Potent acetylcholinesterase inhibitors: design, synthesis, and structure–Activity relationships of bis-interacting ligands in the galanthamine series

Mary, Aude; Renko, Dolor; Guillou, Catherine; Thal, C.

doi:10.1016/s0968-0896(98)00133-3

Cited by 103 publications

(57 citation statements)

References 12 publications

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“…For sake of comparison, the activity of tacrine was also determined. The IC 50 values of tacrine reported in the literature [22,23,24,25] vary between 0.0098 and 0.05 µM. The value determined here falls in the same range (see Table 1b).…”

Section: Inhibition Of Achesupporting

confidence: 76%

Synthesis, Biological Activity, and Docking Studies of New Acetylcholinesterase Inhibitors of the Bispyridinium Type

Kapková

Stiefl

Sürig

et al. 2003

Archiv der Pharmazie

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A novel series of acetylcholinesterase (AChE) inhibitors of the bispyridinium type was synthesized and the inhibitory activity against AChE and butyrylcholinesterase (BChE) measured. In essence, the substitution pattern influenced the inhibitory potency against AChE, where the most active bispyridiniumoxime (TMB-4) was bisbenzyl substituted followed by monobenzyl substituted, bismethyl substituted, and unsubstituted derivatives of TMB-4. Hence, the bisbenzyl ether of TMB-4 was further investigated. In order to obtain diverse lipophilic and electronic properties for these bisbenzyl bispyridinium derivatives (so-called DUO series), the lateral ring substitution was systematically varied. The lowest IC(50) value against AChE found thus far in the DUO series was 0.34 microM. Docking studies were carried out to elucidate the differences in biological activity. A general binding mode for nearly all compounds could be identified by these investigations. In this binding mode, the docked ligands span the narrow, deeply buried active-site gorge, interacting with Trp84 at the bottom of the gorge, Tyr334 or Phe331 halfway down the gorge, and Trp279 at the peripheral anionic site at the mouth of the gorge. For specific ligands, additional interactions were found which helped to explain their deviating activity. Based on the promising characteristics of the novel acetylcholinesterase inhibitors presented, a series of structurally related, optimized candidates will be developed.

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Section: Inhibition Of Achesupporting

confidence: 76%

Synthesis, Biological Activity, and Docking Studies of New Acetylcholinesterase Inhibitors of the Bispyridinium Type

Kapková

Stiefl

Sürig

et al. 2003

Archiv der Pharmazie

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“…The length of the linker for the most potent EeAChE inhibitors varies from two to four methylene units. The most potent and selective inhibitor was ethyl 6-(2-(1-benzylpiperidin-4-yl)ethylamino)-5-cyano-2-methyl-4-phenylnicotinate (16) 51 The inhibitory activities of the hybrids were compared to those determined for the parent compound, donepezil. 42 Unfortunately, compound 14 was not soluble; thus, biological assessment was not possible.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Synthesis, Pharmacological Assessment, and Molecular Modeling of Acetylcholinesterase/Butyrylcholinesterase Inhibitors: Effect against Amyloid-β-Induced Neurotoxicity

Silva

Chioua

Samadi

et al. 2013

ACS Chem. Neurosci.

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ABSTRACT:The synthesis, molecular modeling, and pharmacological analysis of phenoxyalkylamino-4-phenylnicotinates (2−7), phenoxyalkoxybenzylidenemalononitriles (12, 13), pyridonepezils (14−18), and quinolinodonepezils (19−21) are described. Pyridonepezils 15−18 were found to be selective and moderately potent regarding the inhibition of hAChE, whereas quinolinodonepezils 19−21 were found to be poor inhibitors of hAChE. The most potent and selective hAChE inhibitor was ethyl 6-(4-(1-benzylpiperidin-4-yl)butylamino)-5-cyano-2-methyl-4-phenylnicotinate (18) [IC 50 (hAChE) = 0.25 ± 0.02 μM]. Pyridonepezils 15−18 and quinolinodonepezils 20−21 are more potent selective inhibitors of EeAChE than hAChE. The most potent and selective EeAChE inhibitor was ethyl 6-(2-(1-benzylpiperidin-4-yl)ethylamino)-5-cyano-2-methyl-4-phenylnicotinate (16) [IC 50 (EeAChE) = 0.0167 ± 0.0002 μM], which exhibits the same inhibitory potency as donepezil against hAChE. Compounds 2, 7, 13, 17, 18, 35, and 36 significantly prevented the decrease in cell viability caused by Aβ 1−42 . All compounds were effective in preventing the enhancement of AChE activity induced by Aβ 1−42 . Compounds 2−7 caused a significant reduction whereas pyridonepezils 17 and 18, and compound 16 also showed some activity . The pyrazolo [3,4-b]quinolines 36 and 38 also prevented the upregulation of AChE induced by Aβ 1−42 . Compounds 2, 7, 12, 13, 17, 18, and 36 may act as antagonists of voltage sensitive calcium channels, since they significantly prevented the Ca 2+ influx evoked by KCl depolarization. Docking studies show that compounds 16 and 18 adopted different orientations and conformations inside the active-site gorges of hAChE and hBuChE. The structural and energetic features of the 16-AChE and 18-AChE complexes compared to the 16-BuChE and 18-BuChE complexes account for a higher affinity of the ligand toward AChE. The present data indicate that compounds 2, 7, 17, 18, and 36 may represent attractive multipotent molecules for the potential treatment of Alzheimer's disease.

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“…To overcome this problem, milder reaction conditions were developed [NBS, AIBN (10 mol%), CCl 4 , 258C]. [24] This protocol is indeed more selective than I 2 /KOAc. However, the oxidation occurs quite slowly.…”

Section: Iminium Salt Formationmentioning

confidence: 99%

Enantioselective Olefin Epoxidation using Axially Chiral Biaryl Azepinium Salts as Catalysts. Rapid in‐situ Screening and Origin of the Stereocontrol

2008

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To unravel the origin of the stereocontrol in epoxidation reactions of unfunctionalized alkenes by diastereomeric biaryl oxaziridinium salts, two series of novel iminium cations were prepared. These moieties combine (R a )-dimethylbiphenyl or (R a )-5,5 ',6,6',7,7',8,8'-octahydrobinaphthyl cores with chiral exocyclic appendages derived from commercially available (S)-or (R)-3,3-dimethylbutan-2-amine and (S)-or (R)-1-phenylpropan-1-amine. Under biphasic enantioselective olefin epoxidation conditions, in-situ generated bromide salts of these derivatives have displayed similar or better asymmetric efficiency than the classical binaphthyl derivatives. A structural analysis was performed in search of a correlation between the origin of the stereocontrol/level of enantioselectivity in the products, and dihedral angles around the biaryl twist of the catalysts.

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Potent acetylcholinesterase inhibitors: design, synthesis, and structure–Activity relationships of bis-interacting ligands in the galanthamine series

Cited by 103 publications

References 12 publications

Synthesis, Biological Activity, and Docking Studies of New Acetylcholinesterase Inhibitors of the Bispyridinium Type

Synthesis, Biological Activity, and Docking Studies of New Acetylcholinesterase Inhibitors of the Bispyridinium Type

Synthesis, Pharmacological Assessment, and Molecular Modeling of Acetylcholinesterase/Butyrylcholinesterase Inhibitors: Effect against Amyloid-β-Induced Neurotoxicity

Enantioselective Olefin Epoxidation using Axially Chiral Biaryl Azepinium Salts as Catalysts. Rapid in‐situ Screening and Origin of the Stereocontrol

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