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 < NO2 < CH3 < OCH3. Furthermore, compounds with electron-withdrawing groups (Cl and NO2) 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.

Crystal Correlation Of Heterocyclic Imidazo[1,2-a]pyridine Analogues and Their Anticholinesterase Potential Evaluation

“…Trp82 and His438. The dichloro-substituted phenyl side chains of 2j and 2k tend to bind tightly to the acyl pocket of the BChE enzyme, similar to a previously reported active compound, 2-(adamantan-1-yl)-2-oxoethyl 2,4-dichlorobenzoate 27 . The halogen···O interaction between the dichloro-substituted phenyl side chain and residue Leu286 of acyl pocket led to stronger BChE inhibitory effects of compounds 2j and 2k as compared to 2g and 2h .

Figure 9Differential validation in GOLD package by docking the native ligands of BChE into their binding sites ( a ).

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Metabolic Profiling of a CB2 Agonist, AM9338, Using LC-MS and Microcoil-NMR: Identification of a Novel Dihydroxy Adamantyl Metabolite

“…There are many drugs on the market containing an adamantyl ring as a key structural subunit used for treatment of serious diseases such as Parkinson's (amantadine) ( Crosby et al, 2003 ), Alzheimer's (memantine) ( Reisberg et al, 2003 ), type2 diabetes (saxaglipitin, vildagliptin) ( Ahren, 2009 ), influenza (rimantidine) ( Jefferson et al, 2004 ), skin disorders (adapalene) ( Thiboutot et al, 2005 ), among others. ( Wanka et al, 2013 ) These types of compounds target a variety of receptors and enzymes of therapeutic interest, including cannabinoid receptors (CB1, CB2) ( Lu et al, 2005 ; Dixon et al, 2010 ), NMDA receptors ( Gilling et al, 2009 ), ion channels ( Stouffer et al, 2008 ), epoxide hydrolase ( Burmistrov et al, 2018 ), 11β-hydroxy steroid dehydrogenase type I ( Ye et al, 2017 ), cholinesterases ( Kwong et al, 2017 ), and tyrosine kinases ( Kaur et al, 2005 ). In many of these cases, especially for cannabinoid receptors, incorporation of the adamantane moiety improves the compound’s binding properties through favorable hydrophobic interactions with key residues within the binding pocket.…”

Anti-Amyloid Aggregation Activity of Black Sesame Pigment: Toward a Novel Alzheimer’s Disease Preventive Agent

“…The cholinergic hypothesis for AD suggests that cognitive deterioration is mainly caused by low levels of acetylcholine (ACh) because maintaining high ACh levels (via AChE inhibitors) has been shown to alleviate these symptoms [ 67 ]. The AChE inhibition properties of VA were evaluated by the Ellman’s method, using AChE from electricus eel and acetylthiocholine iodide as substrate, as described in several papers [ 68 , 69 , 70 ]. Indeed, it was not possible to test the IN sample since it exhibited a significant absorption at the detection wavelength used in the Ellman’s method (412 nm) even at high dilution, therefore leading to interference.…”