New Syntheses of rac-Huperzine A and its rac-7-Ethyl-Derivative. Evaluation of Several Huperzine A Analogues as Acetylcholinesterase Inhibitors

Camps, Pelayo; Contreras, Joan Picas; Achab, Rachid El; Morral, Jordi; Muñoz‐Torrero, Diego; Font-Bardı́a, Mercè; Soláns, Xavier; Badı́a, Albert; Vivas, Nuria M.

doi:10.1016/s0040-4020(00)00363-x

Cited by 21 publications

(16 citation statements)

References 32 publications

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“…As expected for an alicyclic small molecule, considering the case ofˇ-pinene which was solved only recently, 9 a large number of long-range couplings are present, whereas only one such connectivity has been reported so far. 10 Furthermore, while the 1 H/ 13 C assignments have been examined by means of selective INEPT 10 and self-aggregation has been studied by 1 H NMR relaxation experiments, 11 the expected diastereotopism of the two methylene groups that are contained in a highly chiral chemical environment remains unsupported, 10,12 and the assignment of the two olefinic lactam protons remains contradictious in the literature. To fill this knowledge gap, but also sparked by our analytical interest in this key alkaloid, we attempted the full spin analysis of this 15-spin 15-carbon molecule.…”

Section: Introductionmentioning

confidence: 99%

Complete ¹H NMR spectral fingerprint of huperzine A

Niemitz

Laatikainen

Chen

et al. 2007

Magnetic Reson in Chemistry

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Complete analysis of the (1)H NMR spectrum of huperzine A, 1-amino-13-ethylidene-11-methyl-6-aza-tricyclo[7.3.1.0(2, 7)]trideca-2(7),3,10-trien-5-one, a Lycopodium alkaloid and anti-Alzheimer drug lead containing an ABCD(E)(MN)(OP)X(3)Y(3)-type system of 15 nonexchangeable proton spins, is reported for the first time, and earlier assignments are corrected. The complete (1)H parameter set of 11 chemical shifts clarifies the diastereotopism of both methylene groups, and provides a total of 38 observed H,H-couplings including 31 long-range ((4-6)J) connectivities. The NMR data is consistent with the comparatively rigid alicyclic backbone predicted by molecular mechanics calculations, and forms the basis for (1)H NMR fingerprint analysis for the purpose of dereplication, purity analysis, and elucidation of structural analogs.

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Section: Introductionmentioning

confidence: 99%

Complete ¹H NMR spectral fingerprint of huperzine A

Niemitz

Laatikainen

Chen

et al. 2007

Magnetic Reson in Chemistry

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“…1) as AChE inhibitors have been reported recently [11,12,13]. The most potent compound has an inhibition constant (K I ) for human AChE of 26 pM, which means an anity around 1200 times higher than that of tacrine [14,15], making these compounds valuable candidates for the palliative treatment of Alzheimer's disease.…”

Section: Introductionmentioning

confidence: 99%

“…Free-energy (thermodynamic integration, TI) calculations carried out using this binding model re¯ected successfully the dierences in inhibitory activity for a small series of selected huprines [15,16]. These calcula- …”

Section: Introductionmentioning

confidence: 99%

How accurate can molecular dynamics/linear response and Poisson-Boltzmann/solvent accessible surface calculations be for predicting relative binding affinities? Acetylcholinesterase huprine inhibitors as a test case

Barril¹,

Gelpí²,

López³

et al. 2001

Theoretical Chemistry Accounts: Theory, Computation, and Modeli

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This study examines the accuracy of molecular dynamics-linear response (MD/LR) and Poisson± Boltzmann/solvent accessible surface (PB/SAS) calculations to predict relative binding anities. A series of acetylcholinesterase (AChE) huprine inhibitors has been chosen as a test system owing to the availability of freeenergy (thermodynamic integration) calculations. The results obtained with the MD/LR approach point out a clear relationship between the experimental anity and the electrostatic interaction energy alone for a subset of huprines, but the suitability of the MD/LR approach to predict the binding anity of the whole series of compounds is limited. On the other hand, PB/SAS calculations show a marked dependence on both the computational protocol and the nature of the inhibitor± enzyme complex.

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“…Compound 1c shows the best activity, suggesting that its chlorine substituent is able to mimic the carbonyl function of HA. However, the inhibition constants for the compounds tested are much lower than those reported for huperzine A (4.6 n) and huprine X (0.026 n), [16] hence these SAR deductions must be further scrutinised.…”

Section: Enzyme Kinetic Experimentsmentioning

confidence: 88%

Bridged 5,6,7,8‐Tetrahydro‐1,6‐naphthyridines, Analogues of Huperzine A: Synthesis, Modelling Studies and Evaluation as Inhibitors of Acetylcholinesterase

et al. 2009

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Derivatives of 6,8‐bridged 5,6,7,8‐tetrahydro‐1,6‐naphthyridines, designed as analogues of huperzine A, were synthesised and evaluated as inhibitors of acetylcholinesterase. In a first approach, C3‐bridged naphthyridines were constructed by internal nucleophilic aromatic substitution of 2‐chloro‐3‐(1‐piperidinylmethyl)pyridine precursors containing a 3‐CO2Me group on the 1‐piperidinyl ring moiety. Alternatively, ring‐closing metathesis on 6,8‐diallyl‐substituted tetrahydro‐1,6‐naphthyridines was applied to construct an unsaturated C4 bridge. Some of the target compounds showed inhibition of acetylcholinesterase but lower than that of huperzine A. The relative order of inhibition activities could be rationalised by comparative docking simulation studies on the basis of the known crystal structure of the acetylcholinesterase–huperzine A complex.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

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New Syntheses of rac-Huperzine A and its rac-7-Ethyl-Derivative. Evaluation of Several Huperzine A Analogues as Acetylcholinesterase Inhibitors

Cited by 21 publications

References 32 publications

Complete ¹H NMR spectral fingerprint of huperzine A

Complete ¹H NMR spectral fingerprint of huperzine A

How accurate can molecular dynamics/linear response and Poisson-Boltzmann/solvent accessible surface calculations be for predicting relative binding affinities? Acetylcholinesterase huprine inhibitors as a test case

Bridged 5,6,7,8‐Tetrahydro‐1,6‐naphthyridines, Analogues of Huperzine A: Synthesis, Modelling Studies and Evaluation as Inhibitors of Acetylcholinesterase

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New Syntheses of rac-Huperzine A and its rac-7-Ethyl-Derivative. Evaluation of Several Huperzine A Analogues as Acetylcholinesterase Inhibitors

Cited by 21 publications

References 32 publications

Complete 1H NMR spectral fingerprint of huperzine A

Complete 1H NMR spectral fingerprint of huperzine A

How accurate can molecular dynamics/linear response and Poisson-Boltzmann/solvent accessible surface calculations be for predicting relative binding affinities? Acetylcholinesterase huprine inhibitors as a test case

Bridged 5,6,7,8‐Tetrahydro‐1,6‐naphthyridines, Analogues of Huperzine A: Synthesis, Modelling Studies and Evaluation as Inhibitors of Acetylcholinesterase

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Complete ¹H NMR spectral fingerprint of huperzine A

Complete ¹H NMR spectral fingerprint of huperzine A