The complex and multifaceted nature of Alzheimer’s
disease
has brought about a pressing demand to develop ligands targeting multiple
pathways to combat its outrageous prevalence. Embelin is a major secondary
metabolite of Embelia ribes Burm f.,
one of the oldest herbs in Indian traditional medicine. It is a micromolar
inhibitor of cholinesterases (ChEs) and β-site amyloid precursor
protein cleaving enzyme 1 (BACE-1) with poor absorption, distribution,
metabolism, and excretion (ADME) properties. Herein, we synthesize
a series of embelin–aryl/alkyl amine hybrids to improve its
physicochemical properties and therapeutic potency against targeted
enzymes. The most active derivative, 9j (SB-1448), inhibits
human acetylcholinesterase (hAChE), human butyrylcholinesterase (hBChE),
and human BACE-1 (hBACE-1) with IC50 values of 0.15, 1.6,
and 0.6 μM, respectively. It inhibits both ChEs noncompetitively
with k
i values of 0.21 and 1.3 μM,
respectively. It is orally bioavailable, crosses blood–brain
barrier (BBB), inhibits Aβ self-aggregation, possesses good
ADME properties, and protects neuronal cells from scopolamine-induced
cell death. The oral administration of 9j at 30 mg/kg
attenuates the scopolamine-induced cognitive impairments in C57BL/6J
mice.
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