexes. An opposite isomeric preference, however, is expected for the corresponding Pd complexes. Thus, it is likely that some of the catalytic reactions of Pd and Pt complexes are driven by the relative thermodynamic stabilities of their main forms.

18.
Biosens Bioelectron ; 77: 871-8, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26516688

RESUMO

This work highlights the H-function of Tb(III)-doped silica nanoparticles in aqueous solutions of acetic acid as a route to sense acetylcholinesterase-catalyzed hydrolysis of acetylcholine (ACh). The H-function results from H(+)-induced quenching of Tb(III)-centered luminescence due to protonation of Tb(III) complexes located close to silica/water interface. The H-function can be turned on/switched off by the concentration of complexes within core or nanoparticle shell zones, by the silica surface decoration and adsorption of both organic and inorganic cations on silica surface. Results indicate the optimal synthetic procedure for making nanoparticles capable of sensing acetic acid produced by enzymatic hydrolysis of acetylcholine. The H-function of nanoparticles was determined at various concentrations of ACh and AChE. The measurements show experimental conditions for fitting the H-function to Michaelis-Menten kinetics. Results confirm that reliable fluorescent monitoring AChE-catalyzed hydrolysis of ACh is possible through the H-function properties of Tb(III)-doped silica nanoparticles.


Assuntos
Acetilcolina/química , Acetilcolinesterase/análise , Medições Luminescentes/instrumentação , Nanopartículas/química , Dióxido de Silício/química , Acetilcolinesterase/química , Catálise , Desenho de Equipamento , Análise de Falha de Equipamento , Luminescência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
19.
Dalton Trans ; 44(30): 13565-72, 2015 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-26135988

RESUMO

A novel type of 14-membered cyclic polyphosphine, namely 1,8-diaza-3,6,10,13-tetraphosphacyclotetradecanes 2a­4ahas been synthesized by the condensation of 1,2-bis(phenylphosphino)ethane, formaldehyde and alkylamines (isopropylamine, ethylamine and cyclohexylamine) as a RRRR/SSSS-stereoisomer. The structure of macrocycle 2a was investigated by NMR-spectroscopy and X-ray crystal structure analysis. The unique reversible processes of macrocycles 2a­4a splitting onto the corresponding rac- (2b­4b) and meso- (2c­4c) stereoisomers of 1-aza-3,6-diphosphacycloheptanes were discovered.


Assuntos
Aminas/química , Cicloeptanos/química , Compostos Macrocíclicos/química , Fosfinas/química , Aminas/síntese química , Cristalografia por Raios X , Ciclização , Compostos Macrocíclicos/síntese química , Metilação , Modelos Moleculares , Fosfinas/síntese química , Estereoisomerismo
20.
Dalton Trans ; 44(22): 10259-66, 2015 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-25962493

RESUMO

The set of complexes bis-(µ:η(1),η(1)-3,4,5-triaryl-1,2-diphosphacyclopentadienyl)-bis-(tetracarbonyl manganese(i)) (aryl = C6H5 (), p-FC6H4 (), p-ClC6H4 ()) undergo an irreversible rearrangement to mononuclear 3,4,5-triaryl-1,2-diphosphacymantrenes (). According to quantum-chemical calculations binuclear complexes can be considered to be products of kinetic control and mononuclear species are thermodynamically favorable compounds. The antiferromagnetic intramolecular interaction observed for complexes can be effectively tuned by using substituents in the para-position of the arene ring, whereas mononuclear 1,2-diphosphacymantrenes are diamagnetic.

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