RESUMEN
Twenty-six new tacrine-benzofuran hybrids were designed, synthesized, and evaluated in vitro on key molecular targets for Alzheimer's disease. Most hybrids exhibited good inhibitory activities on cholinesterases and ß-amyloid self-aggregation. Selected compounds displayed significant inhibition of human ß-secretase-1 (hBACE-1). Among the 26 hybrids, 2e showed the most interesting profile as a subnanomolar selective inhibitor of human acetylcholinesterase (hAChE) (IC50 = 0.86 nM) and a good inhibitor of both ß-amyloid aggregation (hAChE- and self-induced, 61.3% and 58.4%, respectively) and hBACE-1 activity (IC50 = 1.35 µM). Kinetic studies showed that 2e acted as a slow, tight-binding, mixed-type inhibitor, while X-ray crystallographic studies highlighted the ability of 2e to induce large-scale structural changes in the active-site gorge of Torpedo californica AChE (TcAChE), with significant implications for structure-based drug design. In vivo studies confirmed that 2e significantly ameliorates performances of scopolamine-treated ICR mice. Finally, 2e administration did not exhibit significant hepatotoxicity.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Benzofuranos/química , Nootrópicos/química , Tacrina/química , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Animales , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Conducta Animal/efectos de los fármacos , Benzofuranos/síntesis química , Benzofuranos/farmacología , Línea Celular , Supervivencia Celular , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/farmacología , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Modelos Moleculares , Nootrópicos/síntesis química , Nootrópicos/farmacología , Relación Estructura-Actividad , Tacrina/síntesis química , Tacrina/farmacología , TorpedoRESUMEN
In order to find novel potent inhibitors for signal pathways of FGF/FGFR, nineteen N-(3-aryl acryloyl)aminosaccharide derivatives were designed and synthesized based on the binding sites of FGF and oligosaccharides of heparin. Their structures were confirmed by IR, (1)H NMR, (13)C NMR, MS and elemental analysis. The nineteen target compounds were evaluated for biological activity against HUVEC cell. In vitro assays showed that compound 10s (IC50=5.3µM) exhibited comparable inhibitory effects on endothelial cell growth with topotecan (IC50=2.7µM). Compound 10s (10µg/egg) also showed obvious anti-angiogenetic activity in the in vivo chicken chorio allantoic membrane (CAM) assay, and the potency was similar to topotecan (10µg/egg).