Discovery of a novel tetrahydroacridine acetylcholinesterase inhibitor through an indexed combinatorial library

Pirrung, Michael C.; Chau, Joseph H.-L.; Chen, Jrlung

doi:10.1016/1074-5521(95)90127-2

Cited by 39 publications

(14 citation statements)

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“…Since the paper of Steinberg et al on noncovalent AChE inhibitors related to 9-amino-1,2,3,4-tetrahydroacridine, 7 only few articles have been published dealing with structural modifications of tacrine [8][9][10][11][12][13]15 or with bis-tetrahydroacridine derivatives. 5 In our comparative QSAR paper published in 1997, 14 we pointed Figure 2.…”

Section: Discussionmentioning

confidence: 99%

SAR of 9-Amino-1,2,3,4-tetrahydroacridine-Based Acetylcholinesterase Inhibitors: Synthesis, Enzyme Inhibitory Activity, QSAR, and Structure-Based CoMFA of Tacrine Analogues

et al. 2000

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In this study, we attempted to derive a comprehensive SAR picture for the class of acetylcholinesterase (AChE) inhibitors related to tacrine, a drug currently in use for the treatment of the Alzheimer's disease. To this aim, we synthesized and tested a series of 9-amino-1,2,3,4-tetrahydroacridine derivatives substituted in the positions 6 and 7 of the acridine nucleus and bearing selected groups on the 9-amino function. By means of the Hansch approach, QSAR equations were obtained, quantitatively accounting for both the detrimental steric effect of substituents in position 7 and the favorable electron-attracting effect exerted by substituents in positions 6 and 7 of the 9-amino-1,2,3,4-tetrahydroacridine derivatives. The three-dimensional (3D) properties of the inhibitors were taken into consideration by performing a CoMFA analysis on the series of AChE inhibitors made by 12 9-amino-1,2,3, 4-tetrahydroacridines and 13 11H-indeno[1,2-b]quinolin-10-ylamines previously developed in our laboratory. The alignment of the molecules to be submitted to the CoMFA procedure was carried out by taking advantage of docking models calculated for the interactions of both the unsubstituted 9-amino-1,2,3,4-tetrahydroacridine and 11H-indeno[1,2-b]quinolin-10-ylamine with the target enzyme. A highly significant CoMFA model was obtained using the steric field alone, and the features of such a 3D QSAR model were compared with the classical QSAR equations previously calculated. The two models appeared consistent, the main aspects they had in common being (a) the individuation of the strongly negative contribution of the substituents in position 7 of tacrine and (b) a tentative assignment of the hydrophobic character to the favorable effect exerted by the substituents in position 6. Finally, a new previously unreported tacrine derivative designed on the basis of both the classical and the 3D QSAR equations was synthesized and kinetically evaluated, to test the predictive ability of the QSAR models. The 6-bromo-9-amino-1,2,3,4-tetrahydroacridine was predicted to have a pIC(50) value of 7.31 by the classical QSAR model and 7.40 by the CoMFA model, while its experimental IC(50) value was equal to 0.066 (+/-0.009) microM, corresponding to a pIC(50) of 7.18, showing a reasonable agreement between predicted and observed AChE inhibition data.

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Section: Discussionmentioning

confidence: 99%

SAR of 9-Amino-1,2,3,4-tetrahydroacridine-Based Acetylcholinesterase Inhibitors: Synthesis, Enzyme Inhibitory Activity, QSAR, and Structure-Based CoMFA of Tacrine Analogues

et al. 2000

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“…A method similar to the deconvolution by positional scanning was developed independently by PIRRUNG [90], [91] and D ePREZ [92]. This method has been termed orthogonal library approach or indexed library approach by other authors [100].…”

Section: Deconvolution By Orthogonal Librariesmentioning

confidence: 99%

“…Three deconvolution strategies can be used for the structural determination of the biologically most active compounds in a combinatorial library comprising mixtures of up to several thousand compounds: (1) iterative deconvolution [27], [86], (2) deconvolution by positional scanning [87][88][89], or (3) deconvolution by orthogonal libraries [90][91][92].…”

Section: Deconvolutionmentioning

confidence: 99%

Combinatorial Chemistry

Tiebes

Peters

2000

Ullmann's Encyclopedia of Industrial Chemistry

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The article contains sections titled: 1. Introduction 2. Concept of Combinatorial Chemistry 3. Methods and Techniques of Combinatorial Synthesis 3.1. Synthetic Strategies Towards Combinatorial Libraries 3.1.1. Split ‐ Pool Synthesis Towards Combinatorial Libraries 3.1.1.1. Techniques using Resin Beads 3.1.1.2. Tea‐Bag Method 3.1.2. Parallel Synthesis Towards Combinatorial Libraries 3.1.2.1. Reaction Apparatus using Resin Beads 3.1.2.2. Multipin Technique 3.1.2.3. Spatially Addressable Parallel Synthesis on Silica Wafer 3.1.3. Reagent Mixture Synthesis Towards Combinatorial Libraries 3.2. Synthetic Methodology for Organic Library Construction 3.2.1. Solid‐Phase Organic Synthesis 3.2.1.1. Solid Support, Linker, and Cleavage Strategies 3.2.1.2. Reaction Portfolio 3.2.2. Synthesis in Solution and Liquid‐Phase Synthesis 4. Characterization of Combinatorial Libraries 4.1. Analytical Characterization 4.2. Hit Identification in Combinatorial Libraries by High‐Throughput Screening 4.2.1. Strategies for Libraries of Compound Mixtures 4.2.1.1. On‐Bead Screening 4.2.1.2. Deconvolution 4.2.1.2.1. Iterative Deconvolution 4.2.1.2.2. Deconvolution by Positional Scanning 4.2.1.2.3. Deconvolution by Orthogonal Libraries 4.2.1.3. Encoding 4.2.1.4. Multiple Cleavable Linkers 4.2.2. Strategies for Libraries of Separate Single Compounds 4.2.3. Conclusion 5. Automation and Data Processing 5.1. Synthesis Automation and Data Processing 5.2. Automated Purification 6. Library Design and Diversity Assessment 6.1. Diversity Assessment for Selection of Building Blocks or Compound 6.2. Iterative Optimization Methods 7. Economic Aspects and Industrial Case Studies 8. Further Developments 8.1. Combinatorial Chemistry and Catalysis 8.2. Combinatorial Chemistry and Material Science

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“…Tetrahydroacridine, containing a partially hydrogenated ring, is another privileged scaffold which showed interesting biological activities [48][49][50][51][52][53][54]. As a typical example, 9-amino-1,2,3,4tetrahydroacridine or tacrine was the first drug approved for the treatment of Alzheimer's disease [55][56][57].…”

Section: Introductionmentioning

confidence: 99%

2,4-Bis(arylethynyl)-9-chloro-5,6,7,8-tetrahydroacridines: synthesis and photophysical properties

Tka¹,

Ayed²,

Braiek³

et al. 2021

Beilstein J. Org. Chem.

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Acridine derivatives have attracted considerable interest in numerous areas owing to their attractive physical and chemical properties. Herein, starting from readily available anthranilic acid, an efficient synthesis of 2,4-bis(arylethynyl)-9-chloro-5,6,7,8-tetrahydroacridine derivatives was accomplished via a one-pot double Sonogashira cross-coupling method. The UV-visible absorption and emission properties of the synthesized molecules have been examined. Additionally, theoretical studies based on density functional theory (DFT/B3LYP/6-31G(d)) were carried out.

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Discovery of a novel tetrahydroacridine acetylcholinesterase inhibitor through an indexed combinatorial library

Abstract: In this work, we have provided a relatively rare example of carbon-carbon bond formation in a pool synthesis and have discovered a potentially useful acetylcholinesterase inhibitor.

Cited by 39 publications

References 10 publications

SAR of 9-Amino-1,2,3,4-tetrahydroacridine-Based Acetylcholinesterase Inhibitors: Synthesis, Enzyme Inhibitory Activity, QSAR, and Structure-Based CoMFA of Tacrine Analogues

SAR of 9-Amino-1,2,3,4-tetrahydroacridine-Based Acetylcholinesterase Inhibitors: Synthesis, Enzyme Inhibitory Activity, QSAR, and Structure-Based CoMFA of Tacrine Analogues

Combinatorial Chemistry

2,4-Bis(arylethynyl)-9-chloro-5,6,7,8-tetrahydroacridines: synthesis and photophysical properties

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