ABSTRACT
A series of pterostilbene ß-amino alcohol derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). In vitro assays demonstrated that most of the derivatives were selective acetylacholinesterase (AChE) inhibitors with moderate multifunctional properties. Among them, compound 5f exhibited the best inhibitory activity for EeAChE (IC50â¯=â¯24.04⯵M), that was better than pterostilbene under our experimental condition. In addition, compound 5f displayed reasonable antioxidant activity and could confer significant neuroprotective effect against H2O2-induced PC-12 cell injury. Moreover, 5f also showed self-induced Aß1-42 aggregation inhibitory potency and displayed high BBB permeability in vitro. These multifunctional properties highlight 5f as a promising candidate for further studies directed to the development of novel drugs against AD.
Subject(s)
Alzheimer Disease/drug therapy , Amino Alcohols/pharmacology , Cholinesterase Inhibitors/pharmacology , Drug Design , Neuroprotective Agents/pharmacology , Stilbenes/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/metabolism , Amino Alcohols/chemical synthesis , Amino Alcohols/chemistry , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Electrophorus , Hydrogen Peroxide/antagonists & inhibitors , Hydrogen Peroxide/pharmacology , Models, Molecular , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , PC12 Cells , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/metabolism , Protein Aggregates/drug effects , Rats , Stilbenes/chemical synthesis , Stilbenes/chemistry , Structure-Activity RelationshipABSTRACT
A series of 5,6-dimethoxybenzo[d]isothiazol-3(2H)-one-N-alkylbenzylamine derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease (AD). The in vitro assays indicated that most of these derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compounds 11b and 11d displayed comprehensive advantages, with good AChE (IC50â¯=â¯0.29⯱â¯0.01⯵M and 0.46⯱â¯0.02⯵M, respectively), MAO-A (IC50â¯=â¯8.2⯱â¯0.08⯵M and 7.9⯱â¯0.07⯵M, respectively) and MAO-B (IC50â¯=â¯20.1⯱â¯0.16⯵M and 43.8⯱â¯2.0% at 10⯵M, respectively) inhibitory activities, moderate self-induced Aß1-42 aggregation inhibitory potency (35.4⯱â¯0.42% and 48.0⯱â¯1.53% at 25⯵M, respectively) and potential antioxidant activity. In addition, the two representative compounds displayed high BBB permeability in vitro. Taken together, these multifunctional properties make 11b and 11d as a promising candidate for the development of efficient drugs against AD.
Subject(s)
Acetylcholinesterase/metabolism , Amyloid beta-Peptides/metabolism , Benzylamines/chemistry , Cholinesterase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase/metabolism , Acetylcholinesterase/chemistry , Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Amyloid beta-Peptides/chemistry , Antioxidants/chemistry , Antioxidants/metabolism , Benzylamines/metabolism , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Cholinesterase Inhibitors/metabolism , Cholinesterase Inhibitors/therapeutic use , Drug Design , Humans , Kinetics , Monoamine Oxidase/chemistry , Monoamine Oxidase/genetics , Monoamine Oxidase Inhibitors/metabolism , Monoamine Oxidase Inhibitors/therapeutic use , Permeability/drug effects , Protein Aggregates/drug effects , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Structure-Activity Relationship , Thiazoles/chemistryABSTRACT
A series of pyridoxine-resveratrol hybrids Mannich base derivatives as multifunctional agents have been designed, synthesized and evaluated for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activity. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and metal-chelating properties were also tested. The results showed that most of these compounds could selectively inhibit acetylcholinesterase (AChE) and MAO-B. Among them, compounds 7d and 8b exhibited the highest potency for AChE inhibition with IC50 values of 2.11µM and 1.56µM, respectively, and compound 7e exhibited the highest MAO-B inhibition with an IC50 value of 2.68µM. The inhibition kinetic analysis revealed that compound 7d showed a mixed-type inhibition, binding simultaneously to the CAS and PAS of AChE. Molecular modeling study was also performed to investigate the binding mode of these hybrids with MAO-B. In addition, all target compounds displayed good antioxidant and metal-chelating properties. Taken together, these preliminary findings can be a new starting point for further development of multifunctional agents for Alzheimer's disease.
Subject(s)
Antioxidants/pharmacology , Chelating Agents/pharmacology , Cholinesterase Inhibitors/pharmacology , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Pyridoxine/pharmacology , Stilbenes/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/enzymology , Animals , Antioxidants/chemistry , Chelating Agents/chemistry , Cholinesterase Inhibitors/chemistry , Electrophorus , Humans , Kinetics , Mannich Bases/chemistry , Mannich Bases/pharmacology , Metals/metabolism , Models, Molecular , Monoamine Oxidase Inhibitors/chemistry , Pyridoxine/analogs & derivatives , Rats , Resveratrol , Stilbenes/chemistryABSTRACT
Considering the complex etiology of Alzheimer's disease (AD), multifunctional agents may be beneficial for the treatment of this disease. A series of DL-3-n-butylphthalide-Edaravone hybrids were designed, synthesized and evaluated as novel dual inhibitors of amyloid-ß aggregation and monoamine oxidases. Among them, compounds 9a-d exhibited good inhibition of self-induced Aß1-42 aggregation with inhibition ratio 57.7-71.5%. For MAO, these new hybrids exhibited good balance of inhibition for MAO-A and MAO-B. In addition, all target compounds retained the antioxidant activity of edaravone, showed equal or better antioxidant activity than edaravone. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that compounds 9a-d would be able to cross the blood-brain barrier and reach their biological targets in the central nervous system. The promising results in all assays demonstrated that the strategy behind the designing of compounds was rational and favourable. Taken together, these preliminary findings suggested that the compounds with the strongest bioactivity deserves further investigated for pharmacological development in AD therapy.
Subject(s)
Amyloid beta-Peptides/metabolism , Antioxidants/chemistry , Antipyrine/analogs & derivatives , Benzofurans/chemistry , Monoamine Oxidase Inhibitors/chemistry , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/chemistry , Antioxidants/chemical synthesis , Antioxidants/therapeutic use , Antipyrine/chemistry , Binding Sites , Blood-Brain Barrier/metabolism , Edaravone , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Molecular Docking Simulation , Monoamine Oxidase/chemistry , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/metabolism , Monoamine Oxidase Inhibitors/therapeutic use , Protein Binding , Protein Structure, TertiaryABSTRACT
A series of 4'-aminochalcone-revastigmine hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. The results showed that most of these compounds exhibited good multifunctional activities. In particular, compound 6c displayed the best inhibitory potency on acetylcholinesterase (IC50=4.91µM), and significant antioxidative activity with a value 2.83-fold of Trolox. The kinetic analysis of AChE inhibition revealed that 6c showed mixed-type inhibition, binding simultaneously to the catalytic active site and peripheral anionic site of AChE. In addition, 6c inhibited self-induced Aß1-42 aggregation and Cu2+-induced Aß1-42 aggregation by 89.5% and 79.7% at 25µM respectively, as well as acted as a selective monoamine oxidase B inhibitor (IC50=0.29µM) and a selective biometal chelator. Furthermore, 6c could cross the blood-brain barrier in vitro. Based on these results, Compound 6c could be considered as a very promising lead compound for Alzheimer's disease.
Subject(s)
Alzheimer Disease/drug therapy , Chalcones/pharmacology , Cholinesterase Inhibitors/pharmacology , Drug Design , Monoamine Oxidase Inhibitors/pharmacology , Rivastigmine/pharmacology , Acetylcholinesterase/metabolism , Animals , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Chalcones/chemistry , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Molecular Structure , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/chemistry , Rivastigmine/chemistry , Structure-Activity Relationship , SwineABSTRACT
A series of homoisoflavonoid Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents against Alzheimer's disease. It demonstrated that most of the derivatives were selective AChE and MAO-B dual inhibitors with good multifunctional properties. Among them, compound 10d displayed the comprehensive advantages, with excellent AChE and MAO-B inhibitory activities (IC50=2.49±0.08nM and 1.74±0.0581µM, respectively), good self- and Cu2+-induced Aß1-42 aggregation inhibitory potency, antioxidant activity, biometal chelating ability and high BBB permeability. These multifunctional properties make 10d as an excellent candidate for the development of efficient drugs against AD.
