Evaluation of short-tether Bis-THA AChE inhibitors. A further test of the dual binding site hypothesis

Carlier, Paul R.; Han, Yifan; Chow, Ella; Li, Crystal P.L.; Wang, Hong; Lieu, Thuy Xuan; Wong, Hau Sum; Pang, Yuan Ping

doi:10.1016/s0968-0896(98)00213-2

Cited by 153 publications

(115 citation statements)

References 12 publications

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“…MV006172 was shown to have moderate activity against the liver stage of Plasmodium yoelii (30), and this compound was also found to bind to the recombinant human ␣-2C adrenergic receptor (51). MMV019555 is a dimeric molecule that was originally explored as an acetylcholinesterase inhibitor (52). A search of the Malaria Box revealed three other 9-aminoacridines (MMV000304, MMV000448, and MMV 006513) and no additional 9-amino-tetrahydroacridines (Fig.…”

Section: Discussionmentioning

confidence: 99%

Antiapicoplast and Gametocytocidal Screening To Identify the Mechanisms of Action of Compounds within the Malaria Box

Bowman

Merino

Brooks

et al. 2014

Antimicrob Agents Chemother

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129

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cMalaria remains a significant infectious disease that causes millions of clinical cases and >800,000 deaths per year. The Malaria Box is a collection of 400 commercially available chemical entities that have antimalarial activity. The collection contains 200 drug-like compounds, based on their oral absorption and the presence of known toxicophores, and 200 probe-like compounds, which are intended to represent a broad structural diversity. These compounds have confirmed activities against the asexual intraerythrocytic stages of Plasmodium falciparum and low cytotoxicities, but their mechanisms of action and their activities in other stages of the parasite's life cycle remain to be determined. The apicoplast is considered to be a promising source of malaria-specific targets, and its main function during intraerythrocytic stages is to provide the isoprenoid precursor isopentenyl diphosphate, which can be used for phenotype-based screens to identify compounds targeting this organelle. We screened 400 compounds from the Malaria Box using apicoplast-targeting phenotypic assays to identify their potential mechanisms of action. We identified one compound that specifically targeted the apicoplast. Further analyses indicated that the molecular target of this compound may differ from those of the current antiapicoplast drugs, such as fosmidomycin. Moreover, in our efforts to elucidate the mechanisms of action of compounds from the Malaria Box, we evaluated their activities against other stages of the life cycle of the parasite. Gametocytes are the transmission stage of the malaria parasite and are recognized as a priority target in efforts to eradicate malaria. We identified 12 compounds that were active against gametocytes with 50% inhibitory concentration values of <1 M.

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Section: Discussionmentioning

confidence: 99%

Antiapicoplast and Gametocytocidal Screening To Identify the Mechanisms of Action of Compounds within the Malaria Box

Bowman

Merino

Brooks

et al. 2014

Antimicrob Agents Chemother

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129

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“…1-4 were docked into the active site of the enzyme. The resulting poses were critically investigated targeting the ones including π-π interactions between a compound and aromatic amino acids of PAS and choline binding sites -a type of interaction typical of enzyme-inhibitor/reactivator complex observed by X-ray crystallography for both AChE and BChE [12,[18][19][20][21][22][23]28,56,57]. Poses that had fulfilled these criteria were chosen for the prediction of key interactions between the compound and the enzyme summarized in Table 2.…”

Section: Molecular Modelingmentioning

confidence: 99%

“…bistacrine, K d of 250 nmol/L in fetal bovine serum AChE) [12,13] and non-symmetrical tacrine analogues (e.g. syn-TZ2PA6, K d of 0.41 nmol/L in mouse AChE) [14,15], as well as donepezil (K d in hAChE of 3.35 nmol/L (R-donepezil), 17.5 nmol/L (S-donepezil)) an anti-AD drug that binds with a basic nitrogen in the CAS and an aromatic system in the PAS [16,17].…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of N-substituted-2-hydroxyiminoacetamides and interactions with cholinesterases

Maraković

Knežević

Vinković

et al. 2016

Chemico-Biological Interactions

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Within this study, we designed and synthesized four new oxime compounds of the N-substituted 2-hydroxyiminoacetamide structure and evaluated their interactions with acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Our aim was to explore the possibility of extending the dual-binding mode of interaction between the enzyme and the inhibitor to a so-called triple-binding mode of interaction through the introduction of an additional binding moiety. N-substituted 2-hydroxyiminoacetamide 1 was prepared via BOP catalyzed amidation of hydroxyiminoacetic acid with 3-azido-1-phenylpropylamine. An azide group enabled us to prepare more elaborate structures 2 -4 by the copper-catalyzed azide-alkyne cycloaddition. The new compounds 1 -4 differed in their presumed AChE peripheral site binding moiety, which ranged from an azide group to functionalized heterocycles.Molecular docking studies revealed that all three binding moieties are involved in the non-covalent interactions with ChEs for all of the four compounds, albeit not always in the complete accordance with the proposed hypothesis. All of the four compounds reversibly inhibited the ChEs with their inhibition potency increasing in the same order for both enzymes (1 < 2 < 4 < 3). A higher preference for binding to BChE (K i from 0.30 μmol/L to 130 μmol/L) over AChE (K i from 50 μmol/L to 1200 μmol/L) was observed for all of the compounds.

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“…Following the general procedure, ethyl 6-chloro-5-cyano-2-methyl-4-phenylnicotinate (22) 41 (100 mg, 0.33 mmol), triethylamine (0.9 mL, 6.46 mmol), commercial 4-amino-1-benzylpiperidine (23) (0.08 mL, 0.38 mmol), in THF/EtOH 3:1 (v/v) (4 mL), after 25 h, followed by flash chromatography (n-hexane/ethyl acetate 40%), afforded compound 14 (100 mg, 66% Ethyl 6-((1-Benzylpiperidin-4-yl)methylamino)-5-cyano-2-methyl-4-phenylnicotinate (15). Following the general procedure, ethyl 6-chloro-5-cyano-2-methyl-4-phenylnicotinate (22) 41 (84 mg, 0.28 mmol), triethylamine (0.47 mL, 3.37 mmol), (1-benzylpiperidin-4-yl)methanamine (24) 42 (67 mg Ethyl 6-(3-(1-Benzylpiperidin-4-yl)propylamino)-5-cyano-2-methyl-4-phenylnicotinate (17).…”

Section: ■ Methodsmentioning

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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Evaluation of short-tether Bis-THA AChE inhibitors. A further test of the dual binding site hypothesis

Cited by 153 publications

References 12 publications

Antiapicoplast and Gametocytocidal Screening To Identify the Mechanisms of Action of Compounds within the Malaria Box

Antiapicoplast and Gametocytocidal Screening To Identify the Mechanisms of Action of Compounds within the Malaria Box

Design and synthesis of N-substituted-2-hydroxyiminoacetamides and interactions with cholinesterases

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

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