Bioorganic and Medicinal Chemistry (2020)
Update date:2022-08-15
Topics:
Rivera-Marrero, Suchitil
Bencomo-Martínez, Alberto
Orta Salazar, Erika
Sablón-Carrazana, Marquiza
García-Pupo, Laura
Zoppolo, Florencia
Arredondo, Florencia
Dapueto, Rosina
Daniela Santi, María
Kreimerman, Ingrid
Pardo, Tania
Reyes, Laura
Galán, Lídice
León-Chaviano, Samila
Espinosa-Rodríguez, Luis A.
Menéndez-Soto del Valle, Roberto
Savio, Eduardo
Díaz Cintra, Sofía
Rodríguez-Tanty, Chryslaine
The aggregation of β-amyloid peptides is associated to neurodegeneration in Alzheimer's disease (AD) patients. Consequently, the inhibition of both oligomerization and fibrillation of β-amyloid peptides is considered a plausible therapeutic approach for AD. Herein, the synthesis of new naphthalene derivatives and their evaluation as anti-β-amyloidogenic agents are presented. Molecular dynamic simulations predicted the formation of thermodynamically stable complexes between the compounds, the Aβ1-42 peptide and fibrils. In human microglia cells, these compounds inhibited the aggregation of Aβ1-42 peptide. The lead compound 8 showed a high affinity to amyloid plaques in mice brain ex vivo assays and an adequate log Poct/PBS value. Compound 8 also improved the cognitive function and decreased hippocampal β-amyloid burden in the brain of 3xTg-AD female mice. Altogether, our results suggest that 8 could be a novel therapeutic agent for AD.
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Doi:10.1021/ja025997f
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