Abstract
To discover novel BChE inhibitors, a hierarchical virtual screening protocol followed by biochemical evaluation was applied. The most potent compound 8012-9656 (eqBChE IC50 = 0.18 ± 0.03 μM, hBChE IC50 = 0.32 ± 0.07 μM) was purchased and synthesized. It inhibited BChE in a noncompetitive manner and could occupy the binding pocket forming diverse interactions with the target. 8012-9656 was proven to be safe in vivo and in vitro and showed comparable performance in ameliorating the scopolamine-induced cognition impairment to tacrine. Additionally, treatment with 8012-9656 could almost entirely recover the Aβ1-42 (icv)-impaired cognitive function to the normal level and showed better behavioral performance than donepezil. The evaluation of the Aβ1-42 total amount confirmed its anti-amyloidogenic profile. Moreover, 8012-9656 possessed blood-brain barrier (BBB) penetrating ability, a long T1/2, and low intrinsic clearance. Hence, the novel potential BChE inhibitor 8012-9656 can be considered as a promising lead compound for further investigation of anti-AD agents.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminoquinolines / chemical synthesis
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Aminoquinolines / metabolism
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Aminoquinolines / pharmacology*
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Aminoquinolines / toxicity
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Animals
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Benzimidazoles / chemical synthesis
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Benzimidazoles / metabolism
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Benzimidazoles / pharmacology*
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Benzimidazoles / toxicity
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Butyrylcholinesterase / metabolism*
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Cell Line, Tumor
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Cholinesterase Inhibitors / chemical synthesis
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Cholinesterase Inhibitors / metabolism
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Cholinesterase Inhibitors / pharmacology*
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Cholinesterase Inhibitors / toxicity
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Drug Discovery
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Drug Evaluation, Preclinical
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Female
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Humans
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Male
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Mice, Inbred ICR
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Microsomes, Liver / metabolism
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Molecular Docking Simulation
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Molecular Dynamics Simulation
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Neuroprotective Agents / chemical synthesis
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Neuroprotective Agents / metabolism
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Neuroprotective Agents / pharmacology*
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Neuroprotective Agents / toxicity
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Protein Binding
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Small Molecule Libraries / chemical synthesis
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Small Molecule Libraries / metabolism
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Small Molecule Libraries / pharmacology
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Small Molecule Libraries / toxicity
Substances
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Aminoquinolines
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Benzimidazoles
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Cholinesterase Inhibitors
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Neuroprotective Agents
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Small Molecule Libraries
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Butyrylcholinesterase