Discovery of carbamate-based N-salicyloyl tryptamine derivatives as novel pleiotropic agents for the treatment of Alzheimer's disease.
Bioorg Chem
; 127: 105993, 2022 10.
Article
em En
| MEDLINE
| ID: mdl-35834980
ABSTRACT
In this work, based on the potential anti-AD molecule previously studied by our group, we continue to introduce different substituents at different positions to improve both drug-like properties and on target activities. 33 N-salicyloyl tryptamine-carbamate hybrids were designed, synthesized and evaluated as cholinesterase inhibitors. H327 was the most potent BChE inhibitor (eqBChE IC50 = 0.057 ± 0.005 µM), and showed threefold improved inhibitory potency than the positive drug rivastigmine (eqBChE IC50 = 0.19 ± 0.001 µM). In addition, H327 as a pseudo-irreversible BChE inhibitor was endowed with neuroprotective, antioxidative and anti-neuroinflammatory properties. Cytotoxicity and acute toxicity tests confirmed the safety of compound H327. The pharmacokinetics study showed that compound H327 had a longer T1/2 time and higher bioavailability than the lead compound 1 g. Compound H327 was able to cross the blood-brain barrier (BBB) in vivo. Moreover, the behavioral tests showed that compound H327 could significantly improve scopolamine-induced cognitive impairment in vivo. Overall, these results demonstrated that compound H327 is a promising multi-target agent for the treatment of AD.
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Base de dados:
MEDLINE
Assunto principal:
Fármacos Neuroprotetores
/
Doença de Alzheimer
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article