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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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Related in: MedlinePlus

Binding interaction of 4e with active site of AChE receptor. (Hydrogen atoms are not shown for clarity.)
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Related In: Results  -  Collection


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fig1: Binding interaction of 4e with active site of AChE receptor. (Hydrogen atoms are not shown for clarity.)

Mentions: The most active AChE inhibitor, 4e, was docked into the active site of AChE enzyme derived from crystal structure of Torpedo californica AChE (TcAChE). The docking analysis revealed that this compound is properly inserted into the active site of AChE enzyme with free binding energy of 8.71 kcal/mol and strongly bound to the residues comprising aromatic side chains such as Tyr70 (H-bonding 1.16 Å), Tyr121 (hydrophobic), Tyr334 (hydrophobic) at peripheral anionic site as well as Phe330 (hydrophobic), and Trp84 (π,π-stacking) at choline binding site of the enzyme (Figure 1). 4e also exhibited mild polar interaction with Gly116 and Gly117 at oxyanion hole of the AChE enzyme. The crystal structure of the TcAChE in complex with available AD drugs such as galantamine and huperzine A showed similar interactions with residues composing peripheral anionic site along with stacking against Trp84 at bottom of the gorge. It seems that the presence of methoxy group in 4e has notable influence on proper positioning of this compound in AChE active site. This orientation effectively avoids insertion and hydrolysis of substrate inside the AChE active site channel and completely coincides with the activity observed for this compound.


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)

Binding interaction of 4e with active site of AChE receptor. (Hydrogen atoms are not shown for clarity.)
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Binding interaction of 4e with active site of AChE receptor. (Hydrogen atoms are not shown for clarity.)
Mentions: The most active AChE inhibitor, 4e, was docked into the active site of AChE enzyme derived from crystal structure of Torpedo californica AChE (TcAChE). The docking analysis revealed that this compound is properly inserted into the active site of AChE enzyme with free binding energy of 8.71 kcal/mol and strongly bound to the residues comprising aromatic side chains such as Tyr70 (H-bonding 1.16 Å), Tyr121 (hydrophobic), Tyr334 (hydrophobic) at peripheral anionic site as well as Phe330 (hydrophobic), and Trp84 (π,π-stacking) at choline binding site of the enzyme (Figure 1). 4e also exhibited mild polar interaction with Gly116 and Gly117 at oxyanion hole of the AChE enzyme. The crystal structure of the TcAChE in complex with available AD drugs such as galantamine and huperzine A showed similar interactions with residues composing peripheral anionic site along with stacking against Trp84 at bottom of the gorge. It seems that the presence of methoxy group in 4e has notable influence on proper positioning of this compound in AChE active site. This orientation effectively avoids insertion and hydrolysis of substrate inside the AChE active site channel and completely coincides with the activity observed for this compound.

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