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An expedient synthesis, acetylcholinesterase inhibitory activity, and molecular modeling study of highly functionalized hexahydro-1,6-naphthyridines.

Almansour AI, Kumar RS, Arumugam N, Basiri A, Kia Y, Ali MA - Biomed Res Int (2015)

Bottom Line: A series of hexahydro-1,6-naphthyridines were synthesized in good yields by the reaction of 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones with cyanoacetamide in the presence of sodium ethoxide under simple mixing at ambient temperature for 6-10 minutes and were assayed for their acetylcholinesterase (AChE) inhibitory activity using colorimetric Ellman's method.Compound 4e with methoxy substituent at ortho-position of the phenyl rings displayed the maximum inhibitory activity with IC50 value of 2.12 μM.Molecular modeling simulation of 4e was performed using three-dimensional structure of Torpedo californica AChE (TcAChE) enzyme to disclose binding interaction and orientation of this molecule into the active site gorge of the receptor.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.

ABSTRACT
A series of hexahydro-1,6-naphthyridines were synthesized in good yields by the reaction of 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones with cyanoacetamide in the presence of sodium ethoxide under simple mixing at ambient temperature for 6-10 minutes and were assayed for their acetylcholinesterase (AChE) inhibitory activity using colorimetric Ellman's method. Compound 4e with methoxy substituent at ortho-position of the phenyl rings displayed the maximum inhibitory activity with IC50 value of 2.12 μM. Molecular modeling simulation of 4e was performed using three-dimensional structure of Torpedo californica AChE (TcAChE) enzyme to disclose binding interaction and orientation of this molecule into the active site gorge of the receptor.

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Synthesis of naphthyridines (4a–k).
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sch1: Synthesis of naphthyridines (4a–k).

Mentions: In the present investigation, the reaction of a series of bisarylmethylidene piperidones with 2-cyanoacetamide in the presence of sodium ethoxide with few drops of ethanol under simple mixing at ambient temperature for 6–10 min afforded functionalized 1,6-naphthyridines in good yields (65–78%; Scheme 1). The prerequisite bisarylmethylidene piperidones were synthesized following the literature reported method [28]. In a typical reaction, an equimolar mixture of 3,5-bis[(E)-2-methylphenylmethylidene]tetrahydro-4(1H)-pyridinones (2b) and 2-cyanoacetamide (3) in catalytic amount of sodium ethoxide were ground well in a semimicro boiling tube with few drops of ethanol at ambient temperature for about 7 min and after completion of the reaction water was added to the mixture and the product was filtered and dried in vacuo. In this case, the 2-pyridone was obtained as a sole reaction product and does not require column chromatography for purification. Easy availability of the reagents, short reaction time, and simple reaction condition rendered this method more attractive from the viewpoint of green chemistry.


An expedient synthesis, acetylcholinesterase inhibitory activity, and molecular modeling study of highly functionalized hexahydro-1,6-naphthyridines.

Almansour AI, Kumar RS, Arumugam N, Basiri A, Kia Y, Ali MA - Biomed Res Int (2015)

Synthesis of naphthyridines (4a–k).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4325472&req=5

sch1: Synthesis of naphthyridines (4a–k).
Mentions: In the present investigation, the reaction of a series of bisarylmethylidene piperidones with 2-cyanoacetamide in the presence of sodium ethoxide with few drops of ethanol under simple mixing at ambient temperature for 6–10 min afforded functionalized 1,6-naphthyridines in good yields (65–78%; Scheme 1). The prerequisite bisarylmethylidene piperidones were synthesized following the literature reported method [28]. In a typical reaction, an equimolar mixture of 3,5-bis[(E)-2-methylphenylmethylidene]tetrahydro-4(1H)-pyridinones (2b) and 2-cyanoacetamide (3) in catalytic amount of sodium ethoxide were ground well in a semimicro boiling tube with few drops of ethanol at ambient temperature for about 7 min and after completion of the reaction water was added to the mixture and the product was filtered and dried in vacuo. In this case, the 2-pyridone was obtained as a sole reaction product and does not require column chromatography for purification. Easy availability of the reagents, short reaction time, and simple reaction condition rendered this method more attractive from the viewpoint of green chemistry.

Bottom Line: A series of hexahydro-1,6-naphthyridines were synthesized in good yields by the reaction of 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones with cyanoacetamide in the presence of sodium ethoxide under simple mixing at ambient temperature for 6-10 minutes and were assayed for their acetylcholinesterase (AChE) inhibitory activity using colorimetric Ellman's method.Compound 4e with methoxy substituent at ortho-position of the phenyl rings displayed the maximum inhibitory activity with IC50 value of 2.12 μM.Molecular modeling simulation of 4e was performed using three-dimensional structure of Torpedo californica AChE (TcAChE) enzyme to disclose binding interaction and orientation of this molecule into the active site gorge of the receptor.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.

ABSTRACT
A series of hexahydro-1,6-naphthyridines were synthesized in good yields by the reaction of 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones with cyanoacetamide in the presence of sodium ethoxide under simple mixing at ambient temperature for 6-10 minutes and were assayed for their acetylcholinesterase (AChE) inhibitory activity using colorimetric Ellman's method. Compound 4e with methoxy substituent at ortho-position of the phenyl rings displayed the maximum inhibitory activity with IC50 value of 2.12 μM. Molecular modeling simulation of 4e was performed using three-dimensional structure of Torpedo californica AChE (TcAChE) enzyme to disclose binding interaction and orientation of this molecule into the active site gorge of the receptor.

Show MeSH
Related in: MedlinePlus