ABSTRACT
In the present study, a series of novel azaoxoisoaporphine derivatives were reported and their inhibitory activities toward acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and Aß aggregation were evaluated. The new compounds remained high inhibitory potency on Aß aggregation, with inhibitory activity from 29.42% to 89.63% at a concentration of 10µM, but had no action on AChE or BuChE, which was very different from our previously reported oxoaporphine and oxoisoaporphine derivatives. By 3D-QSAR studies, we constructed a reliable CoMFA model (q(2)=0.856 and r(2)=0.986) based on the inhibitory activities toward AChE and discovered key information on structure and anti-AChE activities among the azaoxoisoaporphine, oxoaporphine, and oxoisoaporphine derivatives. The model was further confirmed by the test-set validation (q(2)=0.873, r(2)=0.937, and slope k=0.902) and Y-randomization examination. The statistically significant and physically meaningful 3D-QSAR/CoMFA model provided better insight into understanding the inhibitory behaviors of those chemicals, which may provide useful information for the rational molecular design of azaoxoisoaporphine derivatives anti-AChE and anti-AD agents.
Subject(s)
Acetylcholinesterase/chemistry , Aporphines/chemistry , Butyrylcholinesterase/chemistry , Cholinesterase Inhibitors/chemistry , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/chemistry , Aporphines/pharmacology , Cell Line , Cell Survival/drug effects , Cholinesterase Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Models, Molecular , Quantitative Structure-Activity RelationshipABSTRACT
A series of 3-substituted (5c-5f, 6c-6f) and 4-substituted (10a-10g) oxoisoaporphine derivatives were synthesized. It was found that all these synthetic compounds had IC50 values at micro or nano molar range for cholinesterase inhibition, and most of them could inhibit amyloid ß (Aß) self-induced aggregation with inhibition ratio from 31.8% to 57.6%. The structure-activity relationship studies revealed that the derivatives with higher selectivity on AChE also showed better inhibition on Aß self-induced aggregation. The results from cell toxicity study indicated that most quaternary methiodide salts had higher IC50 values than the corresponding non-quaternary compounds. This study provided potentially important information for further development of oxoisoaporphine derivatives as lead compounds for the treatment of Alzheimer's disease.
Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/metabolism , Cell Survival/drug effects , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Structure , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Stereoisomerism , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Aporphine alkaloids, isolated from Chinese medicinal herb, are important natural products. We recently reported that synthetic derivatives of oxoisoaporphine alkaloids exhibited high acetylcholinesterase inhibitory activity and high selectivity for AChE over BuChE (Bioorg. Med. Chem. Lett. 2007, 17, 3765-3768). In this paper, further research results were presented. A series of novel derivatives of oxoaporphine alkaloids (5a-j, 4-carboxylic amide-7-oxo-7H-dibenzo[de,g]quinoline, Ar-CONH(CH(2))(n)NR) and their quaternary methiodide salts (6a-h, Ar-CONH(CH(2))(n)N(+)(CH(3))RI(-)) were designed and synthesized as acetylcholinesterase (AChE) and/or butyrylcholinesterase (BuChE) inhibitors. The AChE inhibition potency of synthetic oxoaporphine derivatives was decreased about 2-3 orders of magnitude as compared with that of oxoisoaporphine derivatives. Non-competitive binding mode was found for both kinds of derivatives. Molecular docking simulations on the oxoisoaporphine derivatives 7 series and oxoaporphine derivatives 6 series with AChE from Torpedo californica have demonstrated that the ligands bound to the dual-site of the enzyme.
Subject(s)
Acetylcholinesterase/metabolism , Aporphines/chemical synthesis , Aporphines/pharmacology , Butyrylcholinesterase/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Alkaloids/chemical synthesis , Alkaloids/chemistry , Alkaloids/pharmacology , Animals , Aporphines/chemistry , Computer Simulation , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Models, Chemical , Models, Molecular , Molecular Structure , Reproducibility of Results , Stereoisomerism , Torpedo/metabolismABSTRACT
A series of 9-aminoalkanamido-1-azabenzanthrones derviatives (3a-i Ar-NHCO(CH(2))(n)NR(1)R(2)) and their quaternary methiodide salts (4a-g Ar-NHCO(CH(2))(n)N(+)(CH(3))R(1)R(2)I(-)) were designed and synthesized as acetylcholinesterase (AChE) or butyrylcholinesterase (BuChE) inhibitors. The synthetic compounds exhibited high AChE inhibitory activity with IC(50) values in the nanomolar range and high selectivity for AChE over BuChE (45- to 1980-fold). The structure-activity relationships (SARs) were discussed.
