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1.
Biochemistry ; 60(39): 2925-2931, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34506130

RESUMO

Rupintrivir targets the 3C cysteine proteases of the picornaviridae family, which includes rhinoviruses and enteroviruses that cause a range of human diseases. Despite being a pan-3C protease inhibitor, rupintrivir activity is extremely weak against the homologous 3C-like protease of SARS-CoV-2. In this study, the crystal structures of rupintrivir were determined bound to enterovirus 68 (EV68) 3C protease and the 3C-like main protease (Mpro) from SARS-CoV-2. While the EV68 3C protease-rupintrivir structure was similar to previously determined complexes with other picornavirus 3C proteases, rupintrivir bound in a unique conformation to the active site of SARS-CoV-2 Mpro splitting the catalytic cysteine and histidine residues. This bifurcation of the catalytic dyad may provide a novel approach for inhibiting cysteine proteases.


Assuntos
Antivirais/metabolismo , Proteases 3C de Coronavírus/metabolismo , Inibidores de Cisteína Proteinase/metabolismo , Isoxazóis/metabolismo , Fenilalanina/análogos & derivados , Pirrolidinonas/metabolismo , SARS-CoV-2/enzimologia , Valina/análogos & derivados , Antivirais/química , Domínio Catalítico , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Cristalografia por Raios X , Inibidores de Cisteína Proteinase/química , Enterovirus Humano D/enzimologia , Ligação de Hidrogênio , Isoxazóis/química , Fenilalanina/química , Fenilalanina/metabolismo , Ligação Proteica , Pirrolidinonas/química , Eletricidade Estática , Valina/química , Valina/metabolismo
2.
J Org Chem ; 86(17): 11845-11861, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34378926

RESUMO

We report synthesis of two diastereomeric structures previously proposed for the complex secondary metabolite pseurotin A2. Both structures were accessed from the same building blocks taking advantage of a stereodivergent nickel(II)-diamine-catalyzed 1,4-addition of a chiral 2-alkoxycarbonyl-3(2H)-furanone. Late-stage Csp-Csp3 cross-coupling of a highly functionalized bromoalkyne featured in the pseurotin A2 side-chain assembly. The work supports the 2016 stereochemical revision of pseurotin A2 and represents the first chemical synthesis of this natural product.


Assuntos
Produtos Biológicos , Pirrolidinonas , Estereoisomerismo
3.
ACS Appl Mater Interfaces ; 13(33): 38969-38978, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34399054

RESUMO

Controlling the microstructure of materials by means of phase separation is a versatile tool for optimizing material properties. Phase separation has been exploited to fabricate intricate microstructures in many fields including cell biology, tissue engineering, optics, and electronics. The aim of this study was to use phase separation to tailor the spatial location of drugs and thereby generate release profiles of drug payload over periods ranging from 1 week to months by exploiting different mechanisms: polymer degradation, polymer diluent dissolution, and control of microstructure. To achieve this, we used drop-on-demand inkjet three-dimensional (3D) printing. We predicted the microstructure resulting from phase separation using high-throughput screening combined with a model based on the Flory-Huggins interaction parameter and were able to show that drug release from 3D-printed objects can be predicted from observations based on single drops of mixtures. We demonstrated for the first time that inkjet 3D printing yields controllable phase separation using picoliter droplets of blended photoreactive oligomers/monomers. This new understanding gives us hierarchical compositional control, from droplet to device, allowing release to be "dialled up" without manipulation of device geometry. We exemplify this approach by fabricating a biodegradable, long-term, multiactive drug delivery subdermal implant ("polyimplant") for combination therapy and personalized treatment of coronary heart disease. This is an important advance for implants that need to be delivered by cannula, where the shape is highly constrained and thus the usual geometrical freedoms associated with 3D printing cannot be easily exploited, which brings a hitherto unseen level of understanding to emergent material properties of 3D printing.


Assuntos
Anti-Hipertensivos/química , Doença das Coronárias/tratamento farmacológico , Portadores de Fármacos/química , Excipientes/química , Indóis/química , Polímeros/química , Anti-Hipertensivos/farmacologia , Dioxanos/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Humanos , Indóis/farmacologia , Metacrilatos/química , Transição de Fase , Poliésteres/química , Impressão Tridimensional , Pirrolidinonas/química , Relação Estrutura-Atividade
5.
ACS Chem Biol ; 16(7): 1288-1297, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34232635

RESUMO

Inducing the formation of new oligodendrocytes from oligodendrocyte progenitor cells (OPCs) represents a potential approach to repairing the loss of myelin observed in multiple sclerosis and other diseases. Recently, we demonstrated that accumulation of specific cholesterol precursors, 8,9-unsaturated sterols, is a dominant mechanism by which dozens of small molecules enhance oligodendrocyte formation. Here, we evaluated a library of 56 sterols and steroids to evaluate whether other classes of bioactive sterol derivatives may also influence mouse oligodendrocyte precursor cell (OPC) differentiation or survival. From this library, we identified U-73343 as a potent enhancer of oligodendrocyte formation that induces 8,9-unsaturated sterol accumulation by inhibition of the cholesterol biosynthesis enzyme sterol 14-reductase. In contrast, we found that mouse OPCs are remarkably vulnerable to treatment with the glycosterol OSW-1, an oxysterol-binding protein (OSBP) modulator that induces Golgi stress and OPC death in the low picomolar range. A subsequent small-molecule suppressor screen identified mTOR signaling as a key effector pathway mediating OSW-1's cytotoxic effects in mouse OPCs. Finally, evaluation of a panel of ER and Golgi stress-inducing small molecules revealed that mouse OPCs are highly sensitive to these perturbations, more so than closely related neural progenitor cells. Together, these studies highlight the wide-ranging influence of sterols and steroids on OPC cell fate, with 8,9-unsaturated sterols positively enhancing differentiation to oligodendrocytes and OSW-1 able to induce lethal Golgi stress with remarkable potency.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Esteróis/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Colestenonas/farmacologia , Colestenonas/toxicidade , Avaliação Pré-Clínica de Medicamentos , Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estrenos/farmacologia , Complexo de Golgi/efeitos dos fármacos , Células HeLa , Humanos , Camundongos , Células Precursoras de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismo , Pirrolidinonas/farmacologia , Saponinas/farmacologia , Saponinas/toxicidade , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/toxicidade , Esteróis/toxicidade
6.
J Med Econ ; 24(1): 939-948, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34311671

RESUMO

AIMS: To study the association between initiation of first adjunctive therapy with eslicarbazepine acetate (ESL) vs. brivaracetam (BRV) on healthcare resource utilization (HCRU) and charges among patients with treated focal seizures (FS). MATERIALS AND METHODS: Symphony Health's Integrated Dataverse (IDV) claims data (1 April 2015 to 30 June 2018) were used to identify two cohorts as first adjunctive therapy with ESL or BRV following a generic anti-seizure drug (ASD). The index date was the earliest claim for a new ESL or BRV prescription. Key inclusion criteria were only 1 generic ASD in the 12 months before the index date; ≥1 medical claim with an FS diagnosis. Unit of analysis was the 90-day person-time-block. Changes in HCRU and charges were assessed using a difference-in-differences framework. Both unadjusted and adjusted analyses were performed. The adjusted model utilized person-specific fixed effects and propensity score-based weighting to control for differences in baseline covariates. Bias-corrected bootstrap confidence intervals (CIs) were calculated for charge outcomes. RESULTS: 208 and 137 patients initiated first adjunctive therapy with ESL (43.7 years, 51.9% female) or BRV (39.3 years, 51.8% female). Patients in the ESL cohort had numerically larger reductions in all-cause and FS-related inpatient hospitalizations and outpatient visits and FS-related emergency department visits. Compared to patients initiating BRV, patients treated with ESL had significantly larger reductions in total charges (-$3,446, CI: -$13,716, -$425), all-cause (-$3,166, CI: -$13,991, -$323) and FS-related (-$2,969, CI: -$21,547, -$842) medical charges, all-cause (-$3,397, CI: -$15,676, -$818) and FS-related (-$2,863, CI: -$19,707, -$787) outpatient charges, and non-ASD-related prescription charges (-$420, CI: -$1,058, -$78). LIMITATIONS: Claims may be missing, or miscoded; outcomes may be influenced by variables not accounted for in the analysis; only information on submitted charges was included. CONCLUSIONS: Among patients with FS, initiation of first adjunctive therapy with ESL was associated with significantly larger reductions in medical and non-ASD-related prescriptions charges compared to BRV.


Assuntos
Anticonvulsivantes , Dibenzazepinas , Custos de Cuidados de Saúde , Pirrolidinonas , Convulsões , Anticonvulsivantes/economia , Anticonvulsivantes/uso terapêutico , Dibenzazepinas/economia , Dibenzazepinas/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pirrolidinonas/economia , Pirrolidinonas/uso terapêutico , Convulsões/tratamento farmacológico , Resultado do Tratamento
7.
Phytochemistry ; 190: 112851, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34217043

RESUMO

Fungal endophytes are remarkable sources of biologically active metabolites of ecological and pharmacological significance. In this study, fungal isolates producing yellow pigments and originating from grass roots, were identified as the recently described grass root colonizing dark septate endophyte (DSE), Flavomyces fulophazii (Periconiaceae, Pleosporales). While analyzing the metabolite composition of 17 isolates of this fungus, 11 previously undescribed compounds, including four tetramic acids (dihydroxyvermelhotin, hydroxyvermelhotin, methoxyvermelhotin, oxovermelhotin), and seven chlorinated azaphilones (flavochlorines A-G), together with the known tetramic acid vermelhotin, were tentatively identified by high performance liquid chromatography (HPLC)-tandem mass spectrometry (MS/MS). Among them, flavochlorine A, flavochlorine G, hydroxyvermelhotin and vermelhotin could be isolated by preparative HPLC, thus their structures were also confirmed by nuclear magnetic resonance (NMR) spectroscopy. Vermelhotin was found to be the main compound, reaching its maximum level of 5.5 mg/g in the in vitro cultures of a selected F. fulophazii isolate. A significant amount of vermelhotin was isolated by preparative HPLC from these cultures (4.8 mg from 1.0 g lyophilized culture), confirming the practical utility of F. fulophazii in high-yield vermelhotin production. The main compounds of this endophyte expressed no activity in standardized plant bioassays (i.e., in the Lactuca sativa seed germination and Lemna minor growth tests). An antiproliferative study of the isolated compounds confirmed moderate activity of vermelhotin against a panel of twelve cancer cell lines, with IC50 ranges of 10.1-37.0 µM, without inhibiting the non-cancer Vero cells, suggesting its selectivity towards cancers.


Assuntos
Ascomicetos , Espectrometria de Massas em Tandem , Animais , Benzopiranos , Chlorocebus aethiops , Endófitos , Pigmentos Biológicos , Pirrolidinonas , Células Vero
8.
Biomolecules ; 11(6)2021 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067463

RESUMO

Submerged mycelial cultures of the ascomycete Colpoma quercinum CCTU A372 were found to produce five previously undescribed tetramic acids, for which we propose the trivial names colposetins A-C (1-3) and colpomenoic acids A and B (4 and 5), along with the known compounds penicillide (6) and monodictyphenone (7). The planar structures of 1-5 were determined by high-resolution electrospray ionization mass spectrometry (HR-ESIMS) and extensive 1D and 2D nuclear magnetic resonance (NMR) spectroscopy. Their absolute configurations were determined by the combination of electronic circular dischroism (ECD) analysis, J-based configurational analysis, and a rotating-frame Overhauser effect spectroscopy (ROESY) experiment. Colposetin B displayed weak antimicrobial activity against Bacillus subtilis and Mucor hiemalis (MIC 67 µg/mL).


Assuntos
Ascomicetos/química , Bacillus subtilis/crescimento & desenvolvimento , Mucor/crescimento & desenvolvimento , Micélio/química , Pirrolidinonas , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Irã (Geográfico) , Pirrolidinonas/química , Pirrolidinonas/isolamento & purificação , Pirrolidinonas/farmacologia
9.
J Biomed Nanotechnol ; 17(5): 846-858, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34082871

RESUMO

The blood-retina barrier (BRB), analogous to the blood-brain barrier, is a major hurdle for the passage of drugs from the blood to the central nervous system. Here, we designed polymeric nanoparticles from amphiphilic poly-/V-vinylpyrrolidone (Amph-PVP NPs) as a new carrier-system and investigated their ability to pass the BRB using a live In-Vivo neuroimaging system for the retina in rats and ex-vivo wholemounted retinae preparation. Amph-PVP NPs were loaded with hydrophobic fluorescent markers as a surrogate for hydrophobic drugs. Linking these NPs with the hydrophobic fluorescence marker Carboxyfluorescein-succinimidyl-ester (CFSE) to the surface, induced the passage of the cargo into the retina tissue. In particular, we observed a substantial internalization of the CFSE-linked NPs into blood cells. We propose surface- modified Amph-PVP NPs as a potential new nano-carrier platform to target posterior eye and potentially brain diseases while camouflaged by blood cells.


Assuntos
Nanopartículas , Animais , Barreira Hematoencefálica , Neuroimagem , Pirrolidinonas , Ratos , Retina
10.
Adv Ther ; 38(7): 4082-4099, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34155568

RESUMO

INTRODUCTION: The aim was to evaluate the efficacy and tolerability of adjunctive brivaracetam (BRV) in adults with severely drug-resistant focal seizures versus adults with less drug-resistant disease. METHODS: Data were pooled from patients with focal seizures on 1-2 concomitant antiseizure medications (ASMs) randomized to BRV 50, 100, 200 mg/day, or placebo in 3 phase 3 trials (N01252 [NCT00490035], N01253 [NCT00464269], and N01358 [NCT01261325]) with a 12-week treatment period. Outcomes were assessed in patients with ≥ 5 and 0-4 previous ASMs (stopped before trial drug initiation). RESULTS: In ≥ 5 previous ASMs subgroup (BRV 50, 100, 200 mg/day: n = 26, n = 137, n = 120; placebo: n = 151), percentage reduction over placebo in 28-day adjusted focal seizure frequency was 13.0% for 50 mg/day (p = 0.38), 18.1% for 100 mg/day (p = 0.006), 19.8% for 200 mg/day (p = 0.004), and 17.0% for all BRV-treated patients (p = 0.001). The 50% responder rate was 26.9%, 29.9%, 30.0%, and 29.7% for BRV 50, 100, 200, and 50-200 mg/day, respectively (placebo: 13.2%); odds ratios versus placebo were statistically significant (p < 0.05) for BRV 100, 200, and 50-200 mg/day. In 0-4 previous ASMs subgroup (BRV 50, 100, 200 mg/day: n = 135, n = 195, n = 129; placebo: n = 267), all BRV dosages showed statistically significant (1) percentage reduction over placebo in 28-day adjusted focal seizure frequency (21.4-28.7%); (2) differences from placebo in median percentage reduction in 28-day adjusted focal seizure frequency from baseline (35.5-45.9%; placebo: 21.3%); and (3) odds ratios versus placebo (favoring BRV) for 50% responder rates. In BRV-treated patients, treatment-emergent adverse event (TEAE) incidence (73.8% [217/294] vs. 64.6% [329/509]) and discontinuation due to TEAEs (10.5% vs. 4.5%) were higher in the ≥ 5 versus 0-4 previous ASMs subgroup; serious TEAEs were rare in both subgroups (≥ 5 previous ASMs: 3.1%; 0-4 previous ASMs: 2.9%). CONCLUSION: Adjunctive BRV showed efficacy and was generally well tolerated in adults with focal seizures independent of the number of previous ASMs.


Assuntos
Anticonvulsivantes , Convulsões , Adulto , Anticonvulsivantes/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Humanos , Pirrolidinonas , Convulsões/tratamento farmacológico , Resultado do Tratamento
11.
Spectrochim Acta A Mol Biomol Spectrosc ; 262: 120097, 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34182296

RESUMO

Formation of catechins-human serum albumin (HSA) complex contributes to stably transporting catechins and regulating their bioavailability. Recently, a new class of catechins namely flavoalkaloids have been reported from tea. The unique structural modification with an N-ethyl-2-pyrrolidinone ring at catechins from these flavoalkaloids has raised our interest in their HSA binding affinity. Thus, we investigated the interaction between HSA and flavoalkaloids by molecular docking, UV-Vis spectroscopy (UV), fluorescence quenching approaches, and surface plasmon resonance (SPR). Thermodynamic parameters suggest that electrostatic forces contribute greatly to the interaction. The binding ability is affected by different ester group (galloyl or cinnamoyl) at 3-OH, N-ethyl-2-pyrrolidinone substituted position (C-6 or C-8), C-2, C-3 and C-5''' configurations, and hydroxyl group numbers at B ring, among which the 3-O-cinnamoyl substitution and 5'''-R configuration present the strongest contributions. UV showed slight changes in the conformation and microenvironment of HSA during the binding process. The quenching and binding constants suggest that the quenching is a static type. The small KD values (1-20 µM) detected by SPR confirmed the strong binding affinities between HSA and flavoalkaloids. Present study will help us to understand the interaction mechanism between flavoalkaloids and HSA, shedding light on structural modification of common catechins to enhance the stability, bioavailability and bioactivities.


Assuntos
Catequina/química , Pirrolidinonas , Albumina Sérica Humana , Chá/química , Alcaloides/química , Sítios de Ligação , Dicroísmo Circular , Flavanonas/química , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Espectrometria de Fluorescência , Termodinâmica
12.
Mater Sci Eng C Mater Biol Appl ; 124: 112063, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33947557

RESUMO

Drug solid dispersions improve the dissolution of drugs in aqueous media for enhancement of oral bioavailability. The current preparation methods of drug solid dispersions mainly involve the evaporation of solvents or the melting of drugs and matrix. Here, we create a new and simple method for the preparation of drug solid dispersions by dissolving drugs in N-vinyl-2-pyrrolidone (NVP) and then NVP photopolymerization. A variety of drugs were explored to find whether they were suitable for this method and only some of them were soluble in NVP and formed transparent and hard solid dispersions, including fluconazole, ketoconazole, bifonazole, miconazole nitrate, sulfamethoxazole, aspirin, ibuprofen and artesunate. The formation of photocuring solid dispersions was highly related to the free radical scavenging function of drugs. Those drugs with strong free radical scavenging capability, including curcumin, resveratrol, quercetin, genistein, puerarin, nicergoline, olanzapine, indomethacin, did not form solid dispersions. They scavenged 2,2-diphenyl-1-picrylhydrazyl free radicals, which was demonstrated by ultraviolet spectrometry and electron spin resonance. The scavenging of free radicals stopped the chain polymerization of NVP. The Fourier transform infrared spectra, X-ray diffraction and differential scanning calorimetry of ibuprofen solid dispersions and artesunate solid dispersions showed the molecularly miscible state of the drugs and the hydrogen bonding between the drugs and polyvinyl pyrrolidone. The NVP-based solid dispersions of the two drugs had faster and more complete dissolution than their traditional solid dispersions. The NVP photopolymerization-based solid dispersion method provides a new choice for the production of solid dispersions in the research and industrial fields.


Assuntos
Preparações Farmacêuticas , Varredura Diferencial de Calorimetria , Pirrolidinonas , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
13.
Toxicol Appl Pharmacol ; 423: 115568, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-33965371

RESUMO

N-methyl pyrrolidone (NMP) is an FDA approved molecule used as an excipient in pharmaceutical industry. Besides having a central role in formulation of drugs, the most important function of any excipient is to guarantee the safety of the medicine during and after its administration. Several studies have shown that exposure to NMP and especially in rats produce a gonadotoxic effect leading to infertility. However, the mechanisms underlying the effect of NMP on male reproduction are unknown. The aim of this study was to assess the reproductive toxicity of NMP in male rats and to elucidate the underlying mechanism. Male Sprague Dawley rats were injected intraperitoneally, twice/ week, at a dose of 108 mg/ 100 g of body weight with NMP. Analysis of reproductive parameters revealed testicular atrophy in NMP treated animals compared to control animals. Germ cell composition within the seminiferous tubules was disturbed and manifested in an increase in number of cells with fragmented DNA. A subsequent decrease in number of spermatocytes and spermatids was observed. Alpha screen assay shows that NMP acts at the concentrations we applied in vivo as a low affinity inhibitor for BRDT (testis specific bromodomain protein). BRDT inhibition is mirrored by a significant decrease in the expression of early stage spermatocyte markers (lmna, aurkc and ccna1), during which BRDT expression predominates. A significant decrease in testosterone levels was also observed. Since NMP interferes with spermatogenesis on various levels, its use in humans must be carefully monitored.


Assuntos
Proteínas Cromossômicas não Histona/antagonistas & inibidores , Proteínas Cromossômicas não Histona/metabolismo , Pirrolidinonas/toxicidade , Espermatogênese/efeitos dos fármacos , Teratógenos/toxicidade , Animais , Relação Dose-Resposta a Droga , Hormônio Foliculoestimulante/sangue , Masculino , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Ratos , Ratos Sprague-Dawley , Espermatogênese/fisiologia , Testosterona/sangue
14.
Acta Biomed ; 92(S1): e2021156, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33944839

RESUMO

BACKGROUND AND AIM OF THE WORK: We present a case of a woman affected by nonconvulsive status epilepticus (NCSE) caused by cerebral hyperperfusion syndrome (CHS) after carotid endarterectomy (CEA) who was successfully treated with Brivaracetam (BRV) administered via nasogastric tube (NGT). CASE PRESENTATION: An 82-years old woman was referred for increasing blood pressure, severe headache and two focal motor seizures on postoperative day four after right CEA. CT scan showed edema of the right hemisphere with a midline shift of 5 mm. The patient underwent daily Electroencephalography (EEG) monitoring which showed continuous epileptiform discharges over the right hemisphere, compatible with a diagnosis of status epilepticus. She was treated with standard antiepileptic drugs (Phenytoin, Lacosamide and Levetiracetam iv) without clinical response. A therapeutic trial with BRV 200mg administered via nasogastric tube (NGT) was tried which resulted in substantial clinical benefit. CONCLUSIONS: The administration of new antiepileptic drugs (AEDs) such as BRV may result in significant clinical improvement in refractory cases of status epilepticus. The enteral administration of AEDs via NGT should always be considered for refractory cases of status epilepticus when standard iv treatment has failed or is not possible.


Assuntos
Eletroencefalografia , Estado Epiléptico , Idoso de 80 Anos ou mais , Feminino , Humanos , Fenitoína , Pirrolidinonas/uso terapêutico , Estado Epiléptico/tratamento farmacológico
15.
Int J Biol Macromol ; 183: 1222-1235, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-33984386

RESUMO

Bacterial contamination in implanted biomedical devices is a critical daily concern. The most used material for permanent implant in biomedical field is Ti6Al4V alloy due to its beneficial mechanical properties and high biocompatibility. Accordingly, in this work different polymeric antibacterial coatings poly(N-vinyl pyrrolidone) (PVP), hyaluronic acid (HA) and chitosan (CHI) were developed and comparatively analysed for Ti6Al4V surface covering. The adhesion of these coatings to Ti6Al4V substrates were carried out after the conjugation of these polymers with the so well-known bioadhesive properties of catechol (CA) anchor group. These surface modifications were characterized by X-ray photoelectronic spectroscopy, contact angle measurements and atomic force microscopy. In addition, the stability of CA-conjugated polymeric coatings was compared with the coatings formed with unconjugated polymers. Finally, the cytocompatibility and antibacterial properties against gram-positive and gram-negative strains on coated Ti6Al4V substrates were assessed confirming the effectiveness of these polymeric coatings against bacterial infections for future applications in protecting biomedical implants.


Assuntos
Ligas/síntese química , Antibacterianos/síntese química , Catecóis/química , Ácido Hialurônico/química , Pirrolidinonas/química , Ligas/química , Ligas/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Linhagem Celular , Quitosana , Materiais Revestidos Biocompatíveis/síntese química , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Teste de Materiais , Testes de Sensibilidade Microbiana , Microscopia de Força Atômica , Espectroscopia Fotoeletrônica , Próteses e Implantes , Propriedades de Superfície , Titânio/química , Titânio/farmacologia
16.
Macromol Rapid Commun ; 42(14): e2100186, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33987942

RESUMO

This study reports for the first time the excellent nonvolatile and volatile digital memory characteristics of polymers bearing 2-pyrrolidone and succinimide moieties. A series of new polymers is synthesized from poly(ethylene-alt-maleic anhydride) and four alcohol derivatives with and without 2-pyrrolidone and succinimide moieties. All polymers, including polyvinylpyrrolidone, are found to be thermally stable up to 195 °C or higher, and characterized regarding their molecular orbital energy levels, bandgap, and resistive digital memory behaviors. Excitingly, the polymers bearing either 2-pyrrolidone or succinimide moiety demonstrate p-type digital memory behaviors with high ON/OFF current ratios and long reliabilities. Nonvolatile digital memory performance is achieved over the film thickness range of 10-80 nm, whereas volatile digital memory is demonstrated over a much narrower range of film thickness. All digital memory performances can be originated from the 2-pyrrolidone and succinimide moieties possessing high affinity and stabilization power to charges via charge traps and transformations based on a hopping conduction process. Hence, these new polymers are suitable for the production of high-performance p-type nonvolatile and volatile digital memory devices. Moreover, 2-pyrrolidone and succinimide can be used as new and economical electroactive building blocks for the development of advanced digital memory materials.


Assuntos
Polímeros , Pirrolidinonas , Succinimidas
17.
J Cereb Blood Flow Metab ; 41(6): 1338-1350, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34013797

RESUMO

[11C]UCB-J is a novel radioligand that binds to synaptic vesicle glycoprotein 2A (SV2A). The main objective of this study was to determine the 28-day test-retest repeatability (TRT) of quantitative [11C]UCB-J brain positron emission tomography (PET) imaging in Alzheimer's disease (AD) patients and healthy controls (HCs). Nine HCs and eight AD patients underwent two 60 min dynamic [11C]UCB-J PET scans with arterial sampling with an interval of 28 days. The optimal tracer kinetic model was assessed using the Akaike criteria (AIC). Micro-/macro-parameters such as tracer delivery (K1) and volume of distribution (VT) were estimated using the optimal model. Data were also analysed for simplified reference tissue model (SRTM) with centrum semi-ovale (white matter) as reference region. Based on AIC, both 1T2k_VB and 2T4k_VB described the [11C]UCB-J kinetics equally well. Analysis showed that whole-brain grey matter TRT for VT, DVR and SRTM BPND were -2.2% ± 8.5, 0.4% ± 12.0 and -8.0% ± 10.2, averaged over all subjects. [11C]UCB-J kinetics can be well described by a 1T2k_VB model, and a 60 min scan duration was sufficient to obtain reliable estimates for both plasma input and reference tissue models. TRT for VT, DVR and BPND was <15% (1SD) averaged over all subjects and indicates adequate quantitative repeatability of [11C]UCB-J PET.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Neuroimagem/métodos , Piridinas/farmacocinética , Pirrolidinonas/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Cinética , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Reprodutibilidade dos Testes
18.
Chemistry ; 27(41): 10731-10736, 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-33999453

RESUMO

Efforts towards the first total synthesis of (-)-oxazolomycin B and (+)-oxazolomycin C from the intermediate of our previous synthesis of (+)-neoxazolomycin are reported. The syntheses were achieved in a longest linear sequence of 25 steps from the amino acid serine in 3.6 and 2.7 % overall yields, respectively. The efficiency of our approach is derived from silyl triflate-mediated reductive oxazolidine ring-opening and Fürstner's Ru-catalyzed hydrosilylation and protodesilylation reactions. The obtained spectra and optical rotations were in good agreement with those of natural products, thus confirming the structures.


Assuntos
Produtos Biológicos , Compostos de Espiro , Oxazóis , Pirrolidinonas , Estereoisomerismo
19.
J Am Chem Soc ; 143(15): 5605-5609, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33834778

RESUMO

Hirsutellones are fungal natural products containing a macrocyclic para-cyclophane connected to a decahydrofluorene ring system. We have elucidated the biosynthetic pathway for pyrrocidine B (3) and GKK1032 A2 (4). Two small hypothetical proteins, an oxidoreductase and a lipocalin-like protein, function cooperatively in the oxidative cyclization of the cyclophane, while an additional hypothetical protein in the pyrrocidine pathway catalyzes the exo-specific cycloaddition to form the cis-fused decahydrofluorene.


Assuntos
Produtos Biológicos/metabolismo , Hidrocarbonetos Aromáticos com Pontes/metabolismo , Fungos/química , Compostos Heterocíclicos de 4 ou mais Anéis/metabolismo , Pirrolidinonas/metabolismo , Acremonium/química , Acremonium/metabolismo , Produtos Biológicos/química , Hidrocarbonetos Aromáticos com Pontes/química , Catálise , Reação de Cicloadição , Fungos/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/química , Hypocreales/química , Hypocreales/metabolismo , Conformação Molecular , Oxirredução , Oxirredutases/metabolismo , Pirrolidinonas/química , Estereoisomerismo
20.
Molecules ; 26(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802860

RESUMO

The COVID-19 outbreak continues to spread worldwide at a rapid rate. Currently, the absence of any effective antiviral treatment is the major concern for the global population. The reports of the occurrence of various point mutations within the important therapeutic target protein of SARS-CoV-2 has elevated the problem. The SARS-CoV-2 main protease (Mpro) is a major therapeutic target for new antiviral designs. In this study, the efficacy of PF-00835231 was investigated (a Mpro inhibitor under clinical trials) against the Mpro and their reported mutants. Various in silico approaches were used to investigate and compare the efficacy of PF-00835231 and five drugs previously documented to inhibit the Mpro. Our study shows that PF-00835231 is not only effective against the wild type but demonstrates a high affinity against the studied mutants as well.


Assuntos
Antivirais/química , Antivirais/farmacologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Indóis/química , Indóis/farmacologia , Leucina/química , Leucina/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Sítios de Ligação , COVID-19/tratamento farmacológico , Simulação por Computador , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/genética , Bases de Dados de Proteínas , Diarilquinolinas/química , Diarilquinolinas/farmacologia , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacologia , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Nitrobenzenos/química , Nitrobenzenos/farmacologia , Nitrofenóis/química , Nitrofenóis/farmacologia , Compostos Organofosforados/química , Compostos Organofosforados/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Prolina/análogos & derivados , Prolina/química , Prolina/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética
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