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

Kwong HC, Mah SH, Chia TS, Quah CK, Lim GK, Kumar CSC

Molecules, 2017 Jun 17;22(6).
PMID: 28629119 DOI: 10.3390/molecules22061005

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.
Clitoria ternatea L. root extract ameliorated the cognitive and hippocampal long-term potentiation deficits induced by chronic cerebral hypoperfusion in the rat

Damodaran T, Tan BWL, Liao P, Ramanathan S, Lim GK, Hassan Z

J Ethnopharmacol, 2018 Oct 05;224:381-390.
PMID: 29920356 DOI: 10.1016/j.jep.2018.06.020

ETHNOPHARMACOLOGICAL RELEVANCE: Clitoria ternatea L. (CT), commonly known as Butterfly pea, is used in Indian Ayurvedic medicine to promote brain function and treat mental disorders. Root of CT has been proven to enhance memory, but its role in an animal model of chronic cerebral hypoperfusion (CCH), which has been considered as a major cause of brain disorders, has yet to be explored.
AIM OF THE STUDY: To assess the motor and cognitive effects of acute oral administration of CT root methanolic extract and hippocampal long-term plasticity in the CA1 region of the CCH rat model.
MATERIALS AND METHODS: Male Sprague Dawley rats (200-300 g) were subjected to permanent bilateral occlusion of common carotid arteries (PBOCCA) or sham operation. Then, these rats were given oral administration of CT root extract at doses of 100, 200 or 300 mg/kg on day 28 post-surgery and tested using behavioural tests (open-field test, passive avoidance task, and Morris water maze) and electrophysiological recordings (under urethane anaesthesia).
RESULTS: Treatment with CT root extract at the doses of 200 and 300 mg/kg resulted in a significant enhancement in memory performance in CCH rats induced by PBOCCA. Furthermore, CCH resulted in inhibition of long-term potentiation (LTP) formation in the hippocampus, and CT root extract rescued the LTP impairment. The CT root extract was confirmed to improve the glutamate-induced calcium increase via calcium imaging using primary cultured rat neurons. No significance difference was found in the CaMKII expression. These results demonstrated that CT root extract ameliorates synaptic function, which may contribute to its improving effect on cognitive behaviour.
CONCLUSIONS: Our findings demonstrated an improving effect of CT root extract on memory in the CCH rat model suggesting that CT root extract could be a potential therapeutic strategy to prevent the progression of cognitive deterioration in vascular dementia (VaD) and Alzheimer's disease (AD) patients.
Fulltext Synthesis and Crystallographic Insight into the Structural Aspects of Some Novel Adamantane-Based Ester Derivatives

Kumar CS, Kwong HC, Mah SH, Chia TS, Loh WS, Quah CK, et al.

Molecules, 2015;20(10):18827-46.
PMID: 26501248 DOI: 10.3390/molecules201018827

Adamantyl-based compounds are commercially important in the treatments for neurological conditions and type-2 diabetes, aside from their anti-viral abilities. Their values in drug design are chronicled as multi-dimensional. In the present study, a series of 2-(adamantan-1-yl)-2-oxoethyl benzoates, 2(a-q), and 2-(adamantan-1-yl)-2-oxoethyl 2-pyridinecarboxylate, 2r, were synthesized by reacting 1-adamantyl bromomethyl ketone with various carboxylic acids using potassium carbonate in dimethylformamide medium at room temperature. Three-dimensional structures studied using X-ray diffraction suggest that the adamantyl moiety can serve as an efficient building block to synthesize 2-oxopropyl benzoate derivatives with synclinal conformation with a looser-packed crystal packing system. Compounds 2a, 2b, 2f, 2g, 2i, 2j, 2m, 2n, 2o, 2q and 2r exhibit strong antioxidant activities in the hydrogen peroxide radical scavenging test. Furthermore, three compounds, 2p, 2q and 2r, show good anti-inflammatory activities in the evaluation of albumin denaturation.
Fulltext Novel biphenyl ester derivatives as tyrosinase inhibitors: Synthesis, crystallographic, spectral analysis and molecular docking studies

Kwong HC, Chidan Kumar CS, Mah SH, Chia TS, Quah CK, Loh ZH, et al.

PLoS One, 2017;12(2):e0170117.
PMID: 28241010 DOI: 10.1371/journal.pone.0170117

Biphenyl-based compounds are clinically important for the treatments of hypertension and inflammatory, while many more are under development for pharmaceutical uses. In the present study, a series of 2-([1,1'-biphenyl]-4-yl)-2-oxoethyl benzoates, 2(a-q), and 2-([1,1'-biphenyl]-4-yl)-2-oxoethyl pyridinecarboxylate, 2(r-s) were synthesized by reacting 1-([1,1'-biphenyl]-4-yl)-2-bromoethan-1-one with various carboxylic acids using potassium carbonate in dimethylformamide at ambient temperature. Single-crystal X-ray diffraction studies revealed a more closely packed crystal structure can be produced by introduction of biphenyl moiety. Five of the compounds among the reported series exhibited significant anti-tyrosinase activities, in which 2p, 2r and 2s displayed good inhibitions which are comparable to standard inhibitor kojic acid at concentrations of 100 and 250 μg/mL. The inhibitory effects of these active compounds were further confirmed by computational molecular docking studies and the results revealed the primary binding site is active-site entrance instead of inner copper binding site which acted as the secondary binding site.
The effect of spent coffee ground (SCG) loading, matrix ratio and biological treatment of SCG on poly(hydroxybutyrate) (PHB)/poly(lactic acid) (PLA) polymer blend

Boey JY, Kong U, Lee CK, Lim GK, Oo CW, Tan CK, et al.

Int J Biol Macromol, 2024 May;266(Pt 2):131079.
PMID: 38537860 DOI: 10.1016/j.ijbiomac.2024.131079

This study investigates the effects of SCG embedded into biodegradable polymer blends and aimed to formulate and characterise biomass-reinforced biocomposites using spent coffee ground (SCG) as reinforcement in PHB/PLA polymer blend. The effect of SCG filler loading and varying PHB/PLA ratios on the tensile properties and morphological characteristics of the biocomposites were examined. The results indicated that tensile properties reduction could be due to its incompatibility with the PHB/PLA matrixSCG aggregation at 40 wt% content resulted in higher void formation compared to lower content at 10 wt%. A PHB/PLA ratio of 50/50 with SCG loading 20 wt% was chosen for biocomposites with treated SCG. Biological treatment of SCG using Phanerochaete chrysosporium CK01 and Aspergillus niger DWA8 indicated P. chrysosporium CK01 necessitated a higher moisture content for optimum growth and enzyme production, whereas the optimal conditions for enzyme production (50-55 %, w/w) differed from those promoting A. niger DWA8 growth (40 %, w/w). SEM micrographs highlighted uniform distribution and effective wetting of treated SCG, resulting in improvements of tensile strength and modulus of biocomposites, respectively. The study demonstrated the effectiveness of sustainable fungal treatment in enhancing the interfacial adhesion between treated SCG and the PHB/PLA matrix.
Fulltext Crystal Correlation Of Heterocyclic Imidazo[1,2-a]pyridine Analogues and Their Anticholinesterase Potential Evaluation

Kwong HC, Chidan Kumar CS, Mah SH, Mah YL, Chia TS, Quah CK, et al.

Sci Rep, 2019 Jan 30;9(1):926.
PMID: 30700752 DOI: 10.1038/s41598-018-37486-7

Imidazo[1,2-a]pyridine-based compounds are clinically important to the treatments of heart and circulatory failures, while many are under development for pharmaceutical uses. In this study, a series of imidazo[1,2-a]pyridine-based derivatives 2(a-o) were synthesized by reacting a-haloketones with 2-aminopyridines in a basic media at ambient temperature. Single crystal X-ray diffraction studies suggest that with low degree-of-freedom, the introduction of bulky adamantyl or electron-rich biphenyl moiety into the imidazopyridine derivatives will not affect its structural occupancy. Imidazo[1,2-a]pyridine-based derivatives with biphenyl side chain are potential AChE inhibitors. Compound 2h which bears a biphenyl side chain and methyl substituent at the position R4 of the imidazo[1,2-a]pyridine ring showed the strongest AChE inhibition with an IC50 value of 79 µM. However, imidazo[1,2-a]pyridine derivatives with phenyl side chain exhibit better BChE inhibition effect among the series. Compound 2j with 3,4-dichlorophenyl side chain and unsubstituted imidazo[1,2-a]pyridine ring appears to be the strongest BChE inhibitor with an IC50 value of 65 µM and good selectivity. The inhibitory effects of active compounds were further confirmed by computational molecular docking studies. The results unveiled that peripheral anionic sites of AChE and acyl pocket of BChE were the predominated binding sites for the subjected inhibitors.