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1.
Chemosphere ; 314: 137686, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36584824

RESUMEN

The flammability of polypropylene (PP) not only has negative effects on human health but also causes environmental pollution. Herein, from the molecular polarity point of view, rationally designed hyperbranched charring foaming agents (HCFA) modified black phosphorus nanosheets by in situ polymerization to solve the fire hazards of PP. Based on the UL-94 test V-0 rating, the conventional flame retardant of piperazine pyrophosphate (PAPP) is substituted partly by the BP@PPC. Surprisingly, compared with 27 wt% of PAPP/PP, composites consisting of only 2 wt% of BP@PPC and 20 wt% PAPP/PP also passes the V-0 rating. The results of the cone calorimeter test confirmed that adding BP@PPC decreases the total heat release (THR) and peak heat release (PHRR) by a large amount, which are decreased by 23.4%, 85.8% respectively compared with PP. Moreover, it is uncommon for the fire growth index of BP@PPC composites to be 66.7% lower than that of PAPP/PP composites. In addition, the incorporation of BP@PPC has almost no impact on the mechanical characteristics of PP composites. This study offers a reference for combining established flame retardants with novel compounds to modify the burning behaviors of PP.


Asunto(s)
Difosfatos , Retardadores de Llama , Humanos , Polipropilenos , Fósforo , Piperazina
2.
Acta Biomater ; 154: 572-582, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36265791

RESUMEN

The second near-infrared IIa window (NIR-IIa, 1300nm∼1400nm) enables high-resolution imaging and deep-tissue tumor treatment due to its unique low tissue scattering and autofluorescence, high temporal-spatial resolution, and deep tissue penetration. Therefore, NIR-IIa fluorescence imaging-guided phototherapy is of specific interest. However, organic dyes and their nanoparticles for NIR-IIa phototheranostics are still scarce. Here, we have synthesized a Br- and piperazine-modified cyanine dye (FN) and its nanomicelles encapsulated by an amphiphilic polypeptide with sidechains of tertiary amine (PEA). The J-aggregates of P@FN9 with 1116 nm absorption and efficient NIR-IIa fluorescence emission were formed by the self-assembly of FN and PEA. P@FN9 nanoparticles (NPs) showed good stability and high photothermal conversion efficiency (55.4%). In addition, the high spatial resolution and signal-to-background ratio (SBR) of P@FN9 were demonstrated by NIR-IIa fluorescence imaging of mouse vasculature. The P@FN9 NPs successfully performed the NIR-IIa fluorescence imaging-guided photothermal therapy, and both in vitro and in vivo experiments indicated that the P@FN9 NPs exhibited effective antitumor effects under the NIR-II (1064 nm) laser irradiation. STATEMENT OF SIGNIFICANCE.


Asunto(s)
Nanopartículas , Neoplasias , Animales , Ratones , Piperazina , Fototerapia , Imagen Óptica , Nanopartículas/uso terapéutico , Colorantes , Neoplasias/terapia , Péptidos/farmacología , Línea Celular Tumoral
3.
Bioorg Chem ; 119: 105581, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34990933

RESUMEN

The therapeutic indications for monoamine oxidases A and B (MAO-A and MAO-B) inhibitors that have emerged from biological studies on animal and cellular models of neurological and oncological diseases have focused drug discovery projects upon identifying reversible MAO inhibitors. Screening of our in-house academic compound library identified two hit compounds that inhibit MAO-B with IC50 values in micromolar range. Two series of indole (23 analogues) and 3-(benzyloxy)benzyl)piperazine (16 analogues) MAO-B inhibitors were derived from hits, and screened for their structure-activity relationships. Both series yielded low micromolar selective inhibitors of human MAO-B, namely indole 2 (IC50 = 12.63 ± 1.21 µM) and piperazine 39 (IC50 = 19.25 ± 4.89 µM), which is comparable to selective MAO-B inhibitor isatin (IC50 = 6.10 ± 2.81 µM), yet less potent in comparison to safinamide (IC50 = 0.029 ± 0.002 µM). Selective MAO-B inhibitors 2, 14, 38 and 39 exhibited favourable permeation of the blood-brain barrier and low cytotoxicity in the human neuroblastoma cell line SH-SY5Y.


Asunto(s)
Antineoplásicos/farmacología , Indoles/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Piperazina/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Indoles/síntesis química , Indoles/química , Ratones , Modelos Moleculares , Estructura Molecular , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/química , Nitritos/análisis , Piperazina/síntesis química , Piperazina/química , Relación Estructura-Actividad
4.
Eur J Med Chem ; 223: 113644, 2021 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-34182358

RESUMEN

A series of novel 1-(4-(piperazin-1-yl)phenyl)pyridin-2(1H)-one derivatives were synthesized and evaluated for their serotonin (5-HT) reuptake inhibitory activity. The results in vitro indicated that most of the evaluated compounds displayed potent 5-HT reuptake inhibition. The most promising compound A20 was stable in human liver microsomes and possessed good pharmacokinetic properties. Antidepressant study in vivo of the compound A20 showed that A20 could potently antagonize the p-chloroamphetamine (PCA)-induced depletion of serotonin in hypothalamus and reduce immobility times in the rat forced swimming test (FST).


Asunto(s)
Antidepresivos/química , Piridonas/química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Animales , Antidepresivos/metabolismo , Antidepresivos/farmacología , Estabilidad de Medicamentos , Semivida , Humanos , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Piperazina/química , Piridonas/metabolismo , Piridonas/farmacología , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Relación Estructura-Actividad
5.
Eur J Med Chem ; 219: 113416, 2021 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-33887682

RESUMEN

Parasites of the Plasmodium genus are unable to produce purine nucleotides de novo and depend completely on the salvage pathway. This fact makes plasmodial hypoxanthine-guanine-(xanthine) phosphoribosyltransferase [HG(X)PRT] a valuable target for development of antimalarial agents. A series of nucleotide analogues was designed, synthesized and evaluated as potential inhibitors of Plasmodium falciparum HGXPRT, P. vivax HGPRT and human HGPRT. These novel nucleoside phosphonates have a pyrrolidine, piperidine or piperazine ring incorporated into the linker connecting the purine base to a phosphonate group(s) and exhibited a broad range of Ki values between 0.15 and 72 µM. The corresponding phosphoramidate prodrugs, able to cross cell membranes, have been synthesized and evaluated in a P. falciparum infected human erythrocyte assay. Of the eight prodrugs evaluated seven exhibited in vitro antimalarial activity with IC50 values within the range of 2.5-12.1 µM. The bis-phosphoramidate prodrug 13a with a mean (SD) IC50 of 2.5 ± 0.7 µM against the chloroquine-resistant P. falciparum W2 strain exhibited low cytotoxicity in the human hepatocellular liver carcinoma (HepG2) and normal human dermal fibroblasts (NHDF) cell lines at a concentration of 100 µM suggesting good selectivity for further structure-activity relationship investigations.


Asunto(s)
Antimaláricos/síntesis química , Inhibidores Enzimáticos/química , Nucleótidos/química , Pentosiltransferasa/antagonistas & inhibidores , Proteínas Protozoarias/antagonistas & inhibidores , Antimaláricos/metabolismo , Antimaláricos/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Resistencia a Medicamentos/efectos de los fármacos , Inhibidores Enzimáticos/metabolismo , Eritrocitos/citología , Eritrocitos/metabolismo , Eritrocitos/parasitología , Humanos , Nucleótidos/metabolismo , Pentosiltransferasa/metabolismo , Piperazina/química , Piperidinas/química , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/enzimología , Plasmodium vivax/enzimología , Profármacos/síntesis química , Profármacos/química , Profármacos/metabolismo , Profármacos/farmacología , Proteínas Protozoarias/metabolismo , Pirrolidinas/química , Relación Estructura-Actividad
6.
Eur J Med Chem ; 209: 112909, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33081987

RESUMEN

17beta-Hydroxysteroid dehydrogenase type 10 (17ß-HSD10) is the only mitochondrial member of 17ß-HSD family. This enzyme can oxidize estradiol (E2) into estrone (E1), thus reducing concentration of this neuroprotective steroid. Since 17ß-HSD10 possesses properties that suggest a possible role in Alzheimer's disease, its inhibition appears to be a therapeutic strategy. After we identified the androsterone (ADT) derivative 1 as a first steroidal inhibitor of 17ß-HSD10, new analogs were synthesized to increase the metabolic stability, to improve the selectivity of inhibition over 17ß-HSD3 and to optimize the inhibitory potency. From six D-ring derivatives of 1 (17-CO), two compounds (17ß-H/17α-OH and 17ß-OH/17α-CCH) were more metabolically stable and did not inhibit the 17ß-HSD3. Moreover, solid phase synthesis was used to extend the molecular diversity on the 3ß-piperazinylmethyl group of the steroid base core. Eight over 120 new derivatives were more potent inhibitors than 1 for the transformation of E2 to E1, with the 4-(4-trifluoromethyl-3-methoxybenzyl)piperazin-1-ylmethyl-ADT (D-3,7) being 16 times more potent (IC50 = 0.14 µM). Finally, D-ring modification of D-3,7 provided 17ß-OH/17α-CCH derivative 25 and 17ß-H/17α-OH derivative 26, which were more potent inhibitor than 1 (1.8 and 2.4 times, respectively).


Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores Enzimáticos/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Esteroides/síntesis química , Biocatálisis , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Estradiol/química , Estrona/química , Células HEK293 , Humanos , Piperazina/química , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Técnicas de Síntesis en Fase Sólida , Esteroides/metabolismo , Esteroides/farmacología , Relación Estructura-Actividad
7.
Bioorg Med Chem Lett ; 30(17): 127366, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32738975

RESUMEN

Antagonism of the Toll-like receptors (TLRs) 7 and TLR8 has been hypothesized to be beneficial to patients suffering from autoimmune conditions. A phenotypic screen for small molecule antagonists of TLR7/8 was carried out in a murine P4H1 cell line. Compound 1 was identified as a hit that showed antagonistic activity on TLR7 and TLR8 but not TLR9, as shown on human peripheral blood mononuclear cells (hPBMCs). It was functionally cross reactive with mouse TLR7 but lacked oral exposure and had only modest potency. Chemical optimization resulted in 2, which showed in vivo efficacy following intraperitoneal administration. Further optimization resulted in 8 which had excellent in vitro activity, exposure and in vivo activity. Additional work to improve physical properties resulted in 15, an advanced lead that had favorable in vitro and exposure properties. It was further demonstrated that activity of the series tracked with binding to the extracellular domain of TLR7 implicating that the target of this series are endosomal TLRs rather than downstream signaling pathways.


Asunto(s)
Piperazina/química , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 8/metabolismo , Administración Oral , Animales , Línea Celular , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Interferón gamma/metabolismo , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Piperazina/administración & dosificación , Piperazina/farmacocinética , Piperazina/farmacología , Bazo/citología , Bazo/efectos de los fármacos , Bazo/metabolismo , Relación Estructura-Actividad , Receptor Toll-Like 7/antagonistas & inhibidores , Receptor Toll-Like 8/antagonistas & inhibidores
8.
Int J Parasitol ; 50(3): 235-252, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32135179

RESUMEN

With emerging resistance to frontline treatments, it is vital that new drugs are identified to target Plasmodium falciparum. One of the most critical processes during parasites asexual lifecycle is the invasion and subsequent egress of red blood cells (RBCs). Many unique parasite ligands, receptors and enzymes are employed during egress and invasion that are essential for parasite proliferation and survival, therefore making these processes druggable targets. To identify potential inhibitors of egress and invasion, we screened the Medicines for Malaria Venture Pathogen Box, a 400 compound library against neglected tropical diseases, including 125 with antimalarial activity. For this screen, we utilised transgenic parasites expressing a bioluminescent reporter, nanoluciferase (Nluc), to measure inhibition of parasite egress and invasion in the presence of the Pathogen Box compounds. At a concentration of 2 µM, we found 15 compounds that inhibited parasite egress by >40% and 24 invasion-specific compounds that inhibited invasion by >90%. We further characterised 11 of these inhibitors through cell-based assays and live cell microscopy, and found two compounds that inhibited merozoite maturation in schizonts, one compound that inhibited merozoite egress, one compound that directly inhibited parasite invasion and one compound that slowed down invasion and arrested ring formation. The remaining compounds were general growth inhibitors that acted during the egress and invasion phase of the cell cycle. We found the sulfonylpiperazine, MMV020291, to be the most invasion-specific inhibitor, blocking successful merozoite internalisation within human RBCs and having no substantial effect on other stages of the cell cycle. This has significant implications for the possible development of an invasion-specific inhibitor as an antimalarial in a combination based therapy, in addition to being a useful tool for studying the biology of the invading parasite.


Asunto(s)
Antimaláricos/farmacología , Evaluación Preclínica de Medicamentos , Plasmodium falciparum/efectos de los fármacos , Animales , Eritrocitos/parasitología , Humanos , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Merozoítos/efectos de los fármacos , Piperazina , Piperazinas/farmacología , Plasmodium falciparum/crecimiento & desarrollo , Plasmodium falciparum/metabolismo , Esquizontes/efectos de los fármacos
9.
Bioorg Chem ; 95: 103513, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31884144

RESUMEN

BACKGROUND: A series of eight new flavone derivatives containing a piperazine chain with different substitution were synthesized and their structures were determined. METHODS: Their antiradical and antioxidant activities were evaluated using superoxide anion radical, hydroxyl radical, 2,2-diphenyl-1-picrylhydrazyl radical, 2,2'-azino-di(3-ethylbenzthiazoline sulphonate) radical cation (ABTS+) scavenging (as measure total antioxidant status TAS), ferric reducing antioxidant power (TAC), and hydrogen peroxide decomposition. The antioxidant activities of the synthesized compounds were compared with standard antioxidants trolox, ascorbic acid, butylated hydroxytoluene (BHT) as positive controls, reference antibiotics (doxycycline, dicloxacillin), and medicinal plants (Menthae piperita, Cistus incanus). Chemiluminescence, spectrophotometry, electron spin resonance (ESR) spectroscopy in conjunction with 5,5-dimethyl-1-pyrroline-1-oxide (DMPO) as the spin trap were the measurement techniques. RESULTS: The results show that the synthesized compounds exhibit weak, albeit a wide spectrum of antiradical and antioxidant activities. The TAS values were measured as trolox equivalents, ranging from 209.6 ± 6.1 to 391.1 ± 8.2 µM TE/g; the TAC values were in ranges from 10.8 ± 0.5 to 49.5 ± 0.5 µM TE/g being higher than that of dicloxacillin (241.0 ± 16.5 and 9.73 ± 0.8 µM TE/g, respectively), but lower than ascorbic acid, BHT, doxycycline, and medicinal plants. Best antioxidant activities were found for the piperazinyl analogues with methoxy group on phenyl piperazine ring. CONCLUSION: We suggest that the synthesized compounds may be used as lead molecules for optimization of molecular structure to maximize the antioxidant potency.


Asunto(s)
Antioxidantes/farmacología , Flavonas/farmacología , Piperazina/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Compuestos de Bifenilo/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Flavonas/síntesis química , Flavonas/química , Peróxido de Hidrógeno/antagonistas & inhibidores , Radical Hidroxilo/antagonistas & inhibidores , Estructura Molecular , Picratos/antagonistas & inhibidores , Piperazina/química , Relación Estructura-Actividad , Superóxidos/antagonistas & inhibidores
10.
Mol Inform ; 39(3): e1900054, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31508903

RESUMEN

Melanogenesis controls the formation of melanin pigment whose overproduction is related to various hyperpigmentary disorders in humans. Tyrosinase is a type-3 copper enzyme involved in the rate limiting step of melanin synthesis, therefore its inhibition could represent an efficient way for the development of depigmenting agents. In this work, a combination of pharmacophore and docking-based studies has been employed to screen two in-house 3D compound databases containing about 2,000 molecules from natural and synthetic sources. As result we selected two "hit compounds" which proved to inhibit tyrosinase activity showing IC50 values in the micromolar range.


Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Simulación del Acoplamiento Molecular , Monofenol Monooxigenasa/antagonistas & inhibidores , Piperazina/farmacología , Piperidinas/farmacología , Agaricales/enzimología , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Estructura Molecular , Monofenol Monooxigenasa/metabolismo , Piperazina/química , Piperidinas/química
11.
ChemMedChem ; 14(13): 1238-1247, 2019 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-30957954

RESUMEN

Histamine H3 receptor (H3R) inverse agonists that have been in clinical trials for the treatment of excessive sleep disorders, have been plagued with insomnia as a mechanism-based side effect. We focused on the identification of compounds that achieve high receptor occupancy within a short time, followed by rapid disengagement from the receptor, a target profile that could provide therapeutic benefits without the undesired side effect of insomnia. This article describes the optimization work that led to the discovery of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate (18 b, LML134).


Asunto(s)
Agonistas de los Receptores Histamínicos/uso terapéutico , Piperazina/química , Piperazinas/química , Receptores Histamínicos H3/metabolismo , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Animales , Evaluación Preclínica de Medicamentos , Agonismo Inverso de Drogas , Semivida , Agonistas de los Receptores Histamínicos/química , Agonistas de los Receptores Histamínicos/farmacocinética , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Piperazina/farmacocinética , Piperazina/uso terapéutico , Piperazinas/farmacocinética , Piperazinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Receptores Histamínicos H3/química , Relación Estructura-Actividad
12.
Bioorg Med Chem Lett ; 27(4): 855-861, 2017 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-28108251

RESUMEN

As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.


Asunto(s)
Aminas/química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Aminas/metabolismo , Aminas/uso terapéutico , Animales , Enfermedades Autoinmunes/tratamiento farmacológico , Sitios de Unión , Fosfatidilinositol 3-Quinasa Clase I , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Piperazina , Piperazinas/química , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Relación Estructura-Actividad , Triazinas/química
13.
J Pharm Biomed Anal ; 137: 132-138, 2017 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-28113089

RESUMEN

A novel dithio-carbodenafil compound was isolated and identified from a health supplement. The structure of the unknown compound has been characterized using LC-UV, Fourier Transform Infrared (FTIR), high-resolution mass spectrometry, 1D and 2D nuclear magnetic resonance (NMR) spectroscopy. It has been revealed as 3,5-dimethylpiperazinyl dithio-desmethylcarbodenafil as a result of two additional methyl groups on the piperazine ring.


Asunto(s)
Suplementos Dietéticos/análisis , Piperazinas/química , Compuestos de Azufre/química , Cromatografía Liquida/métodos , Espectroscopía de Resonancia Magnética/métodos , Espectrometría de Masas/métodos , Piperazina , Espectroscopía Infrarroja por Transformada de Fourier/métodos
14.
Org Biomol Chem ; 14(39): 9388-9405, 2016 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-27714195

RESUMEN

The sigma-1 receptor (S1R) has attracted a great deal of attention as a prospective drug target due to its involvement in numerous neurological disorders and, more recently, for its therapeutic potential in neuropathic pain. As there was no crystal structure of this membrane-bound protein reported until 2016, ligand generation was driven by pharmacophore refinements to the general model suggested by Glennon and co-workers. The generalised S1R pharmacophore comprises a central region where a basic amino group is preferred, flanked by two hydrophobic groups. Guided by this pharmacophore, S1R ligands containing piperazines, piperazinones, and ethylenediamines have been developed. In the current work, we systematically deconstructed the piperazine core of a prototypic piperazine S1R ligand (vide infra) developed in our laboratories. Although we did not improve the affinity at the S1R compared to the lead, we identified several features important for affinity and selectivity. These included at least one basic nitrogen atom, conformational flexibility and, for S1R, a secondary or tertiary amine group proximal to the anisole. Furthermore, S2R selectivity can be tailored with functional group modifications of the N-atom proximal to the anisole.


Asunto(s)
Diaminas/química , Diaminas/metabolismo , Receptores sigma/metabolismo , Animales , Sitios de Unión , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Etilenodiaminas/química , Cobayas , Ligandos , Piperazina , Piperazinas/química , Ensayo de Unión Radioligante , Ratas , Receptores sigma/química , Relación Estructura-Actividad , Receptor Sigma-1
15.
Bioorg Khim ; 41(2): 235-48, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26165131

RESUMEN

In frames of the search for new biological entities to fight against recent drug-resistant microbial strains, we report a library of quinazoline-based thiourea/4-thiazolidinone/chalcone hybrids. The newly synthesized compounds were studied for efficacy against several bacteria (Staphylococcus aureus, Bacillus cereus, Pseudomonas aeruginosa, and Klebsiella pneumoniae) and fungi (Candida albicans and Aspergillus clavatus) using the broth dilution technique. From the biological evaluation, (E)-3-(3,4-dimethoxyphenyl)-1-(4-((4-(4-ethylpiperazin-1-yl)quinazolin-2-yl)amino)phenyl)prop-2-en-1-one was found to be the most active analogue (microbial inhibition concentration 3.12 µg/mL) to inhibit the bacterial growth. The rest of the compounds showed equipotent efficacy (3.12-12.5 µg/mL) as compared to the standard. Final compounds were characterized by FT-IR, 1H NMR, 13C NMR, mass spectroscopy, and elemental analysis.


Asunto(s)
Antiinfecciosos , Aspergillus/crecimiento & desarrollo , Bacterias/crecimiento & desarrollo , Candida albicans/crecimiento & desarrollo , Antiinfecciosos/síntesis química , Antiinfecciosos/química , Antiinfecciosos/farmacología , Chalcona/síntesis química , Chalcona/química , Chalcona/farmacología , Evaluación Preclínica de Medicamentos , Piperazina , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/farmacología , Quinazolinas/síntesis química , Quinazolinas/química , Quinazolinas/farmacología , Tiourea/síntesis química , Tiourea/química , Tiourea/farmacología
16.
Antiviral Res ; 109: 141-8, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25019406

RESUMEN

Hepatitis C virus (HCV) remains a serious global health problem that lacks an effective cure. Although the introduction of protease inhibitors to the current standard-of-care interferon/ribavirin therapy for HCV infection has improved sustained virological response of genotype 1-infected patients, these inhibitors exacerbate already problematic side effects. Thus, new HCV antivirals are urgently needed. Using a cell-protection screen previously developed in our laboratory, we evaluated 30,426 compounds for inhibitors of potentially any stage of the HCV life cycle and identified 49 new HCV inhibitors. The two most potent hits, hydroxyzine and chlorcyclizine, belong to the family of benzhydrylpiperazines and were found to inhibit the entry of cell culture-produced HCV with IC50 values of 19 and 2.3 nM, respectively, and therapeutic indices of >500 and >6500. Both compounds block HCV entry at a late stage of entry prior to viral fusion and their inhibitory activities are highly dependent on the host's cholesterol content. Both compounds are currently used in the clinic for treating allergy-related disorders and the reported peak plasma level (160 nM) and estimated liver concentration (1.7 µM) of hydroxyzine in humans are much higher than the molecule's anti-HCV IC90 in cell culture (64 nM). Further studies are therefore justified to evaluate the use of these molecules in an anti-HCV therapeutic regimen.


Asunto(s)
Antivirales/farmacología , Colesterol/metabolismo , Hepacivirus/efectos de los fármacos , Hepatitis C/virología , Piperazinas/farmacología , Internalización del Virus/efectos de los fármacos , Antivirales/química , Línea Celular , Regulación hacia Abajo , Evaluación Preclínica de Medicamentos , Hepacivirus/fisiología , Hepatitis C/metabolismo , Humanos , Piperazina , Piperazinas/química
17.
Artículo en Inglés | MEDLINE | ID: mdl-24146510

RESUMEN

The objective of the study was to investigate the effectiveness and efficacy of the randomized, parallel, and controlled trial of Traditional Chinese Medicine, general acteoside of Rehmanniae leaves, compared with piperazine ferulate in the treatment of primary chronic glomerulonephritis. Rehmanniae leaves and piperazine ferulate can reduce proteinuria and erythrocyturia effectively in the treatment of primary chronic glomerulonephritis. A total of 400 patients diagnosed with primary chronic glomerulonephritis were recruited from outpatient clinics and were randomly assigned to the treatment group (general acteoside of Rehmanniae leaves, two 200mg tablets, bid) or the control group (piperazine ferulate, four 50-mg tablets, bid ). The primary outcome was 24-h urinary protein. Secondary outcome measures included estimated glomerular filtration rate (eGFR), erythrocyturia, and electrolytes. After 8 weeks of treatment, the treatment group and the control group showed a mean reduction in 24-h proteinuria of 34.81% and 37.66%. The 95% CI of difference of the mean reduction in 24-h proteinuria between the two groups was [-11.50%, 5.80%]. No significant differences were found between the two groups in the erythrocyturia reduction. Neither group showed obvious changes between baseline and 8 weeks in eGFR or electrolytes. Adverse events occurred at a similarly low rate in the treatment group (1.5%) and control group (2.5%, P = 0.7238). Both general acteoside of Rehmanniae leaves and piperazine ferulate can reduce proteinuria and erythrocyturia effectively in the treatment of primary chronic glomerulonephritis.


Asunto(s)
Glomerulonefritis/tratamiento farmacológico , Glucósidos/uso terapéutico , Fenoles/uso terapéutico , Fitoterapia , Piperazinas/uso terapéutico , Extractos Vegetales/uso terapéutico , Proteinuria/tratamiento farmacológico , Rehmannia/química , Adulto , Enfermedad Crónica , Electrólitos/sangre , Eritrocitos/efectos de los fármacos , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Glomerulonefritis/sangre , Glomerulonefritis/complicaciones , Glomerulonefritis/orina , Glucósidos/farmacología , Humanos , Masculino , Medicina Tradicional China , Fenoles/farmacología , Piperazina , Piperazinas/farmacología , Extractos Vegetales/farmacología , Hojas de la Planta/química , Proteinuria/etiología
18.
Mini Rev Med Chem ; 13(11): 1579-601, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23895191

RESUMEN

This article purposes to provide insights to piperazine based molecular designs that will facilitate drug discovery program in future. In our pursuit to summarize the reservoir of bioactive agents, and in line with the synthetic economy of new heterocycles, many new roles are being identified for the multiple biotargets of piperazine moieties. We mark out how series of different scaffolds provide an extensive range of various piperazine-based analogues displaying antimicrobial, antituberculosis, anticancer, antiviral and antimalarial activities. We believe that piperazine family of compounds, and their various co-components, highlight the existence of several potential leads for the furtherance of novel bioactive agents.


Asunto(s)
Diseño de Fármacos , Piperazinas/química , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Antimaláricos/síntesis química , Antimaláricos/química , Antimaláricos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antituberculosos/síntesis química , Antituberculosos/química , Antituberculosos/farmacología , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacología , Evaluación Preclínica de Medicamentos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , VIH/efectos de los fármacos , Humanos , Mycobacterium tuberculosis/efectos de los fármacos , Piperazina , Piperazinas/síntesis química , Piperazinas/farmacología , Plasmodium falciparum/efectos de los fármacos
19.
Bioorg Med Chem Lett ; 23(15): 4419-23, 2013 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-23787101

RESUMEN

A series of new xanthone derivatives with piperazine moiety [1-7] was synthesized and evaluated for their pharmacological properties. They were subject to binding assays for α1 and ß1 adrenergic as well as 5-HT1A, 5-HT6 and 5-HT7b serotoninergic receptors. Five of the tested compounds were also evaluated for their anticonvulsant properties. The compound 3a 3-methoxy-5-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-9H-xanthen-9-one hydrochloride exhibited significantly higher affinity for serotoninergic 5-HT1A receptors (Ki=24 nM) than other substances. In terms of anticonvulsant activity, 6-methoxy-2-{[4-(benzyl)piperazin-1-yl]methyl}-9H-xanthen-9-one (5) proved best properties. Its ED50 determined in maximal electroshock (MES) seizure assay was 105 mg/kg b.w. (rats, p.o.). Combining of xanthone with piperazine moiety resulted in obtaining of compounds with increased bioavailability after oral administration.


Asunto(s)
Anticonvulsivantes/síntesis química , Piperazinas/química , Xantonas/química , Administración Oral , Animales , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapéutico , Evaluación Preclínica de Medicamentos , Electrochoque , Semivida , Cinética , Piperazina , Unión Proteica , Ratas , Receptor de Serotonina 5-HT1A/química , Receptor de Serotonina 5-HT1A/metabolismo , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Convulsiones/tratamiento farmacológico , Xantonas/farmacocinética , Xantonas/uso terapéutico
20.
Arch Pharm Res ; 36(7): 802-11, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23595553

RESUMEN

In this study, we synthesized eight novel 1-phenyl-2-(4-substituted-piperazin-1-yl)-propanol derivatives and evaluated their antidepressant-like activities. The chemical structures of the synthesised compounds were elucidated by spectroscopy and elemental analyses. Potential antidepressant-like effects of the test compounds (20 mg kg(-1)) were investigated using the tail-suspension test and modified forced swimming test (MFST) in mice. Additionally, the spontaneous locomotor activity of the mice was assessed using the activity cage apparatus. Both the reference drug fluoxetine (20 mg kg(-1)) and the test compounds 3a-3e and 3g significantly shortened the immobility time of the mice in both the behavioural tests. These test compounds also increased the swimming time in MFST without any change in the climbing duration. Compounds 3c-3e and 3g were significantly more potent in inducing these effects than 3a and 3b. None of the compounds changed the locomotor activities of the animals, thus antidepressant-like effects of test compounds were specific. The findings support those of previous studies that reported antidepressant-like activities of aryl alkanol piperazine derivatives.


Asunto(s)
Antidepresivos/síntesis química , Depresión/tratamiento farmacológico , Piperazinas/síntesis química , Propranolol/síntesis química , Animales , Antidepresivos/uso terapéutico , Depresión/psicología , Evaluación Preclínica de Medicamentos/métodos , Suspensión Trasera/psicología , Ratones , Ratones Endogámicos BALB C , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Piperazina , Piperazinas/farmacología , Piperazinas/uso terapéutico , Propranolol/farmacología , Propranolol/uso terapéutico , Distribución Aleatoria , Natación/psicología , Resultado del Tratamiento
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