ABSTRACT
AIM: To design novel bifunctional derivatives of huperzine B (HupB) based on the concept of dual binding site of acetylcholinesterase (AChE) and evaluate their pharmacological activities for seeking new drug candidates against Alzheimer's disease (AD). METHODS: Novel 16-substituted bifunctional derivatives of HupB were synthesized through chemical reactions. The inhibitory activities of the derivatives toward AChE and butyrylcholinesterase (BuChE) were determined in vitro by modified Ellman's method. Cell viability was quantified by the reduction of MTT. RESULTS: A new preparative method was developed for the generation of 16-substituted derivatives of HupB, and pharmacological trials indicated that the derivatives were multifunctional cholinesterase inhibitors targeting both AChE and BuChE. Among the derivatives tested, 9c, 9e, 9f, and 9i were 480 to 1360 times more potent as AChE inhibitors and 370 to 1560 times more potent as BuChE inhibitors than the parent HupB. Further preliminary pharmacological trials of derivatives 9c and 9i were performed, including examining the mechanism of AChE inhibition, the substrate kinetics of the enzyme inhibition, and protection against hydrogen peroxide (H2O2)-induced cytotoxicity in PC12 cells. CONCLUSION: Preliminary pharmacological evaluation indicated that 16-substituted derivatives of HupB, particularly 9c and 9i, would be potentially valuable new drug candidates for AD therapy, and further exploration is needed to evaluate their pharmacological and clinical efficacies.
Subject(s)
Alkaloids/chemistry , Alkaloids/pharmacology , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Animals , Butyrylcholinesterase/metabolism , Cell Survival/drug effects , PC12 Cells , Rats , Structure-Activity RelationshipABSTRACT
The severe acute respiratory syndrome (SARS) coronavirus 3CL protease is an attractive target for the development of anti-SARS drugs. In this paper, cinanserin (1) analogs were synthesized and tested for the inhibitory activities against SARS-coronavirus (CoV) 3CL protease by fluorescence resonance energy transfer (FRET) assay. Four analogs show significant activities, especially compound 26 with an IC(50) of 1.06 microM.
Subject(s)
Antiviral Agents/pharmacology , Cinanserin/analogs & derivatives , Cinanserin/pharmacology , Protease Inhibitors/pharmacology , Serotonin Antagonists/pharmacology , Severe acute respiratory syndrome-related coronavirus/enzymology , Viral Proteins/antagonists & inhibitors , Antiviral Agents/chemical synthesis , Cinanserin/chemical synthesis , Coronavirus 3C Proteases , Cysteine Endopeptidases , Drug Design , Fluorescence Resonance Energy Transfer , Indicators and Reagents , Magnetic Resonance Spectroscopy , Models, Molecular , Protease Inhibitors/chemical synthesis , Serotonin Antagonists/chemical synthesis , Spectrophotometry, Infrared , Structure-Activity RelationshipABSTRACT
Natural (-)-huperzine B (HupB), isolated from Chinese medicinal herb, displayed moderate inhibitory activity of acetylcholinesterase (AChE). Based on the active dual-site of AChE, a series of novel derivatives of bis- and bifunctional HupB were designed and synthesized. The AChE inhibition potency of most derivatives of HupB was enhanced about 2-3 orders of magnitude as compared with the parental HupB. Among bis-HupB derivatives, 12h exhibited the most potent in the AChE inhibition and has been evaluated for its pharmacological actions in vivo on ChE inhibition, cognitive enhancement, and neuroprotection. The docking study on the bis-HupB derivatives 12 series with TcAChE has demonstrated that the ligands bound to the dual-site of the enzyme in different level.
Subject(s)
Acetylcholinesterase/chemistry , Alkaloids/pharmacology , Butyrylcholinesterase/chemistry , Cholinesterase Inhibitors/pharmacology , Alkaloids/chemical synthesis , Alkaloids/chemistry , Animals , Binding Sites , Butyrylcholinesterase/blood , Cerebral Cortex/enzymology , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Rats , Structure-Activity RelationshipABSTRACT
In search of small molecule compounds as the ligands of cyclophilin A, a series of quinoxalines were prepared, and their K(d) values of cyclophilin A and IC50 values for peptidyl-prolyl isomerase activity of cyclophilin A were tested. The results suggest that some quinoxalines are promising ligands of cyclophilin A.
Subject(s)
Cyclophilin A/chemistry , Enzyme Inhibitors/pharmacology , Peptidylprolyl Isomerase/antagonists & inhibitors , Quinoxalines/chemistry , Enzyme Inhibitors/chemical synthesis , Indicators and Reagents , Kinetics , Magnetic Resonance Spectroscopy , Spectrophotometry, Infrared , Structure-Activity Relationship , Surface Plasmon ResonanceSubject(s)
Anti-HIV Agents/chemistry , HIV Protease Inhibitors/chemistry , 4-Hydroxycoumarins/chemical synthesis , 4-Hydroxycoumarins/chemistry , 4-Hydroxycoumarins/pharmacology , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Atazanavir Sulfate , HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/pharmacology , Humans , Molecular Structure , Oligopeptides/chemical synthesis , Oligopeptides/chemistry , Oligopeptides/pharmacology , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacology , Saquinavir/chemical synthesis , Saquinavir/chemistry , Saquinavir/pharmacology , Urea/analogs & derivatives , Urea/chemical synthesis , Urea/chemistry , Urea/pharmacologyABSTRACT
By targeting dual active sites of AChE, a series of bis-huperzine B analogues with various lengths of the tether were designed, synthesized, and tested for their inhibition and selectivity. The most potent bis-huperzine B (5g) exhibited 3900-fold increase in AChE inhibition and 930-fold greater in selectivity for AChE vs BuChE than its parent huperzine B.
Subject(s)
Bridged-Ring Compounds/chemical synthesis , Cholinesterase Inhibitors/chemical synthesis , Pyridones/chemical synthesis , Acetylcholinesterase/chemistry , Alkaloids/chemistry , Animals , Bridged-Ring Compounds/chemistry , Bridged-Ring Compounds/pharmacology , Butyrylcholinesterase/chemistry , Catalytic Domain , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , In Vitro Techniques , Lycopodiaceae , Models, Molecular , Pyridones/chemistry , Pyridones/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
By targeting dual active sites of AChE, a number of new derivatives of HupB have been synthesized and tested as acetylcholinesterase inhibitors. The most potent compound, bis-HupB 5b is 72-fold more potent in AChE inhibition and 79-fold more selective for AChE versus BChE than HupB.
Subject(s)
Alkaloids/chemical synthesis , Cholinesterase Inhibitors/chemical synthesis , Alkaloids/pharmacology , Animals , Binding Sites , Cerebral Cortex , Cholinesterase Inhibitors/pharmacology , Drugs, Chinese Herbal/chemical synthesis , Drugs, Chinese Herbal/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
(-)-Huperzine A (5, HupA), an alkaloid isolated from the herb Huperzia serrata, is a potent, selective and reversible acetylcholinesterase (AchE) inhibitor. Based on the hypothesis with respect to two binding sites in the active gorge of AChE and the good example of bis-tacrine, it was predicted from the docking studies of alkylene-linked dimers of HupA that dimers 6 (n = 5, 7, 9) might have good AChE inhibitory activity. Therefore, six dimers with 7-12 methylene units as tethers were thus prepared. It was found that these dimers were less potent than HupA in inhibition of AChE. The difference of the inhibitory potency between these dimers is coincident with the results of the docking studies.
Subject(s)
Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/chemical synthesis , Sesquiterpenes/chemistry , Sesquiterpenes/chemical synthesis , Alkaloids , Alkylation , Binding Sites , Indicators and Reagents , Polymers , Protein Conformation , Tacrine/chemistry , Tacrine/pharmacologyABSTRACT
AIM: To study asymmetric total synthesis of 14-nor-huperzine A 2 and its inhibitory activity on acetylcholinesterase. METHODS: Highly enantioselective synthesis of compound 5 from beta-keto-ester 3 and 2-methylene-1,3-propanediol diacetate 4 by palladium-catalyzed bicycloannulation was carried out using new chiral ferrocenylphosphine ligands, such as 10, 11, followed by regioselective double-bond migration to produce compound 6. Optically pure 6 was obtained after enantio-enrichment recrystallization. Then, according to similar procedures of huperzine A synthesis, the target compound 14-nor-huperzine A 2 was prepared. The inhibitory activity was tested with rat erythrocyte membrame acetylcholinesterase. RESULTS: The inhibitory activity of synthetic (-)-14-nor-huperzine A was 8 fold less potent than that of (-)-huperzine A. CONCLUSION: A hydrogen-bond between 14-methyl group of (-) huperzine A and the main-chain oxygen of His 440 is necessary for the highly acetylcholinesterase inhibitory activity of huperzine A.
Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Sesquiterpenes/chemical synthesis , Alkaloids , Alzheimer Disease/drug therapy , Animals , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/therapeutic use , Erythrocyte Membrane/drug effects , Erythrocyte Membrane/enzymology , Molecular Conformation , Molecular Structure , Rats , Sesquiterpenes/chemistry , Sesquiterpenes/pharmacology , Sesquiterpenes/therapeutic useABSTRACT
A number of aglycon analogues of sarmentosin were prepared and their bioactivities on the proliferation of T-lymphocytes and B-lymphocytes were assayed.
