RESUMEN
A library of thirty novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives belonging to four series designated as 12, 13, 14 and 15 was efficiently prepared, helped by microwave-assisted technology when required. The efficient multistep synthesis of methyl 6-amino-2-cyano- benzo[d]thiazole-7-carboxylate (1) has been reinvestigated and performed on a multigram scale. The inhibitory potency of the final products against five kinases involved in Alzheimer's disease was evaluated. This study demonstrates that some molecules of the 12 and 13 series described in this paper are particularly promising for the development of new multi-target inhibitors of kinases.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Quinazolinonas/síntesis química , Tiazoles/síntesis química , Animales , Humanos , Ligandos , Estructura Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/metabolismo , Quinazolinonas/metabolismo , Quinazolinonas/uso terapéutico , Porcinos , Tiazoles/metabolismo , Tiazoles/uso terapéuticoRESUMEN
Cycloisomerisation of polyenes such as diethyl geranylprenylmalonate [(E)-1 a], diethyl geranylphenylmalonate [(E)-2 a] and diethyl cinnamylgeranylmalonate [(E,E)-3 a] catalysed by bismuth triflate was studied from experimental and theoretical viewpoints. Several intermediates were isolated and characterised, and calculated transition-state structures are proposed for the three reactions. The diastereoselectivity observed during the reaction of (E)- or (Z)-2 a in favour of the formation of trans-fused bicyclic products is discussed in detail. The nature of the active catalytic species derived from bismuth triflate was also investigated, and the formation of a hybrid Lewis acid/Brønsted acid catalyst with water molecules is proposed, supported by experimental and theoretical data.
Asunto(s)
Compuestos Bicíclicos con Puentes/síntesis química , Malonatos/química , Mesilatos/química , Modelos Químicos , Polienos/química , Terpenos/química , Compuestos Bicíclicos con Puentes/química , Catálisis , Técnicas de Química Sintética , Ácidos de Lewis/química , Estructura Molecular , EstereoisomerismoRESUMEN
A microwave-assisted method for the palladium-catalyzed direct arylation of quinazolin-4-one has been developed under copper-assistance. This method is applicable to a wide range of aryl iodides and substituted (2H)-quinazolin-4-ones. This protocol provides a simple and efficient way to synthesize biologically relevant 2-arylquinazolin-4-one backbones.
Asunto(s)
Cobre/química , Yoduros/química , Paladio/química , Quinazolinonas/química , Catálisis , Enlace de Hidrógeno , Microondas , Estructura MolecularRESUMEN
Nonactivated trienes and aryltrienes were cyclized into polycyclic compounds in good to excellent yields under bismuth triflate catalysis in a biomimetic fashion. The reaction showed broad applicability and allowed for the formation of functionalized bicyclic to tetracyclic structures from simple precursors in one pot. For some specific substrates, the cyclization was followed by a methyl shift as encountered in terpenoid biosynthesis.