当前位置： SCI文献检索 > EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Discovery of novel series of 2-substituted benzo[d]oxazol-5-amine derivatives as multi-target directed ligands for the treatment of Alzheimer's disease.

Discovery of novel series of 2-substituted benzo[d]oxazol-5-amine derivatives as multi-target directed ligands for the treatment of Alzheimer's disease.

Abstract：

:Alzheimer's disease (AD) is associated with multifactorial neuropathological conditions, which include cholinergic deficit, amyloid-beta plaques formation, loss of neuronal plasticity and neuronal death. Treating such multifactorial conditions with a single target directed approach is considered to be inadequate. Accordingly, multi-target directed ligand (MTDL) strategy has been evolved as an auspicious approach for the treatment of AD. In light of that, a library of 2-substituted benzo[d]oxazol-5-amine derivatives (29-39; 86-107) was designed using the scaffold hopping guided MTDLs strategy, synthesized and evaluated through various in-vitro and in-vivo biological studies. The optimal compound 92 exhibited potent inhibitory activities against AChE (IC50 = 0.052 ± 0.010 μM), BuChE (IC50 = 1.085 ± 0.035 μM), and significant amyloid-beta aggregation (20 μM) inhibition. The compound possessed better blood-brain barrier permeability (Pe = 10.80 ± 0.055 × 10-6 cm s-1) in PAMPA assay and neuro protective properties (40 μM) on SH-SY5Y neuroblastoma cell lines. Furthermore, in-vivo behavioural studies were performed on Y-maze test (scopolamine-induced amnesia model) and Morris water maze test (Aβ1-42 induced ICV rat model). The compound 92, at a dose of 10 mg/kg oral administration, demonstrated a substantial improvement of the cognitive and special memory impairment. In summary, both in-vitro and in-vivo investigations evidenced that compound 92 was a potential lead for the discovery of safe and effective disease-modifying agents for AD.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Gutti G,Kakarla R,Kumar D,Beohar M,Ganeshpurkar A,Kumar A,Krishnamurthy S,Singh SK

doi

10.1016/j.ejmech.2019.111613

subject

Has Abstract

pub_date

2019-11-15 00:00:00

pages

111613

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(19)30747-0

journal_volume

182

pub_type

杂志文章

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