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2026-04-16

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cc-by (c) Verano, A.B. et al., 2026
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/230059

Synthesis and biological profiling of new 1,2,3,4-tetrahydrobenzo [h] naphthyridine-based hybrids as dual inhibitors of β-amyloid and tau aggregation with anticholinesterase activity

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Recurs relacionat

https://doi.org/10.3390/biom16040593

Resum

DP-128 is a multitarget benzonaphthyridine-6-chlorotacrine hybrid molecule with potent in vitro anticholinesterase and Aβ42 and tau anti-aggregating activity. While often used as a reference protein aggregation inhibitor, its further development as an anti-Alzheimer agent is limited by significant cytotoxicity, suboptimal aqueous solubility and microsomal stability. Since these drawbacks might arise from its rather high lipophilicity, in this work we have developed a series of more polar analogues, designed by structural modifications at the benzonaphthyridine or 6-chlorotacrine moieties or within the eight-atom linker. Half of the new analogues are indeed slightly more soluble and clearly less cytotoxic than DP-128, display single-digit acetylcholinesterase inhibitory activity, and retain the Aβ42 and tau anti-aggregating potency of the lead, as well as favourable brain permeation and high plasma stability. While further optimization of microsomal stability is necessary for a potential therapeutic use of this class of compounds, hybrids 16 and 17 , with similar or even higher Aβ42 and tau anti-aggregating activity and lower cytotoxicity than DP-128, might represent novel pharmacological tools for protein aggregation studies.

Matèries

Farmacocinètica, Malaltia d'Alzheimer, Acetilcolinesterasa, Amiloides

Matèries (anglès)

Pharmacokinetics, Alzheimer's disease, Acetylcholinesterase, Amyloid

Citació

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Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica)

Citació

VERANO BUENAVIDEZ, Aldrick, et al. Synthesis and biological profiling of new 1,2,3,4-tetrahydrobenzo [h] naphthyridine-based hybrids as dual inhibitors of β-amyloid and tau aggregation with anticholinesterase activity. Biomolecules. 2026. Vol. 16. ISSN 2218-273X. [consulted: 4 of August of 2026]. Available at: https://hdl.handle.net/2445/230059

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