RESUMEN
In our effort towards the identification of novel BuChE-IDO1 dual-targeted inhibitor for the treatment of Alzheimer's disease (AD), sertaconazole was identified through a combination of structure-based virtual screening followed by MM-GBSA rescoring. Preliminary chemical optimization was performed to develop more potent and selective sertaconazole analogues. In consideration of the selectivity and the inhibitory activity against target proteins, compounds 5c and 5d were selected for the next study. Further modification of compound 5c led to the generation of compound 10g with notably improved selectivity towards BuChE versus AChE. The present study provided us with a good starting point to further design potent and selective BuChE-IDO1 inhibitors, which may benefit the treatment of late stage AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Imidazoles/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Isoindoles/farmacología , Tiofenos/farmacología , Enfermedad de Alzheimer/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Imidazoles/síntesis química , Imidazoles/química , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Isoindoles/síntesis química , Isoindoles/química , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/químicaRESUMEN
Designing small molecule inhibitors targeting cholinesterases (ChEs) is considered as an efficient strategy for the treatment of Alzheimer's disease (AD). In the present study, based on a shaped-based pharmacophore (SBP) model that we reported previously, virtual screening was performed on four commercial compound databases, from which eight small molecules containing new structurally scaffolds were retained and evaluated. In general, six of these potential hits were identified to be selective ChEs inhibitors. Three compounds exhibited IC50 values and Ki values in micromolar range on acetylcholinesterase (AChE), the most active compound 4 showed IC50 value of 6.31⯱â¯2.68⯵M and Ki value of 4.76⯵M. Other three compounds displayed IC50 values and Ki values in micromolar range on butyrylcholinesterase (BChE) with high target selectivity, the most active compound 1 showed IC50 value of 3.87⯱â¯2.48⯵M and Ki value of 1.52⯵M. Multiple biological evaluations were performed to determine their cytotoxicity, cyto-protective effects, antioxidant effect as well as druglike properties. These compounds provide new cores for the further design and optimization, with the aim to discover new ChEs inhibitors for the treatment of AD.