RESUMEN
The 2-acylamino-5-nitro-1,3-thiazole derivatives (1-14) were prepared using a one step reaction. All compounds were tested in vitro against four neglected protozoan parasites (Giardia intestinalis, Trichomonas vaginalis, Leishmania amazonensis and Trypanosoma cruzi). Acetamide (9), valeroylamide (10), benzamide (12), methylcarbamate (13) and ethyloxamate (14) derivatives were the most active compounds against G. intestinalis and T. vaginalis, showing nanomolar inhibition. Compound 13 (IC50=10nM), was 536-times more active than metronidazole, and 121-fold more effective than nitazoxanide against G. intestinalis. Compound 14 was 29-times more active than metronidazole and 6.5-fold more potent than nitazoxanide against T. vaginalis. Ureic derivatives 2, 3 and 5 showed moderate activity against L. amazonensis. None of them were active against T. cruzi. Ligand efficiency indexes analysis revealed higher intrinsic quality of the most active 2-acylamino derivatives than nitazoxanide and metronidazole. In silico toxicity profile was also computed for the most active compounds. A very low in vitro mammalian cytotoxicity was obtained for 13 and 14, showing selectivity indexes (SI) of 246,300 and 141,500, respectively. Nitazoxanide showed an excellent leishmanicidal and trypanocidal effect, repurposing this drug as potential new antikinetoplastid parasite compound.
Asunto(s)
Antiprotozoarios/farmacología , Infecciones por Protozoos/inmunología , Tiazoles/química , Animales , Diseño de Fármacos , HumanosRESUMEN
A small series of thiazolidine-2,4-dione and barbituric acid derivatives 1-4 was prepared using a short synthetic route, and all compounds were characterized by elemental analysis, mass spectrometry, and NMR ((1)H, (13)C) spectroscopy. Their in vitro relative expression of peroxisome proliferator-activated receptor α and peroxisome proliferator-activated receptor γ was evaluated. Compound 1 showed an increase in the mRNA expression of both peroxisome proliferator-activated receptor isoforms, as well as the GLUT-4 levels. The antidiabetic activity of compound 1 was determined at 50 mg/kg single dose using a non-insulin-dependent diabetes mellitus rat model. The results indicated a significant decrease in plasma glucose levels. Additionally, we performed a molecular docking of compound 1 into the ligand binding pocket of peroxisome proliferator-activated receptor α and peroxisome proliferator-activated receptor γ. In these binding models, compound 1 may bind into the active site of both isoforms showing important short contacts with the peroxisome proliferator-activated receptor γ residues: Tyr 473, His 449, Ser 289, His 323; and peroxisome proliferator-activated receptor α residues: Tyr 464, His 440, Ser 280 and Tyr 314.
Asunto(s)
Barbitúricos/química , Hipoglucemiantes/química , Nitrilos/química , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Tiazolidinedionas/química , Tiazolidinas/química , Células 3T3-L1 , Animales , Barbitúricos/farmacología , Sitios de Unión , Glucemia/análisis , Dominio Catalítico , Diabetes Mellitus Experimental/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Transportador de Glucosa de Tipo 4/genética , Transportador de Glucosa de Tipo 4/metabolismo , Humanos , Enlace de Hidrógeno , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Masculino , Ratones , Simulación del Acoplamiento Molecular , Nitrilos/farmacología , Nitrilos/uso terapéutico , PPAR alfa/agonistas , PPAR alfa/genética , PPAR gamma/agonistas , PPAR gamma/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Tiazolidinedionas/farmacología , Tiazolidinedionas/uso terapéutico , Tiazolidinas/farmacología , Tiazolidinas/uso terapéutico , Transcripción Genética/efectos de los fármacosRESUMEN
The 2-arylsulfonylaminobenzothiazole derivatives 1-27 were prepared using a one step reaction. The in vitro inhibitory activity of the compounds against protein tyrosine phosphatase 1B (PTP-1B) was evaluated. Compounds 4 and 16 are rapid reversible (mixed-type) inhibitors of PTP-1B with IC(50) values in the low micromolar range. The most active compounds (4 and 16) were docked into the crystal structure of PTP-1B. Docking results indicate potential hydrogen bond interactions between the nitro group in both compounds and the catalytic amino acid residues Arg 221 and Ser 216. Both compounds were evaluated for their in vivo antihyperglycemic activity in a type 2 diabetes mellitus rat model, showing significant lowering of plasma glucose concentration, during the 7h post-intragastric administration.
Asunto(s)
Benzotiazoles/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Hipoglucemiantes/química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Animales , Benzotiazoles/síntesis química , Benzotiazoles/farmacología , Glucemia/efectos de los fármacos , Simulación por Computador , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/síntesis química , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Cinética , Masculino , Modelos Moleculares , Unión Proteica , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
N-(6-Substituted-1,3-benzothiazol-2-yl)benzenesulfonamide derivatives 1-8 were synthesized and evaluated for their in vivo antidiabetic activity in a non-insulin-dependent diabetes mellitus rat model. Several compounds synthesized showed significant lowering of plasma glucose level in this model. As a possible mode of action, the compounds were in vitro evaluated as 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitors. The most active compounds (3 and 4) were docked into the crystal structure of 11beta-HSD1. Docking results indicate potential hydrogen bond interactions with catalytic amino acid residues.