RESUMEN
Chronic kidney disease (CKD) is associated with numerous metabolic and endocrine disturbances, including abnormalities of calcium and phosphate metabolism and an inflammatory syndrome. The latter occurs early in the course of CKD and contributes to the development and progression of vascular calcification. A few therapeutic strategies are today contemplated to target vascular calcification in patients with CKD: vitamin K2, calcimimetics and phosphate binders. However, none has provided complete prevention of vascular calcification and there is an urgent need for alternate efficient treatments. Recent findings indicate that tissue-nonspecific alkaline phosphatase (TNAP) may represent a very promising drug target due to its participation in mineralization by vascular smooth muscle cells. We report the synthesis of four levamisole derivatives having better inhibition property on TNAP than levamisole. Their IC50, Ki and water solubility have been determined. We found that the four inhibitors bind to TNAP in an uncompetitive manner and are selective to TNAP. Indeed, they do not inhibit intestinal and placental alkaline phosphatases. Survival MTT tests on human MG-63 and Saos-2 osteoblast-like cells have been performed in the presence of inhibitors. All the inhibitors are not toxic at concentrations that block TNAP activity. Moreover, they are able to significantly reduce mineralization in MG63 and Saos-2 osteoblast-like cells, indicating that they are promising molecules to prevent vascular calcification.
Asunto(s)
Fosfatasa Alcalina/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Levamisol/farmacología , Tiofenos/farmacología , Fosfatasa Alcalina/metabolismo , Línea Celular Tumoral , Supervivencia Celular , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Cinética , Levamisol/síntesis química , Levamisol/química , Estructura Molecular , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/químicaRESUMEN
A chiral oxazoline-based organocatalyst has been found to efficiently catalyze asymmetric Strecker reactions of various aromatic and aliphatic N-benzhydrylimines with trimethylsilyl cyanide (TMSCN) as a cyanide source at -20 °C to give α-aminonitriles in high yield (96 %) with excellent chiral induction (up to 98 %â ee). DFT calculations have been performed to rationalize the enantioselective formation of the product with the organocatalyst in these reactions. The organocatalyst has been characterized by single-crystal X-ray diffraction analysis, as well as by other analytical methods. This protocol has been extended to the synthesis of the pharmaceutically important drug molecule levamisole in high yield and with high enantioselectivity.
Asunto(s)
Compuestos de Bencidrilo/química , Cianuros/química , Iminas/química , Levamisol/síntesis química , Nitrilos/química , Oxazoles/química , Compuestos de Trimetilsililo/química , Catálisis , Levamisol/química , Estructura Molecular , Teoría Cuántica , Estereoisomerismo , Difracción de Rayos XRESUMEN
Inhibition of angiogenesis is a promising addition to current cancer treatment strategies. Neutralization of vascular endothelial growth factor by monoclonal antibodies is clinically effective but may cause side effects due to thrombosis. Low molecular weight angiogenesis inhibitors are currently less effective than antibody treatment and are also associated with serious side effects. The discovery of new chemotypes with efficient antiangiogenic activity is therefore of pertinent interest. (S)-levamisole hydrochloride, an anthelminthic drug approved for human use and with a known clinical profile, was recently shown to be an inhibitor of angiogenesis in vitro and exhibited tumor growth inhibition in mice. Here we describe the synthesis and in vitro evaluation of a series of N-alkylated analogues of levamisole with the aim of characterizing structure-activity relationships with regard to inhibition of angiogenesis. N-methyllevamisole and p-bromolevamisole proved more effective than the parent compound, (S)-levamisole hydrochloride, with respect to inhibition of angiogenesis and induction of undifferentiated cluster morphology in human umbilical vein endothelial cells grown in co-culture with normal human dermal fibroblasts. Interestingly, the cluster morphology caused by N-methyllevamisole was different than the clusters observed for levamisole, and a third "cord-like" morphology resembling that of the known drug suramin was observed for an aniline-containing derivative. New chemotypes exhibiting antiangiogenic effects in vitro are thus described, and further investigation of their underlying mechanism of action is warranted.
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/farmacología , Levamisol/síntesis química , Levamisol/farmacología , Neovascularización Fisiológica/efectos de los fármacos , Fosfatasa Alcalina/antagonistas & inhibidores , Fibroblastos/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Levamisol/análogos & derivados , Conformación Molecular , Sirtuina 1/antagonistas & inhibidoresRESUMEN
PURPOSE: To study the stability of levamisole oral solutions (25 mg/mL) prepared from powder and tablets stored at 4 +/- 3 degrees C and 23 +/- 2 degrees C in amber glass prescription bottles. METHODS: Levamisole 25 mg/mL solutions were prepared from commercially available 50-mg tablets or from pure powder in sterile water. Levamisole concentrations were determined in duplicate by a stability-indicating HPLC method at 0, 1, 2, 3, 4, 7, 14, 30, 60 and 90 days. The initial and final pHs of solutions were measured. RESULTS: The recovery of levamisole from tablets was 100 +/- 2.1%. No color or odour changes were observed during the study period. The oral solutions prepared from powder were stable at least 90 days stored at 4 and 23 degrees C. The oral solutions prepared from tablets were stable at least 90 days at 4 degrees C and 15 days when stored at 23 degrees C. The initial pH of solutions prepared from powder and tablets were 5.30 and 4.55, respectively. Initial and final pH values were significantly different (p<0.001) for the two solutions. CONCLUSIONS: Levamisole 25 mg/mL oral solutions can be prepared from tablets or powder with sterile water for irrigation and stored for 90 days under refrigeration, taking account of the lack of microbiological contamination.
Asunto(s)
Levamisol/análisis , Levamisol/síntesis química , Administración Oral , Estabilidad de Medicamentos , Levamisol/administración & dosificación , Soluciones Farmacéuticas/administración & dosificación , Soluciones Farmacéuticas/análisis , Soluciones Farmacéuticas/síntesis química , Polvos , ComprimidosRESUMEN
An efficient and facile chemoenzymatic synthesis of levamisole by employing lipase-mediated resolution of 3-hydroxy-3-phenylpropanenitrile followed by its conversion to beta-amino alcohol as the key intermediate is described.
Asunto(s)
Levamisol/síntesis química , Lipasa/química , Acetatos/química , Alcoholes/química , Humanos , Nitrilos/química , Relación Estructura-ActividadRESUMEN
Co(II), Ni(II), Cu(II) and Zn(II) complexes of levamisole (LMS) were prepared and characterized by elemental analyses, IR spectroscopy, 1H and 13C NMR and mass spectrometry. The following general formula was derived: M(LMS)2Cl2, where M = Co, Ni, Cu, Zn. It was established that LMS behaved as a monodentate ligand and the coordination was accomplished through the N-7 atom. The toxicity and the immunomodulating activity of the complexes on mice and rats in comparison with uncomplexed LMS was assayed. The metals in the complexes exerted different changes in the toxicity of LMS. The complex containing Zn(II) was less toxic and manifested higher immunomodulating activity than LMS.
Asunto(s)
Adyuvantes Inmunológicos/síntesis química , Levamisol/síntesis química , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/toxicidad , Administración Oral , Animales , Eritrocitos/inmunología , Inyecciones Intraperitoneales , Dosificación Letal Mediana , Levamisol/farmacología , Levamisol/toxicidad , Masculino , Espectrometría de Masas , Metales/química , Ratones , Ratones Endogámicos , Ratas , Ratas Wistar , Ovinos/inmunología , Espectrofotometría InfrarrojaRESUMEN
New compounds containing 5,6-dihydro imidazo[2,1-b]thiazole, 2,3,5,6-tetrahydro imidazo[2,1-b]thiazole and 2,3-dihydro imidazo[2,1-b]benzothiazole rings, substituted by heterocycles analogue to chromones, were synthesized and screened against three nematodes, in vitro. The results indicate moderate anthelmintic properties, compared to levamisole; nevertheless, some products exhibit a significant degree of activity.