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1.
Bioorg Med Chem ; 22(24): 6814-25, 2014 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-25464880

RESUMEN

The effects of side chain modification and chirality in linezolid-like 1,2,4-oxadiazoles have been studied to design new potent antibacterials against Gram-positive multidrug-resistant pathogens. The adopted strategy involved a molecular modelling approach, the synthesis and biological evaluation of new designed compounds, enantiomers separation and absolute configuration assignment. Experimental determination of the antibacterial activity of the designed (S)-1-((3-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-oxazolidin-2-one-5-yl)methyl)-3-methylthiourea and (S)-1-((3-(3-fluoro-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-oxazolidin-2-one-5-yl)methyl)-3-methylthiourea against multidrug resistant linezolid bacterial strains was higher than that of linezolid.


Asunto(s)
Acetamidas/química , Antibacterianos/química , Oxadiazoles/química , Oxazolidinonas/química , Acetamidas/farmacología , Antibacterianos/síntesis química , Antibacterianos/farmacología , Sitios de Unión , Supervivencia Celular/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/genética , Células Hep G2 , Humanos , Linezolid , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Simulación del Acoplamiento Molecular , Conformación de Ácido Nucleico , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Oxazolidinonas/farmacología , ARN Ribosómico 23S/química , ARN Ribosómico 23S/genética , Staphylococcus aureus/efectos de los fármacos , Estereoisomerismo
2.
J Org Chem ; 74(1): 351-8, 2009 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-19046122

RESUMEN

The thermal rearrangements of 3-acylamino-5-methylisoxazoles 1 have been investigated under basic and neutral conditions and interpreted with the support of computational data. The density functional theory (DFT) study on the competitive routes available for the base-catalyzed thermal rearrangement of isoxazoles 1 showed that the Boulton-Katritzky (BK) rearrangement, producing the less stable 3-acetonyl-1,2,4-oxadiazoles 5, is a much more favored process than either the migration-nucleophilic attack-cyclization (MNAC) or the ring contraction-ring expansion (RCRE). In turn, an increase in reaction temperature will promote the MNAC of oxadiazoles 5, producing the more stable 2-acylaminooxazoles 8. The thermal rearrangement of 3-acylaminoisoxazoles 1 into oxazoles 8 can therefore be interpreted in terms of a cascade BK-MNAC rearrangement involving 3-acetonyl-1,2,4-oxadiazoles 5 as ancillary intermediates.


Asunto(s)
Simulación por Computador , Modelos Químicos , Oxazoles/química , Ciclización , Estructura Molecular , Oxazoles/síntesis química , Estereoisomerismo , Temperatura
3.
Org Biomol Chem ; 7(21): 4337-48, 2009 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-19830279

RESUMEN

The synthesis, the chemical and photochemical reactivity, and the use of 1,2,4-oxadiazoles in materials and as bioactive compounds have been reviewed. The material in this survey includes some historical background, general features, state-of-the-art applications together with a critical discussion about current limitations and suggestions for future developments.

4.
Drug Deliv ; 11(1): 41-6, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15168790

RESUMEN

A mesoporous material based on aluminosilicate mixture was studied to investigate its ability to include drugs and then release them. Nonsteroidal anti-inflammatory agents such as diflunisal, naproxen, ibuprofen and its sodium salt have been used in this study. The preparation of the mesoporous material and its characterization by X-ray, N2 absorption-desorption isotherm, and thermogravimetry analysis have been described. Drug loading was performed by a soaking procedure. Drug-loaded matrices were characterized for entrapped drug amount, water absorption ability, and thermogravimetric behavior. Drug release studies also were performed at pH 1.1 and 6.8 mimicking gastrointestinal fluids. Experimental results showed that this type of matrix is able to trap the bioactive agents by a soaking procedure and, then, to release them in conditions mimicking the biological fluids. Also, the high affinity of these matrices for water makes them potentially biocompatible. Release data suggest that the matrix impregnated with diflunisal offers good potential as a system for the modified drug release.


Asunto(s)
Silicatos de Aluminio/química , Sistemas de Liberación de Medicamentos/instrumentación , Compuestos de Organosilicio/química , Porosidad/efectos de los fármacos , Adsorción/efectos de los fármacos , Aluminio/química , Silicatos de Aluminio/síntesis química , Diflunisal/administración & dosificación , Diflunisal/farmacocinética , Estabilidad de Medicamentos , Ibuprofeno/administración & dosificación , Ibuprofeno/farmacocinética , Ensayo de Materiales , Naproxeno/administración & dosificación , Naproxeno/farmacocinética , Nitrógeno/química , Compuestos de Organosilicio/síntesis química , Solubilidad , Termogravimetría/métodos , Agua , Rayos X
5.
J Int AIDS Soc ; 17(4 Suppl 3): 19676, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25397426

RESUMEN

INTRODUCTION: Diagnosis of HIV infection during early stages is mandatory to catch up with the challenge of limiting HIV viral replication and reservoirs formation, as well as decreasing HIV transmissions by immediate cART initiation. OBJECTIVES: Aims were to describe (a) virological characteristics of AHI identified, (b) epidemiological and clinical factors associated with being diagnosed with AHI. METHODS: Cross-sectional, retrospective study. All individuals diagnosed with AHI according to Fiebig's staging between Jan 2013 and Mar 2014 at the INMI "L. Spallanzani" were included. Serum samples reactive to a fourth generation HIV-1/2 assay (Architect HIV Ag/Ab Combo, Abbott) were retested with another fourth generation assay (VIDAS DUO HIV Ultra, Biomérieux) and underwent confirmation with HIV-1 WB (New Lav I Bio-Rad) and/or with Geenius confirmatory assay (Bio-Rad). WHO criteria (two env products reactivity) were used to establish positivity of confirmatory assays. In case of clinically suspected AHI, HIV-1 RNA (Real time, Abbott) and p24 assay (VIDAS HIV P24 Bio-Rad) were also performed. Avidity test was carried out, on confirmed positive samples lacking p31 reactivity, to discriminate between recent (true Fiebig V phase) and late infections; to avoid possible misclassifications, clinical data were also used. Demographic, epidemiological, clinical and laboratory data are routinely, and anonymously recorded in the SENDIH and SIREA studies. RESULTS: During the study period, we observed 483 newly HIV diagnosed individuals, of whom 40 were identified as AHI (8.3%). Fiebig classification showed: 7 stage II/III, 13 stage IV, 20 stage V. Demographic, epidemiological, and clinical characteristics of patients are shown in the Table. Overall, the study population had a median S/Co ratio at fourth generation EIA (Architect) of 49.50 (IQR, 23.54-98.05): values were significantly lower in Fiebig II-IV than in Fiebig V (38.68 [IQR, 20.08-54.84] vs 75.72 [IQR, 42.66-249.80], p=0.01). Overall, median HIV-1 RNA was 5.44 log copies/mL (IQR, 4.29-6.18) and the value observed in Fiebig phase II-IV was higher than that found in Fiebig stage V (6.10 [IQR, 5.49-7.00] vs 4.69 [3.71-5.44], p<0.001). Median CD4+ cell count was 596/mmc (IQR, 410-737). cART was started in 26 patients: TDF/FTC/DRV/r/RAL=18; TDF/FTC/DRV/r=2; TDF/FTC/ATV/r=2; TDF+FTC+EFV=2; TDF/FTC/RAL=1; DRV/r+RAL=1. CONCLUSIONS: Integration of careful epidemiological investigation, partner notification, and technical advances in virological testing are key elements in AHI case-finding. Significant differences were found between Fiebig stages II-IV and Fiebig V with regard to virological exams.

6.
J Int AIDS Soc ; 16: 18591, 2013 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-24135086

RESUMEN

INTRODUCTION: Translation of the evidence regarding the protective role of highly active antiretroviral therapy (HAART) on HIV sexual transmission rates into sexual behaviour patterns of HIV-infected subjects remains largely unexplored. This study aims to describe frequency of self-reported condom use among women living with HIV in Italy and to investigate the variables associated with inconsistent condom use (ICU). METHODS: DIDI (Donne con Infezione Da HIV) is an Italian multicentre study based on a questionnaire survey performed during November 2010 and February 2011. Women-reported frequency of condom use was dichotomized in "always" versus "at times"/"never" (ICU). RESULTS: Among 343 women, prevalence of ICU was 44.3%. Women declared a stable partnership with an HIV-negative (38%) and with an HIV-positive person (43%), or an occasional sexual partner (19%). Among the 194 women engaged in a stable HIV-negative or an occasional partnership, 51% reported fear of infecting the partner. Nonetheless, 43% did not disclose HIV-positive status. Less than 5% of women used contraceptive methods other than condoms. At multivariable analysis, variables associated with ICU in the subgroup of women with a stable HIV-negative or an occasional HIV-unknown partner were: having an occasional partner (AOR 3.51, 95% confidence interval [CI] 1.44-8.54, p=0.005), and reporting fear of infecting the sexual partner (AOR 3.20, 95% CI 1.43-7.16, p=0.004). Current use of HAART together with virological control in plasma level did not predict ICU after adjusting for demographic, behavioural and HIV-related factors. With regard to socio-demographic factors, lower education was the only variable significantly associated with ICU in the multivariate analysis (AOR 2.27, 95% CI 1.07-4.82, p=0.03). No association was found between high adherence to HAART and ICU after adjusting for potential confounders (AOR 0.89, 95% CI 0.39-2.01, p=0.78). CONCLUSIONS: Currently in Italy, the use of HAART with undetectable HIV RNA in plasma as well as antiretroviral adherence is not associated with a specific condom use pattern in women living with HIV and engaged with a sero-discordant or an HIV-unknown partner. This might suggest that the awareness of the protective role of antiretroviral treatment on HIV sexual transmission is still limited among HIV-infected persons, at least in this country.


Asunto(s)
Condones/estadística & datos numéricos , Infecciones por VIH/prevención & control , Infecciones por VIH/transmisión , Conducta Sexual , Adulto , Femenino , Humanos , Italia , Encuestas y Cuestionarios
7.
Eur J Med Chem ; 65: 533-45, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23811204

RESUMEN

The synthesis and the in vitro antibacterial activity of novel linezolid-like oxadiazoles are reported. Replacement of the linezolid morpholine C-ring with 1,2,4-oxadiazole results in an antibacterial activity against Staphylococcus aureus both methicillin-susceptible and methicillin-resistant comparable or even superior to that of linezolid. While acetamidomethyl or thioacetoamidomethyl moieties in the C(5) side-chain are required, fluorination of the phenyl B ring exhibits a slight effect on an antibacterial activity but its presence seems to reduce the compounds cytotoxicity. Molecular modeling performed using two different approaches - FLAP and Amber software - shows that in the binding pose of the newly synthesized compounds as compared with the crystallographic pose of linezolid, the 1,2,4-oxadiazole moiety seems to perfectly mimic the function of the morpholinic ring, since the H-bond interaction with U2585 is retained.


Asunto(s)
Acetamidas/química , Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Oxadiazoles/farmacología , Oxazolidinonas/química , Antibacterianos/síntesis química , Antibacterianos/química , Línea Celular Tumoral , Supervivencia Celular , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Linezolid , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Programas Informáticos , Relación Estructura-Actividad
8.
Curr Pharm Des ; 19(15): 2757-64, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23092316

RESUMEN

Heat shock protein 60 kDa (Hsp60) is a chaperone classically believed to be involved in assisting the correct folding of other mitochondrial proteins. Hsp60 also plays a role in cytoprotection against cell stressors, displaying for example, antiapoptotic potential. Despite the plethora of studies devoted to the mechanism of Hsp60's function, especially in prokaryotes, fundamental issues still remain unexplored, including the definition of its role in cancer. Key questions still unanswered pertain to the differences in structure-function features that might exist between the well-studied prokaryotic GroEL and the largely unexplored eukaryotic Hsp60 proteins. In this article we discuss these differences in sequence, structure, and roles of Hsp60, focusing on the human ortholog with the view of devising compounds to block its ability to favour tumor-cell growth and survival. Compounds currently known to directly or indirectly affect Hsp60 functions, such as protein folding, HIF-1α accumulation, or Hsp60-induced cell proliferation, are discussed along with strategies that might prove effective for developing Hsp60-targeting drugs for anticancer therapy.


Asunto(s)
Antineoplásicos/farmacología , Chaperonina 60/efectos de los fármacos , Diseño de Fármacos , Neoplasias/tratamiento farmacológico , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Humanos , Relación Estructura-Actividad
9.
Eur J Med Chem ; 50: 441-8, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22365410

RESUMEN

In the present study the synthesis of new Linezolid-like molecules has been achieved by substitution of the oxazolidinone central heterocyclic moiety with a 1,2,4-oxadiazole ring. Two series of 1,2,4-oxadiazoles, bearing different side-chains and containing a varying number of fluorine atoms, were synthesized and preliminarily tested for biological activity against some Gram-positive and Gram-negative bacteria using Linezolid and Ceftriaxone as reference drugs.


Asunto(s)
Acetamidas/química , Antibacterianos/síntesis química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Oxazolidinonas/síntesis química , Oxazolidinonas/farmacología , Acetamidas/farmacología , Ceftriaxona/farmacología , Linezolid , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxazolidinonas/química , Relación Estructura-Actividad
10.
AIDS Res Hum Retroviruses ; 25(10): 979-87, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19795984

RESUMEN

We assessed the safety and efficacy of reconstructive therapy with facial fillers for the treatment of HIV-associated facial lipoatrophy (FLA) through a randomized, controlled, open-label single-center study. A total of 134 HIV-infected patients with severe FLA were randomly assigned to receive immediate (67 patients) or delayed (67 patients) facial injections of poly-l-lactic acid (PLA) or polyacrylamide gel (PAIG). Outcome measures included changes in physician and patient FLA severity scale, adverse events, and changes in health-related quality of life (HRQoL) and anxiety using validated measures. The mean average study follow-up was 27 weeks for the immediate and 25 weeks for the delayed subjects. Adverse events were mild and resolved after a mean of 4 days. Compared to patients randomized to the delayed treatment group, patients assigned to the immediate treatment group had significantly lower physician-rated (0.0 versus -3.0; p < 0.0001) and patient-rated (0.1 versus -1.8; p < 0.0001) FLA severity scores. By contrast, measures exploring HRQoL and anxiety did not show any significant difference between patients randomized to the immediate and deferred groups. Reconstructive therapy with facial fillers was effective and safe and led to significant improvements in FLA severity. However, no significant gains in HRQoL, relational and psychological consequences of body changes, and anxiety-related concerns were observed. Studies should be performed to identify patients who could maximally benefit from filling interventions for FLA.


Asunto(s)
Infecciones por VIH/complicaciones , Infecciones por VIH/cirugía , Síndrome de Lipodistrofia Asociada a VIH/cirugía , Procedimientos de Cirugía Plástica/efectos adversos , Procedimientos de Cirugía Plástica/métodos , Resinas Acrílicas/administración & dosificación , Resinas Acrílicas/efectos adversos , Adulto , Anciano , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Geles/administración & dosificación , Geles/efectos adversos , Humanos , Ácido Láctico/administración & dosificación , Ácido Láctico/efectos adversos , Masculino , Persona de Mediana Edad , Poliésteres , Polímeros/administración & dosificación , Polímeros/efectos adversos , Calidad de Vida
11.
J Org Chem ; 72(7): 2644-6, 2007 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-17328575

RESUMEN

Creating a stationary fluorinated environment inside the zeolite cavity can increase the reactivity observed for intrazeolite photooxidation of alkenes. Exchanging the zeolite with fluorinated organic cations is a much more effective strategy than simply using a fluorinated solvent for slurry irradiations. Use of cations containing C-F bonds is also more efficient than use of deuterated cations for creation of a singlet oxygen friendly environment where the quenching processes are slowed down. Doping the zeolite with fluoro-organic cation 4 resulted in an increase in the singlet oxygen lifetime to 12 micros.

13.
Biomacromolecules ; 7(4): 1302-10, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16602753

RESUMEN

The aim of this work has been the preparation and characterization of novel hydrogels with polysaccharide-poly(amino acid) structure having suitable physicochemical properties for pharmaceutical applications. In the first step, hyaluronic acid (HA) and alpha,beta-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) have been derivatized with methacrylic anhydride (AMA), thus obtaining HA-AMA and PHM derivatives, respectively. In the second step, aqueous solutions of both these derivatives have been irradiated at 313 nm to obtain chemical hydrogels. The hydrogel obtained by irradiating for 15 min an aqueous solution containing 4% w/v of HA-AMA and 4% w/v of PHM resulted in the highest yield. Its swelling ability was dependent on the pH and nature of the external medium. Besides, this hydrogel undergoes a partial hydrolysis, especially in the presence of enzymes, such as esterase or hyaluronidase, but the entity of this degradation is lower than that observed for a hydrogel based on HA-AMA alone. The ability of this hydrogel to entrap drug molecules has been evaluated by using thrombin as a model drug. In vitro release studies and a platelet aggregation test demonstrated that the HA-AMA/PHM hydrogel is able to release thrombin in the active form, thus suggesting its suitability for the treatment of hemorrhages.


Asunto(s)
Aminoácidos/química , Materiales Biocompatibles/química , Química Farmacéutica , Hidrogeles/química , Hidrogeles/síntesis química , Polisacáridos/química , Conformación de Carbohidratos , Secuencia de Carbohidratos , Hidrogeles/efectos de la radiación , Datos de Secuencia Molecular , Factores de Tiempo , Rayos Ultravioleta
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