RESUMEN
An efficient and environmental benign solvent-free synthesis of 5-amino-3-aryl-1-(6'-chloropyridazin-3'-yl)pyrazoles (4A-E): was accomplished by grinding 3-chloro-6-hydrazinopyridazine (2): and ß-ketonitriles (3A-E): in the presence of p-toulenesulfonic acid as a catalyst. Subsequently, 6'-chloro group in 4A-E: was replaced with cyclic 2° amine derivatives viz. pyrrolidine 5A: , piperidine 5B: and morpholine 5C: to obtain 6A-E: , 7A-E: , 8A-E: respectively. The newly synthesized compounds were characterized by using IR, NMR (1H and 13C), mass spectral studies, elemental analyses. All the synthesized compounds were studied for their docking interaction with target protein 6COX and screened for their in vivo analgesic mode of action against swiss albino mice (animal model) using acetic-acid induced writhing test. Consequently, docking simulations data justifies the potential of synthesized series as an analgesic and very well correlated with in vivo study. Preliminary results revealed that most of the synthesized compounds exhibited moderate to good analgesic activity as compared to reference/standard drug (s) sodium diclofenac and candidates 4D: and 7C: protrude out as a promising lead for further investigation.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2/farmacología , Diseño de Fármacos , Dolor/tratamiento farmacológico , Pirazoles/farmacología , Piridazinas/farmacología , Ácido Acético/administración & dosificación , Ácido Acético/toxicidad , Animales , Ciclooxigenasa 2/metabolismo , Ciclooxigenasa 2/ultraestructura , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Simulación del Acoplamiento Molecular , Dolor/inducido químicamente , Pirazoles/química , Pirazoles/uso terapéutico , Piridazinas/química , Piridazinas/uso terapéutico , Relación Estructura-ActividadRESUMEN
Treatment of 1,1,1-trifluoromethyl-3-cyano-3-phenylpropanone (1) with several heteroarylhydrazines (2a-e) in refluxing ethanol affords 1-heteroaryl-5-amino-4-phenyl-3-trifluoromethylpyrazoles (4) in a regioselective manner. The location of trifluoromethyl group at position-3 was established by a combined use of 13C and 19F NMR spectroscopy. The reaction proceeds through the intermediacy of the hydrazone which was isolated and characterized in one case (3e) by performing the reaction at room temperature. The compounds 3e and 4 were tested for their antibacterial property against six Gram-positive and three Gram-negative bacteria. Two compounds, namely 1-(benzothiazol-2'-yl)-5-amino-4-phenyl-3-trifluoromethylpyrazole (4a) and 1-(6'-methylbenzothiazol-2'-yl)-5-amino-4-phenyl-3-trifluoromethylpyrazole (4b) have displayed antibacterial activity comparable to the commercial antibiotics.