RESUMEN
An improved and rapid synthesis of mefenamic acid based indole derivatives has been achieved via the ligand free Cu-catalyzed coupling-cyclization method under ultrasound irradiation. This simple, straightforward and inexpensive one-pot method involved the reaction of a terminal alkyne derived from mefenamic acid with 2-iodosulfanilides in the presence of CuI and K2CO3 in PEG-400. The reaction proceeded via an initial CC bond formation (the coupling step) followed by CN bond formation (the intramolecular cyclization) to afford the mefenamic acid based indole derivatives in good to acceptable yields. Several of these compounds showed inhibition of PDE4 in vitro and the SAR (Structure Activity Relationship) within the series is discussed. The compound 3d has been identified as a promising and selective inhibitor of PDE4B (IC50 = 1.34 ± 0.46 µM) that showed TNF-α inhibition in vitro (IC50 = 5.81 ± 0.24 µM) and acceptable stability in the rat liver microsomes.
Asunto(s)
Cobre/química , Indoles/química , Ácido Mefenámico/química , Sonicación , Sitios de Unión , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Catálisis , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Ciclización , Semivida , Humanos , Indoles/metabolismo , Indoles/farmacología , Ácido Mefenámico/metabolismo , Ácido Mefenámico/farmacología , Simulación del Acoplamiento Molecular , Inhibidores de Fosfodiesterasa 4/química , Inhibidores de Fosfodiesterasa 4/metabolismo , Inhibidores de Fosfodiesterasa 4/farmacología , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
A novel approach for the spiro-isoindolinone dihydroquinazolinones has been demonstrated from 2-aminobenzamide and 2-cyanomethyl benzoate in the presence of KHMDS as a base to get moderate yields. The reaction has been screened in various bases followed by solvents and a gram scale reaction has also been executed under the given conditions. Based on the controlled experiments a plausible reaction mechanism has been proposed. Further the substrate scope of this reaction has also been studied.