Design, synthesis, and evaluation of N-benzylpyrrolidine and 1,3,4-oxadiazole as multitargeted hybrids for the treatment of Alzheimer's disease.
Bioorg Chem
; 111: 104922, 2021 06.
Article
en En
| MEDLINE
| ID: mdl-33945941
ABSTRACT
Novel N-Benzylpyrrolidine hybrids were designed, synthesized, and tested against multiple in-vitro and in-vivo parameters. Among all the synthesized molecules, 8f and 12f showed extensive inhibition against beta-secretase-1 (hBACE-1), human acetylcholinesterase (hAChE) & human butyrylcholinesterase (hBuChE). These molecules are also endowed with significant AChE-peripheral anionic site (PAS) binding capability, blood-brain barrier permeability, potential disassembly of Aß aggregates along with neuroprotection ability on SHSY-5Y cell lines. Results of the Y-Maze and Morris water maze test concluded that compounds 8f and 12f ameliorated cognitive dysfunction induced by scopolamine and Aß. The ex-vivo activity was executed on rat's brain homogenate indicating a reduction in AChE level and oxidative stress. The pharmacokinetic investigation ascertained considerable oral absorption profile of the lead 12f. The results of the in silico docking studies and molecular dynamics simulations demonstrated stable interactions of compounds 8f and 12f with the target residues of hAChE, hBuChE and hBACE-1.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Oxadiazoles
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Pirrolidinas
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Diseño de Fármacos
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Inhibidores de la Colinesterasa
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Fármacos Neuroprotectores
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Enfermedad de Alzheimer
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Bioorg Chem
Año:
2021
Tipo del documento:
Article
País de afiliación:
India