Alzheimer’s disorder is one
of the most common worldwide
health problems, and its prevalence continues to increase, thereby
straining the healthcare budgets of both developed and developing
countries. So far, donepezil is the only Food and Drug Administration-approved
dual-binding site inhibitor of acetylcholinesterase (AChE) that can
amplify the cholinergic activity and also decrease Aβ aggregation
in Alzheimer patients. We report herein a new donepezil-like natural
compound derivative (D1) as a convincing AChE inhibitor. The in silico studies suggests that D1 exhibits a dual-binding
mode of action and interacts with both the catalytic anionic site
and peripheral anionic site (PAS) of human AChE. The biological studies
confirm the dual-binding site character of D1 and revealed that D1
not only enhances the acetylcholine levels but also reduces the accumulation
of Aβ plaques in Caenorhabditis elegans. In fact, 5 μM D1 was seen more potent in elevating the acetylcholine
expression than 25 μM donepezil. While most of the non-cholinergic
functions of donepezil, associated with the PAS of AChE, were gradually
lost at higher concentrations, D1 was more functional at similar doses.
Promisingly, D1 also exerted an agonistic effect on the α7 nicotinic
acetylcholine receptor.
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.
Aberrant activation of NLRP3 inflammasome has been implicated in several inflammatory diseases. Autophagy is one of the primary mechanisms that regulate NLRP3 inflammasome activity. In this study, we attempted to target NLRP3 inflammasome activity by a synthetic compound IIIM-941. We found that IIIM-941 inhibits ATP induced NLRP3 inflammasome by induction of autophagy through AMPK pathway in bone marrow derived macrophages (BMDMs) and J774A.1 cells. It was interesting to observe that IIIM-941 did not show any inhibitory activity against LPS induced pro-inflammatory cytokines TNF-α and IL-6. The anti-NLRP3 activity of IIIM-941 was significantly reversed when we attempted to block autophagy by using either pharmacological inhibitor bafilomycin A1or by using siRNA against AMPK. Further, we found that IIIM-941 downregulated the expression of NLRP3 and prevented the oligomerization of ASC to exert its anti-NLRP3 inflammasome effect in J774A.1 cells. We validated inhibitory activity of IIIM-941 against NLRP3 in three different mice models. The anti-inflammatory effect of IIIM-941 was highly significant in ATP induced peritoneal inflammation model. IIIM-941 was similarly effective in suppressing MSU induced IL-1β in the air pouch model of inflammation without affecting the levels of TNF-α and IL-6. Finally, oral efficacy of IIIM-941 was also proved in MSU indued foot paw edema model of inflammation in mice at 10 and 20 mg/kg (b.w.). The compounds like IIIM-941 can be explored further for the development of therapies against diseases such as Alzheimer’s disease and Parkinson’s disease, where hampered autophagy and NLRP3 activation play a crucial role in the pathological development.
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