4-Aryl-4-oxo-N-phenyl-2-aminylbutyramides as acetyl- and butyrylcholinesterase inhibitors. Preparation, anticholinesterase activity, docking study, and 3D structure–activity relationship based on molecular interaction fields

Vitorović-Todorović, Maja D.; Juranić, Ivan O.; Mandić, Ljuba M.; Drakulić, Branko J.

doi:10.1016/j.bmc.2009.12.042

Cited by 23 publications

(12 citation statements)

References 49 publications

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“…β‐aroyl acrylic acid and its derivatives represent one of the most active classes of compounds possess a wide spectrum of biological activity. Many of these compounds have been used for the treatment of various diseases, such as Alzheimer's disease and exhibit a broad spectrum of physiological (fungicidal, antitumor, hypotensive, hypolipidemic, and antibacterial) activities . In the present work, synthesis of some β‐aroyl acrylic acid and their derivatives were reported.…”

Section: Applicationmentioning

confidence: 92%

“…Recently, β–aroylacrylic acid derivatives showed high biological activity and exhibited a broad spectrum of physiological (fungicidal, antitumor, hypotensive, hypolipedemic, and antibacterial) activities and in recovery of Alzheimer's disease. Beside that, β‐aroylacrylic acids were considered as inhibitors for phospholipase and they have antiproliferative activity against human cervix carcinoma (Hela cells) . In another side, β‐aroylacrylic esters are important intermediates in field of medical science and agrochemicals .…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of Novel Heterocyclic Compounds with Expected Antibacterial Activities from 4‐(4‐Bromophenyl)‐4‐oxobut‐2‐enoic Acid

El‐Hashash

Soliman

Bakeer

et al. 2014

Journal of Heterocyclic Chem

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Section: Applicationmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Synthesis of Novel Heterocyclic Compounds with Expected Antibacterial Activities from 4‐(4‐Bromophenyl)‐4‐oxobut‐2‐enoic Acid

El‐Hashash

Soliman

Bakeer

et al. 2014

Journal of Heterocyclic Chem

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“…unchanged [22]. Alkyl substituted congeners inhibited both AChE and BChE in micromolar concentrations, while chloro-or methoxy-substituted compounds were proved as inactive.…”

Section: Accepted Manuscriptmentioning

confidence: 93%

“…Inhibition potency of the compounds 1-38 toward AChE and BChE, given as IC 50 values, are shown in Table 1, along with potency data of the previously published congeners having unsubstituted phenylamido moiety (1a-9a) [22]. Due to limited solubility of some derivatives, we were unable to obtain entire dose-response curve (spanning range of 20-80% of the enzyme activity inhibition).…”

Section: Structure-activity Relationshipsmentioning

confidence: 99%

Structural modifications of 4-aryl-4-oxo-2-aminylbutanamides and their acetyl- and butyrylcholinesterase inhibitory activity. Investigation of AChE–ligand interactions by docking calculations and molecular dynamics simulations

Vitorović-Todorović¹,

Koukoulitsa²,

Juranić³

et al. 2014

European Journal of Medicinal Chemistry

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Congeneric set of thirty-eight 4-aryl-4-oxo-2-(N-aryl/cycloalkyl)butanamides has been designed, synthesized and evaluated for acetyl- and butyrylcholinesterase inhibitory activity. Structural variations included cycloalkylamino group attached to C2 position of butanoyl moiety, and variation of amido moiety of molecules. Twelve compounds, mostly piperidino and imidazolo derivatives, inhibited AChE in low micromolar range, and were inactive toward BChE. Several N-methylpiperazino derivatives showed inhibition of BChE in low micromolar or submicromolar concentrations, and were inactive toward AChE. Therefore, the nature of the cycloalkylamino moiety governs the AChE/BChE selectivity profile of compounds. The most active AChE inhibitor showed mixed-type inhibition modality, indicating its binding to free enzyme and to enzyme-substrate complex. Thorough docking calculations of the seven most potent AChE inhibitors from the set, showed that the hydrogen bond can be formed between amide -NH- moiety of compounds and -OH group of Tyr 124. The 10 ns unconstrained molecular dynamic simulation of the AChE-compound 18 complex shows that this interaction is the most persistent. This is, probably, the major anchoring point for the binding.

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“…BChE is the sole carboxylesterase [6,7] with recognized toxicological and pharmacological importance in scavenging and detoxification of numerous ester-containing drugs, prodrugs [8,9] , and poisonous carbamyl-and phosphoryl-esters, including nerve agents [10,11] . Currently, BChE is emerging as an important pharmacological target in Alzheimer's disease (AD) therapy [12] . A 40%-90% increase in BChE expression and activity have been found in AD brain neuronal plaques [13] .…”

Section: Introductionmentioning

confidence: 99%

Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors

Sakkiah

Lee

2012

Acta Pharmacol Sin

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Aim: To identify the critical chemical features, with reliable geometric constraints, that contributes to the inhibition of butyrylcholinesterase (BChE) function. Methods: Ligand-based pharmacophore modeling was used to identify the critical chemical features of BChE inhibitors. The generated pharmacophore model was validated using various techniques, such as Fischer's randomization method, test set, and decoy set. The best pharmacophore model was used as a query in virtual screening to identify novel scaffolds that inhibit BChE. Compounds selected by the best hypothesis in the virtual screening were tested for drug-like properties, and molecular docking study was applied to determine the optimal orientation of the hit compounds in the BChE active site. To find the reactivity of the hit compounds, frontier orbital analysis was carried out using density functional theory. Results: Based on its correlation coefficient (0.96), root mean square (RMS) deviation (1.01), and total cost (105.72), the quantitative hypothesis Hypo1 consisting of 2 HBA, 1 Hy-Ali, and 1 Hy-Ar was selected as the best hypothesis. Thus, Hypo1 was used as a 3D query in virtual screening of the Maybridge and Chembridge databases. The hit compounds were filtered using ADMET, Lipinski's Rule of Five, and molecular docking to reduce the number of false positive results. Finally, 33 compounds were selected based on their critical interactions with the significant amino acids in BChE's active site. To confirm the inhibitors' potencies, the orbital energies, such as HOMO and LUMO, of the hit compounds and 7 training set compounds were calculated. Among the 33 hit compounds, 10 compounds with the highest HOMO values were selected, and this set was further culled to 5 compounds based on their energy gaps important for stability and energy transfer. From the overall results, 5 hit compounds were confirmed to be potential BChE inhibitors that satisfied all the pharmacophoric features in Hypo1. Conclusion: This study pinpoints important chemical features with geometric constraints that contribute to the inhibition of BChE activity. Five compounds are selected as the best hit BchE-inhibitory compounds.

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4-Aryl-4-oxo-N-phenyl-2-aminylbutyramides as acetyl- and butyrylcholinesterase inhibitors. Preparation, anticholinesterase activity, docking study, and 3D structure–activity relationship based on molecular interaction fields

Cited by 23 publications

References 49 publications

Synthesis of Novel Heterocyclic Compounds with Expected Antibacterial Activities from 4‐(4‐Bromophenyl)‐4‐oxobut‐2‐enoic Acid

Synthesis of Novel Heterocyclic Compounds with Expected Antibacterial Activities from 4‐(4‐Bromophenyl)‐4‐oxobut‐2‐enoic Acid

Structural modifications of 4-aryl-4-oxo-2-aminylbutanamides and their acetyl- and butyrylcholinesterase inhibitory activity. Investigation of AChE–ligand interactions by docking calculations and molecular dynamics simulations

Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors

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