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Cholinesterase Inhibitory Activities of Adamantyl-Based Derivatives and Their Molecular Docking Studies.

ABSTRACT: Adamantyl-based compounds are clinically important for the treatments of type 2 diabetes and for their antiviral abilities, while many more are under development for other pharmaceutical uses. This study focused on the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of adamantyl-based ester derivatives with various substituents on the phenyl ring using Ellman's colorimetric method. Compound 2e with a 2,4-dichloro electron-withdrawing substituent on the phenyl ring exhibited the strongest inhibition effect against AChE, with an IC50 value of 77.15 µM. Overall, the adamantyl-based ester with the mono-substituent at position 3 of the phenyl ring exhibited good AChE inhibition effects with an ascending order for the substituents: Cl < NO? < CH? < OCH?. Furthermore, compounds with electron-withdrawing groups (Cl and NO?) substituted at position 3 on their phenyl rings demonstrated stronger AChE inhibition effects, in comparison to their respective positional isomers. On the other hand, compound 2j with a 3-methoxyphenyl ring showed the highest inhibition effect against BChE, with an IC50 value of 223.30 µM. Molecular docking analyses were conducted for potential AChE and BChE inhibitors, and the results demonstrated that the peripheral anionic sites of target proteins were predominant binding sites for these compounds through hydrogen bonds and halogen interactions instead of hydrophobic interactions in the catalytic active site.

SUBMITTER: Kwong HC

PROVIDER: S-EPMC6152672 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Cholinesterase Inhibitory Activities of Adamantyl-Based Derivatives and Their Molecular Docking Studies.

Kwong Huey Chong HC Mah Siau Hui SH Chia Tze Shyang TS Quah Ching Kheng CK Lim Gin Keat GK Kumar C S Chidan CSC

Molecules (Basel, Switzerland) 20170617 6

Adamantyl-based compounds are clinically important for the treatments of type 2 diabetes and for their antiviral abilities, while many more are under development for other pharmaceutical uses. This study focused on the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of adamantyl-based ester derivatives with various substituents on the phenyl ring using Ellman's colorimetric method. Compound <b>2e</b> with a 2,4-dichloro electron-withdrawing substituent on the p ...[more]

PMID: 28629119

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Project description:IntroductionThe current study was designed to synthesize derivatives of succinimide and compare their biological potency in anticholinesterase, alpha-glucosidase inhibition, and antioxidant assays.MethodsIn this research, two succinimide derivatives including (S)-1-(2,5-dioxo-1-phenylpyrrolidin-3-yl) cyclohexanecarbaldehyde (Compound 1) and (R)-2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-phenylpropanal (Compound 2) were synthesized using Michael addition. Both the compounds, ie, 1 and 2 were evaluated for in-vitro acetylcholinesterase (AChE), butyrylctcholinesterase (BChE), antioxidant, and α-glucosidase inhibitory potentials. Furthermore, molecular docking was performed using Molecular Operating Environment (MOE) to explore the binding mode of both the compounds against different enzymes. Lineweaver-Burk plots of enzyme inhibitions representing the reciprocal of initial enzyme velocity versus the reciprocal of substrate concentration in the presence of synthesized compounds and standard drugs were constructed using Michaelis-Menten kinetics.ResultsIn AChE inhibitory assay, compounds 1 and 2 exhibited IC50 of 343.45 and 422.98 µM, respectively, against AChE enzyme. Similarly, both the compounds showed IC50 of 276.86 and 357.91 µM, respectively, against BChE enzyme. Compounds 1 and 2 displayed IC50 of 157.71 and 471.79 µM against α-glucosidase enzyme, respectively. In a similar pattern, compound 1 exhibited to be more potent as compared to compound 2 in all the three antioxidant assays. Compound 1 exhibited IC50 values of 297.98, 332.94, and 825.92 µM against DPPH, ABTS, and H2O2 free radicals, respectively. Molecular docking showed a triple fold in the AChE and BChE activity for compound 1 compared with compound 2. The compound 1 revealed good interaction against both the AChE and BChE enzymes which revealed the high potency of this compound compared to compound 2.ConclusionBoth succinimide derivatives exhibited considerable inhibitory activities against cholinesterases and α-glucosidase enzymes. Of these two, compound 1 revealed to be more potent against all the in-vitro targets which was supported by molecular docking with the lowest binding energies. Moreover, compound 1 also proved to have antiradical properties.

Dataset Information

Cholinesterase Inhibitory Activities of Adamantyl-Based Derivatives and Their Molecular Docking Studies.

Publications

Cholinesterase Inhibitory Activities of Adamantyl-Based Derivatives and Their Molecular Docking Studies.

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