RESUMEN
Sixteen new thiazine-quinoline-quinones have been synthesised, plus one bicyclic analogue. These compounds inhibited neutrophil superoxide production in vitro with IC(50)s as low 60 nM. Compounds with high in vitro anti-inflammatory activity were also tested in a mouse model of acute inflammation. The most active compounds inhibited both neutrophil infiltration and superoxide production at doses 2.5 micromol/kg, highlighting their potential for development as novel NSAIDs.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacología , Artritis Gotosa/tratamiento farmacológico , Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Neutrófilos/efectos de los fármacos , Estallido Respiratorio/efectos de los fármacos , Animales , Antiinflamatorios no Esteroideos/química , Artritis Gotosa/metabolismo , Proliferación Celular/efectos de los fármacos , Células HL-60 , Humanos , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Quinolinas/química , Quinonas/química , Relación Estructura-Actividad , Superóxidos/metabolismo , Tiazinas/químicaRESUMEN
p-Hydroxyphenylpyruvate dioxygenase (HPPD) is the target site of beta-triketone herbicides in current use. Nineteen beta-triketones and analogues, including the naturally occurring leptospermone and grandiflorone, were synthesized and tested as inhibitors of purified Arabidopsis thaliana HPPD. The most active compound was a beta-triketone with a C(9) alkyl side chain, not reported as natural, which inhibited HPPD with an I(50) of 19 +/- 1 nM. This is significantly more active than sulcotrione, which had an I(50) of 250 +/- 21 nM in this assay system. The most active naturally occurring beta-triketone was grandiflorone, which had an I(50) of 750 +/- 70 nM. This compound is of potential interest as a natural herbicide because it can be extracted with good yield and purity from some Leptospermum shrubs. Analogues without the 1,3-diketone group needed to interact with Fe(2+) at the HPPD active site were inactive (I(50)s > 50 microM), as were analogues with prenyl or ethyl groups on the triketone ring. Modeling of the binding of the triketones to HPPD, three-dimensional QSAR analysis using CoMFA (comparative molecular field analysis), and evaluation of the hydrophobic contribution with HINT (hydropathic interactions) provided a structural basis to describe the ligand/receptor interactions.
Asunto(s)
4-Hidroxifenilpiruvato Dioxigenasa/antagonistas & inhibidores , 4-Hidroxifenilpiruvato Dioxigenasa/química , Arabidopsis/enzimología , Ciclohexanonas/química , Inhibidores Enzimáticos/química , Herbicidas/química , Proteínas de Plantas/química , Arabidopsis/química , Sitios de Unión , Cinética , Modelos Moleculares , Unión ProteicaRESUMEN
(+/-)-3alpha-hydroxy homoepibatidine 4 has been synthesized from the alkaloid scopolamine 5 and its properties as a nicotinic agonist assessed. While still binding strongly, the compound showed reduced agonist potency for the alpha(4)beta(2) nAChR compared with the parent compound epibatidine 1. Compound 4 also displayed generally similar binding and selectivity profiles at alpha(4)beta(2), alpha(2)beta(4), alpha(3)beta(4), and alpha(4)beta(4) nAChR subtypes to those for nicotine.