ABSTRACT
Three types of aromatic-polyamine conjugates (6a-6s) were designed, synthesized and evaluated as potential inhibitors for cholinesterases (ChEs). The results showed that anthraquinone-polyamine conjugates (AQPCs) exhibited the most potent acetylcholinesterase (AChE) inhibitory activity with IC50 values from 1.50 to 11.13 µM. Anthracene-polyamine conjugates (APCs) showed a surprising selectivity (from 76- to 3125-fold) and were most potent at inhibiting butyrylcholinesterase (BChE), with IC50 values from 0.016 to 0.657 µM. A Lineweaver-Burk plot and molecular modeling studies indicated that the representative compounds, 6l and 6k, targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of ChEs. Furthermore, APCs did not affect HepG2 cell viability at the concentration of 100 µM. Consequently, these polyamine conjugates could be thoroughly and systematically studied for the treatment of AD.
Subject(s)
Acetamides/pharmacology , Alzheimer Disease/drug therapy , Anthracenes/pharmacology , Butyrylcholinesterase/chemistry , Cell Proliferation/drug effects , Cholinesterase Inhibitors/pharmacology , Polyamines/pharmacology , Acetamides/chemistry , Alzheimer Disease/enzymology , Amyloid beta-Peptides , Anthracenes/chemistry , Binding Sites , Catalytic Domain , Cholinesterase Inhibitors/chemistry , Drug Design , Hep G2 Cells , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Polyamines/chemistry , Protein Conformation , Structure-Activity RelationshipABSTRACT
A series of 4-dimethylamine flavonoid derivatives 5a-5r were designed, synthesized and evaluated as potential multi-functional anti-Alzheimer agents. The results showed that most of the synthesized compounds exhibited high acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity at the micromolar range (IC50, 1.83-33.20 µM for AChE and 0.82-11.45 µM for BChE). A Lineweaver-Burk plot indicated a mixed-type inhibition for compound 5j with AChE, and molecular modeling study showed that 5j targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, the derivatives showed potent self-induced Aß aggregation inhibitory activity at 20 µM with percentage from 25% to 48%. In addition, some compounds (5j-5q) showed potent oxygen radical absorbance capacity (ORAC) ranging from 1.5- to 2.6-fold of the Trolox value. These compounds should be further investigated as multi-potent agents for the treatment of Alzheimer's disease.
Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Dimethylamines/chemistry , Dimethylamines/pharmacology , Flavonoids/chemistry , Flavonoids/pharmacology , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Alzheimer Disease/enzymology , Alzheimer Disease/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Butyrylcholinesterase/chemistry , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Dimethylamines/chemical synthesis , Drug Design , Flavonoids/chemical synthesis , Humans , Molecular Docking Simulation , Structure-Activity RelationshipABSTRACT
A novel series of bis-nicotine derivatives (3a-3i) were designed, synthesized and evaluated as bivalent anti-Alzheimer's disease agents. The pharmacological results indicated that compounds 3e-3i inhibited both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the micromolar range (IC50, 2.28-117.86 micromol x L(-1) for AChE and 1.67-125 micromol x L(-1) for BChE), which was at the same potency as rivastigmine. A Lineweaver-Burk plot and molecular modeling study showed that these derivatives targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds could significantly inhibit the self-induced Abeta aggregation with inhibition activity (11.85%-62.14%) at the concentration of 20 micromol x L(-1).
Subject(s)
Acetylcholinesterase/metabolism , Amyloid beta-Peptides , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Nicotine/analogs & derivatives , Nicotine/chemical synthesis , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Binding Sites , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Nicotine/chemistry , Nicotine/pharmacologyABSTRACT
A series of tacrine-methoxybenzene hybrids (5a-5i) were designed, synthesized and evaluated as inhibitors of cholinesterases (ChEs). All the compounds had better ChEs inhibitory activities than tacrine with IC50 values at the nanomolar range. Compound 5h exhibited the strongest inhibition on acetylcholinesterase (AChE) with an IC50 value of 6.74 nmol x L(-1) and compound 5f showed the most potent inhibition on butyrylcholinesterase with IC50 value of 3.83 nmol x L(-1). Kinetic and molecular modeling studies showed that these hybrids targeted both the catalytic active site and the peripheral anionic site of AChE.
