Discovery of New Cyclopentaquinoline Analogues as Multifunctional Agents for the Treatment of Alzheimer's Disease.
Int J Mol Sci
; 20(3)2019 Jan 24.
Article
en En
| MEDLINE
| ID: mdl-30678364
ABSTRACT
Here we report the two-step synthesis of 8 new cyclopentaquinoline derivatives as modifications of the tetrahydroacridine structure. Next, the biological assessment of each of them was performed. Based on the obtained results we identified 6-chloro-N-[2-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)-hexyl]]-nicotinamide hydrochloride (3e) as the most promising compound with inhibitory potencies against EeAChE and EqBuChE in the low nanomolar level 67 and 153 nM, respectively. Moreover, 3e compound is non-hepatotoxic, able to inhibit amyloid beta aggregation, and shows a mix-type of cholinesterase's inhibition. The mixed type of inhibition of the compound was confirmed by molecular modeling. Then, yeast three-hybrid (Y3H) technology was used to confirm the known ligand-receptor interactions. New derivatives do not show antioxidant activity (confirmed by the use of two different tests). A pKa assay method was developed to identify the basic physicochemical properties of 3e compound. A LogP assay confirmed that 3e compound fulfills Lipinsky's rule of five.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Quinolinas
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Inhibidores de la Colinesterasa
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Fármacos Neuroprotectores
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Enfermedad de Alzheimer
Límite:
Humans
Idioma:
En
Revista:
Int J Mol Sci
Año:
2019
Tipo del documento:
Article
País de afiliación:
Polonia