RESUMO
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.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Benzofuranos/química , Nootrópicos/química , Tacrina/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Comportamento Animal/efeitos dos fármacos , Benzofuranos/síntese química , Benzofuranos/farmacologia , Linhagem Celular , Sobrevivência Celular , Doença Hepática Induzida por Substâncias e Drogas/patologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Nootrópicos/síntese química , Nootrópicos/farmacologia , Relação Estrutura-Atividade , Tacrina/síntese química , Tacrina/farmacologia , TorpedoRESUMO
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).