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Natural xanthones as modulators of the Nrf2/ARE signaling pathway and potential gastroprotective agents

Gunter NV, Teh SS, Jantan I, Law KP, Morita H, Mah SH

Phytother Res, 2024 Feb 19.
PMID: 38372084 DOI: 10.1002/ptr.8160

Oxidative stress is implicated in the initiation, pathogenesis, and progression of various gastric inflammatory diseases (GID). The prevalence of these diseases remains a concern along with the increasing risks of adverse effects in current clinical interventions. Hence, new gastroprotective agents capable of inhibiting oxidative stress by modulating cellular defense systems such as the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway are critically needed to address these issues. A candidate to solve the present issue is xanthone, a natural compound that reportedly exerts gastroprotective effects via antioxidant, anti-inflammatory, and cytoprotective mechanisms. Moreover, xanthone derivatives were shown to modulate the Nrf2/ARE signaling pathway to counter oxidative stress in both in vitro and in vivo models. Thirteen natural xanthones have demonstrated the ability to modulate the Nrf2/ARE signaling pathway and have high potential as lead compounds for GID as indicated by their in vivo gastroprotective action-particularly mangiferin (2), α-mangostin (3), and γ-mangostin (4). Further studies on these compounds are recommended to validate the Nrf2 modulatory ability in relation to their gastroprotective action.
Fulltext Topical Nanoemulsion Hydrogel Formulated from Supercritical Fluid Extracted Palm-Pressed Fiber Oil and Virgin Coconut Oil with Antioxidant and Antibacterial Effects

Mah SH, Sundrasegaran S, Lau HLN

J Oleo Sci, 2024;73(4):489-502.
PMID: 38556283 DOI: 10.5650/jos.ess23197

Skincare industries are growing rapidly around the globe but most products are formulated using synthetic chemicals and organic solvent extracted plant extracts, thus may be hazardous to the users and incur higher cost for purification that eventually leads to phytonutrient degradation. Therefore, this study aimed to formulate a stable natural formulation with antioxidant and antimicrobial activities by using supercritical carbon dioxide (SC-CO 2 ) extracted palm-pressed fiber oil (PPFO) as an active ingredient with virgin coconut oil (VCO) as a formulation base. PPFO was extracted from fresh palm-pressed fiber (PPF) while VCO was from dried grated coconut copra using SC-CO 2 before being subjected to the analyses of physicochemical properties, phytonutrient content and biological activities including antioxidant and antimicrobial. The nanoemulgel formulations were then developed and examined for their stability through accelerated stability study for 3 months by measuring their pH, particle size, polydispersity index and zeta potential. The results showed that PPFO contained a high amount of phytonutrients, especially total carotenoid (1497 ppm) and total tocopherol and tocotrienol (2269 ppm) contents. The newly developed nanoemulgels maintained their particles in nano size and showed good stability with high negative zeta potentials. Sample nanoemulgel formulated with 3% PPFO diluted in VCO as effective concentration showed significantly stronger antioxidant activity than the control which was formulated from 3% tocopheryl acetate diluted in mineral oil, towards DPPH and ABTS radicals, with IC 50 values of 67.41 and 44.28 µL/mL, respectively. For the antibacterial activities, the sample nanoemulgel was found to inhibit Gram positive bacteria S. aureus and S. epidermidis growth but not the Gram negative strain E. coli. Overall, this study revealed the potential of SF-extracted PPFO as an active ingredient in the antioxidant topical formulations thus future study on in vitro skin cell models is highly recommended for validation.
The Effects and Mechanisms of Xanthones in Alzheimer's Disease: A Systematic Review

Pang LW, Hamzah S, Tan SLJ, Mah SH, Yow HY

Neurochem Res, 2023 Dec;48(12):3485-3511.
PMID: 37578655 DOI: 10.1007/s11064-023-04005-8

Xanthones are natural secondary metabolites that possess great potential as neuroprotective agents due to their prominent biological effects on Alzheimer's disease (AD). However, their underlying mechanisms in AD remain unclear. This study aimed to systematically review the effects and mechanisms of xanthones in cell culture and animal studies, gaining a better understanding of their roles in AD. A comprehensive literature search was conducted in the Medline and Scopus databases using specific keywords to identify relevant articles published up to June 2023. After removing duplicates, all articles were imported into the Rayyan software. The article titles were screened based on predefined inclusion and exclusion criteria. Relevant full-text articles were assessed for biases using the OHAT tool. The results were presented in tables. Xanthones have shown various pharmacological effects towards AD from the 21 preclinical studies included. Cell culture studies demonstrated the anti-cholinesterase activity of xanthones, which protects against the loss of acetylcholine. Xanthones exhibited neuroprotective effects by promoting cell viability, reducing the accumulation of β-amyloid and tau aggregation. The administration of xanthones in animal models resulted in a reduction in neuronal inflammation by decreasing microglial and astrocyte burden. In terms of molecular mechanisms, xanthones prevented neuroinflammation through the modulation of signaling pathways, including TLR4/TAK1/NF-κB and MAPK pathways. Mechanisms such as activation of caspase-3 and -9 and suppression of endoplasmic reticulum stress were also reported. Despite the various neuroprotective effects associated with xanthones, there are limited studies reported on their underlying mechanisms in AD. Further studies are warranted to fully understand their potential roles in AD.
Versatile Applications of Brewer's Spent Grain: Solid-State Fermentation and Nutritional Added Value

Lock TJ, Mah SH, Lai ZW

Appl Biochem Biotechnol, 2023 Nov 16.
PMID: 37971579 DOI: 10.1007/s12010-023-04769-3

Brewer's spent grain (BSG) is a major by-product in the beer-brewing process which contributes to 85% of the entire generated by-product in the brewing process. BSG is rich in proteins, and most of the malt proteins (74-78%) remain insoluble in BSG after the mashing process. Solid-state fermentation (SSF) is a promising bioprocess that enables microorganisms to survive in environments with minimal water and has shown to enhance the nutritional composition of BSG. In this review, the potential application of protein, amino acids (proline, threonine, and serine), phenolic contents, and soluble sugars (glucose, fructose, xylose, arabinose, and cellobiose) extracted from BSG by various microorganisms using SSF is explored. Incorporation of BSG into animal feed, human diets, and as a substrate for microorganisms are the prospects that could be implemented in the industrial scale. This review also discussed various advances to improve the fermentation yield such as symbiotic fermentation, the addition of nitrogen supplements, and an optimal mixture of the agro-industrial waste substrate. Future perspectives on SSF are also addressed to provide important ideas for immediate and future studies. However, challenges include optimizing SSF conditions and design of bioreactors, and operational costs must be addressed in the future to overcome current obstacles. Overall, this mini review highlights the potential benefits of BSG utilization and SSF in a sustainable way.
Synthesis of benzylated amine-substituted xanthone derivatives and their antioxidant and anti-inflammatory activities

Wong KW, Teh SS, Law KP, Ismail IS, Sato K, Mase N, et al.

Arch Pharm (Weinheim), 2023 Jan;356(1):e2200418.
PMID: 36285691 DOI: 10.1002/ardp.202200418

Oxidative stress and its constant companion, inflammation, play a critical part in the pathogenesis of many acute and chronic illnesses. The discovery of new multi-targeted drug candidates with antioxidant and anti-inflammatory properties is deemed necessary. Thus, a series of novel xanthone derivatives with halogenated benzyl (4b-4d, 4f-4h) and methoxylated benzyl groups (4e) attached to the butoxy amine substituent were synthesized in this study. The synthesized xanthone derivatives exhibited stronger antioxidant activity against H2 O2 scavenging than the standard drug, α-tocopherol, but weaker towards DPPH scavenging and ferrous ion chelation. Besides that, 4b-4d, 4f-4h demonstrated good anti-inflammatory activities through NO production inhibition towards lipopolysaccharide (LPS)-induced RAW 264.7 cells and showed 2-4 times stronger effects than the standard drug, diclofenac sodium. Moreover, compound 4b with two brominated benzyl groups attached to the butoxy amine substituent suppressed the production of pro-inflammatory cytokines, TNF-α and IL-1β, significantly. Structure-activity relationship elucidated that the halogenated benzylamine substituent plays an important role in contributing the antioxidant and anti-inflammatory activities of xanthones. In summary, xanthone 4b was identified as a potential lead compound to be further developed into antioxidant and anti-inflammatory drugs. Thus, further studies on the related mechanisms of action of 4b are recommended.
Synthesis of 1-hydroxy-3-O-substituted xanthone derivatives and their structure-activity relationship on acetylcholinesterase inhibitory effect

Vanessa VV, Teh SS, Lam KW, Mah SH

Nat Prod Res, 2023;37(17):2849-2861.
PMID: 36398788 DOI: 10.1080/14786419.2022.2137800

This study focused on the synthesis of 1,3-dihydroxyxanthone (1) and its new derivatives with alkyl (2a-2f), alkenyl (2 g-2k), alkynyl (2 l-2n), and alkylated phenyl (2o-2r) groups at C3 position. The structures of these compounds were confirmed by MS, NMR, and FTIR spectroscopic data. All the substituted xanthones (2a-2r) showed significantly stronger acetylcholinesterase (AChE) inhibitory activities than 1. Compounds 2g and 2j exhibited the strongest activities with the IC50 values of 20.8 and 21.5 μM and their enzyme kinetic analyses indicated a mixed-mode inhibition. Molecular docking study revealed that 2g binds favourably to the active site of AChE via π-π stacking and hydrogen bonding from the xanthone ring, in addition to π-alkyl interaction from the substituent group. These xanthone derivatives are potential lead compounds to be further developed into Alzheimer's disease drugs.
Physicochemical and functional properties of Alcalase-extracted protein hydrolysate from oil palm leaves

Hau EH, Teh SS, Yeo SK, Mah SH

J Sci Food Agric, 2022 Jan 15;102(1):233-240.
PMID: 34081335 DOI: 10.1002/jsfa.11350

BACKGROUND: The oil palm tree produces 90% of wastes and the limited usage of these wastes causes a major disposal problem in the mills. Nevertheless, these by-products have a large amount of nutritional components. Thus, the present study aimed to determine the physicochemical and functional properties of protein hydrolysates (PH) from oil palm leaves (OPL) extracted using different concentrations of Alcalase (0-10%) at 2 h of hydrolysis time.
RESULTS: Fourier transform infrared spectral analyses showed that the enzymatic hydrolysis altered functional groups of OPL where a secondary amine was present in the PH. Changes were also observed in the thermal stability where the enthalpy heat obtained for PH (933.93-1142.57 J g-1 ) was much lower than OPL (7854.11 J g-1 ). The results showed that the PH extracted by 8% Alcalase exhibited absolute zeta potential, as well as a high emulsifying activity index (70.64 m2 g-1 of protein) and emulsion stability index (60.58 min). Furthermore, this PH showed higher solubility (96.32%) and emulsifying properties compared to other PHs. It is also comparable with commercial plant proteins, indicating that 8% Alcalase is an optimum concentration for hydrolysis.
CONCLUSION: In summary, the physicochemical and functional properties of PH extracted from OPL showed good functional properties, suggesting that it can be used as an alternative plant protein in food industries. © 2021 Society of Chemical Industry.
Fulltext Antioxidant Potential of Red Palm-Pressed Mesocarp Olein

Teh SS, Mah SH, Lau HLN, Teng KT, Loganathan R

J Oleo Sci, 2021 Dec 03;70(12):1719-1729.
PMID: 34759109 DOI: 10.5650/jos.ess21147

Oxidative stress occurs due to the imbalance amount of the free radicals and antioxidants in human body which often associated with numerous chronic diseases. The antioxidant properties of red palm-pressed mesocarp olein (PPMO) have not been widely studied. Therefore, antioxidant properties of PPMO relative to commercially available edible oils, namely red palm olein (RPO), palm olein (PO), extra virgin olive oil (OO) and extra virgin coconut oil (CNO) were studied. PPMO exhibited significant higher phytonutrients which more than 2-fold compared to the edible oils. Overall, antioxidant screening indicated that PPMO has significantly higher antioxidant activities than RPO, PO and CNO in term of DPPH, H2O2, NO scavenging and FIC; and significantly higher H2O2 and FIC than OO. The outcomes of this study reveal that PPMO is as good as commercially available edible oil, also a good source for food applications and dietary nutritional supplements. More importantly, the utilization of PPMO could mitigate oil palm waste problem and results in positive environmental impact.
Fulltext In vivo Toxicity Assessment of Refined Red Palm-pressed Mesocarp Olein in Sprague-Dawley Rats

Jin Y, Teh SS, Lau HLN, Mah SH

J Oleo Sci, 2021 Dec 03;70(12):1749-1759.
PMID: 34759114 DOI: 10.5650/jos.ess21215

Refined red palm-pressed mesocarp olein (PPMO) is recovered from palm-pressed mesocarp fiber, which is a by-product from palm oil mill. Its utilization in food industry is extremely limited even though it contains various phytonutrients. Thus, this study aimed to evaluate its toxicity effects by using the male Sprague-Dawley rat model. The rats were administered with a single dose of 2 g/kg PPMO in an acute toxicity study while administered with 2, 1, or 0.5 g/kg PPMO daily for 28 days in a sub-chronic toxicity study. The mortality, oral LD50 value, clinical observation, body and organ weight, hematological and biochemical analyses, pathological and histopathological examinations were assessed. The overall outcomes indicated that PPMO is non-toxic up to 2 g/kg and considered safe to be used in food application, especially as functional food ingredient and supplement attributed to its phytonutrients. Besides, this study provides an insight in alternative utilization of the wastes from palm oil mill.
Immuno-modulatory effects of macluraxanthone on macrophage phenotype and function

Ng IMJ, Mah SH, Chua CLL

Nat Prod Res, 2021 Dec;35(23):5409-5414.
PMID: 32508145 DOI: 10.1080/14786419.2020.1775223

Macluraxanthone was previously reported to have many biological activities, including anti-cholinesterase, anti-oxidant, anti-cancer, anti-malarial and anti-inflammatory effects. The aim of the current study was to further characterise the effect of macluraxanthone on human macrophage, a type of immune cell that has been implicated in the development of various inflammatory diseases. The expression of surface markers and cytokine production by THP-1 human macrophages following treatment with macluraxanthone were investigated. Macluraxanthone was shown to promote polarisation of M1-like pro-inflammatory macrophages by increasing the percentage of macrophages expressing CD86, while decreasing their CD14, CD11b and CD80 expression. However, in the presence of the pro-inflammatory stimulus lipopolysaccharide, macluraxanthone significantly decreased TNF-α and IL-10 cytokine production.
Fulltext New 3-O-substituted xanthone derivatives as promising acetylcholinesterase inhibitors

Loh ZH, Kwong HC, Lam KW, Teh SS, Ee GCL, Quah CK, et al.

J Enzyme Inhib Med Chem, 2021 Dec;36(1):627-639.
PMID: 33557647 DOI: 10.1080/14756366.2021.1882452

A new series of 3-O-substituted xanthone derivatives were synthesised and evaluated for their anti-cholinergic activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The results indicated that the xanthone derivatives possessed good AChE inhibitory activity with eleven of them (5, 8, 11, 17, 19, 21-23, 26-28) exhibited significant effects with the IC50 values ranged 0.88 to 1.28 µM. The AChE enzyme kinetic study of 3-(4-phenylbutoxy)-9H-xanthen-9-one (23) and ethyl 2-((9-oxo-9H-xanthen-3-yl)oxy)acetate (28) showed a mixed inhibition mechanism. Molecular docking study showed that 23 binds to the active site of AChE and interacts via extensive π-π stacking with the indole and phenol side chains of Trp86 and Tyr337, besides the hydrogen bonding with the hydration site and π-π interaction with the phenol side chain of Y72. This study revealed that 3-O-alkoxyl substituted xanthone derivatives are potential lead structures, especially 23 and 28 which can be further developed into potent AChE inhibitors.
Fulltext Editorial: Targeting Human Inflammatory Skin Diseases With Natural Products: Exploring Potential Mechanisms and Regulatory Pathways

Goh BH, Mocan A, Xiao J, Mah SH, Yap WH

Front Pharmacol, 2021;12:791151.
PMID: 34867426 DOI: 10.3389/fphar.2021.791151
Xanthone: Potential Acetylcholinesterase Inhibitor for Alzheimer's Disease Treatment

Vanessa VV, Mah SH

Mini Rev Med Chem, 2021;21(17):2507-2529.
PMID: 33583373 DOI: 10.2174/1389557521666210212152514

Alzheimer's disease is a neurodegenerative disorder that results in progressive and irreversible central nervous system impairment, which has become one of the severe issues recently. The most successful approach of Alzheimer's treatment is the administration of cholinesterase inhibitors to prevent the hydrolysis of acetylcholine and subsequently improve cholinergic postsynaptic transmission. This review highlights a class of heterocycles, namely xanthone, and its remarkable acetylcholinesterase inhibitory activities. Naturally occurring xanthones, including oxygenated, prenylated, pyrano, and glycosylated xanthones, exhibited promising inhibition effects towards acetylcholinesterase. Interestingly, synthetic xanthone derivatives with complex substituents such as alkyl, pyrrolidine, piperidine, and morpholine have shown greater acetylcholinesterase inhibition activities. The structure-activity relationship of xanthones revealed that the type and position of the substituent(s) attached to the xanthone moiety influenced acetylcholinesterase inhibition activities where hydrophobic moiety will lead to an improved activity by contributing to the π-π interactions, as well as the hydroxy substituent(s) by forming hydrogen-bond interactions. Thus, further studies, including quantitative structure-activity relationship, in vivo and clinical validation studies are crucial for the development of xanthones into novel anti-Alzheimer's disease drugs.
Cytotoxic activity of phytochemicals from Garcinia mangostana L. and G. benthamiana (Planch. & Triana) Pipoly against breast cancer cells

See I, Ee GCL, Jong VYM, Teh SS, Acuña CLC, Mah SH

Nat Prod Res, 2020 Oct 23.
PMID: 33094642 DOI: 10.1080/14786419.2020.1836629

Four xanthones, α-mangostin (1), β-mangostin (2), mangostenol (3), mangaxanthone B (4), three benzophenones, mangaphenone (5), benthamianone (6), congestiflorone (7) and one sterol, stigmasterol (8) were isolated from the stem barks of Garcinia mangostana L. and G. benthamiana (Planch. & Triana) Pipoly. Compounds 1, 2, 4 and 5 exhibited significant cytotoxicity through MTT assay towards MCF-7 and MDA-MB-231 cells with the IC50 values range from 4.4 to 12.0 µM. Remarkably, mangaphenone (5) showed non-cytotoxicity against normal Vero cells, revealing its potential as lead compound for anti-breast cancer drug. Structure-activity relationship postulated that the prenyl and hydroxyl groups present in xanthones are important in promoting anti-proliferative effects. Molecular docking simulation study of 1, 2, 4 and 5 with 2OCF and 4PIV implied that the induction of apoptosis for both cancer cells involve ER and FAS signaling pathways. Future study on the lead optimization of 5 is highly recommended.
Fulltext Natural Xanthones and Skin Inflammatory Diseases: Multitargeting Mechanisms of Action and Potential Application

Gunter NV, Teh SS, Lim YM, Mah SH

Front Pharmacol, 2020;11:594202.
PMID: 33424605 DOI: 10.3389/fphar.2020.594202

The pathogenesis of skin inflammatory diseases such as atopic dermatitis, acne, psoriasis, and skin cancers generally involve the generation of oxidative stress and chronic inflammation. Exposure of the skin to external aggressors such as ultraviolet (UV) radiation and xenobiotics induces the generation of reactive oxygen species (ROS) which subsequently activates immune responses and causes immunological aberrations. Hence, antioxidant and anti-inflammatory agents were considered to be potential compounds to treat skin inflammatory diseases. A prime example of such compounds is xanthone (xanthene-9-one), a class of natural compounds that possess a wide range of biological activities including antioxidant, anti-inflammatory, antimicrobial, cytotoxic, and chemotherapeutic effects. Many studies reported various mechanisms of action by xanthones for the treatment of skin inflammatory diseases. These mechanisms of action commonly involve the modulation of various pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor α (TNF-α), as well as anti-inflammatory cytokines such as IL-10. Other mechanisms of action include the regulation of NF-κB and MAPK signaling pathways, besides immune cell recruitment via modulation of chemokines, activation, and infiltration. Moreover, disease-specific activity contributed by xanthones, such as antibacterial action against Propionibacterium acnes and Staphylococcus epidermidis for acne treatment, and numerous cytotoxic mechanisms involving pro-apoptotic and anti-metastatic effects for skin cancer treatment have been extensively elucidated. Furthermore, xanthones have been reported to modulate pathways responsible for mediating oxidative stress and inflammation such as PPAR, nuclear factor erythroid 2-related factor and prostaglandin cascades. These pathways were also implicated in skin inflammatory diseases. Xanthones including the prenylated α-mangostin (2) and γ-mangostin (3), glucosylated mangiferin (4) and the caged xanthone gambogic acid (8) are potential lead compounds to be further developed into pharmaceutical agents for the treatment of skin inflammatory diseases. Future studies on the structure-activity relationships, molecular mechanisms, and applications of xanthones for the treatment of skin inflammatory diseases are thus highly recommended.
Cytotoxic xanthones isolated from Calophyllum depressinervosum and Calophyllum buxifolium with antioxidant and cytotoxic activities

Zamakshshari NH, Ee GCL, Ismail IS, Ibrahim Z, Mah SH

Food Chem Toxicol, 2019 Nov;133:110800.
PMID: 31479710 DOI: 10.1016/j.fct.2019.110800

The stem bark of Calophyllum depressinervosum and Calophyllum buxifolium were extracted and examined for their antioxidant activities, together with cytotoxicity towards human cancer cells. The methanol extract of C. depressinervosum exhibited good DPPH and NO scavenging effects. The strongest BCB inhibition and FIC effects were shown by dichloromethane and ethyl acetate extracts of both species. Overall, DPPH, FRAP and FIC assays showed strong correlation with TPC. For cytotoxicity, hexane extract of C. depressinervosum possessed the strongest anti-proliferative activities towards SNU-1 cells while the hexane extract of C. buxifolium showed the strongest activity towards LS-174T and K562 cells with the IC50 values ranging from 7 to 17 μg/mL. The purification of plant extracts afforded eight xanthones, ananixanthone (1), caloxanthone B (2), caloxanthone I (3), caloxanthone J (4) xanthochymone B (5), thwaitesixanthone (6), 1,3,5,6-tetrahydroxyxanthone (7) and dombakinaxanthone (8). All the xanthones, except 1 were reported for the first time from both Calophyllum species. The xanthones were examined for their cytotoxic effect against K562 leukemic cells. Compounds 1 and 2 showed strong cytotoxicity with the IC50 values of 2.96 and 1.23 μg/mL, respectively. The molecular binding interaction of 2 was further investigated by performing molecular docking study with promising protein receptor Src kinase.
Fulltext Palm-Pressed Mesocarp Fibre Oil as an Alternative Carrier Oil in Emulsion

Teh SS, Lau HLN, Mah SH

J Oleo Sci, 2019 Aug 01;68(8):803-808.
PMID: 31292345 DOI: 10.5650/jos.ess19098

Refined palm-pressed mesocarp fibre oil (PPFO), which can be obtained from one of the by-products of palm oil milling, palm-pressed mesocarp fibre, is categorized as palm sludge oil. So far, it has been given less attention and underutilized until some recent scientific reports revealing its high content of phytonutrients, carotenoids and vitamin E, which have been proven scientifically to possess anti-oxidant activity. The study evaluated the stability of PPFO as a carrier for plant-based emulsion. PPFO was extracted and examined for its positional distribution of fatty acids, saturation levels and iodine value (IV) using NMR spectroscopy. The PPFO-based emulsion was then prepared and subjected to stability tests, including temperature variation, centrifuge test, cycle test, pH and slip melting point for 28 days. Phase separation was observed from PPFO-based emulsion stored at 40℃ from day-21 onwards while no creaming found in all the palm olein-based emulsions stored at the three storage temperatures. Nevertheless, results indicated that the PPFO-based emulsion passed all the tests above showing insignificant phase separation (p > 0.05) compared with those of palm olein commonly used in emulsion preparation. The findings suggested that PPFO enriched with valuable phytonutrients could be used as an alternative carrier oil in emulsion formulation, which is an important component in personal care products.
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.
Isolation and structural modifications of ananixanthone from Calophyllum teysmannii and their cytotoxic activities

Kar Wei L, Zamakshshari NH, Ee GCL, Mah SH, Mohd Nor SM

Nat Prod Res, 2018 Sep;32(18):2147-2151.
PMID: 28826239 DOI: 10.1080/14786419.2017.1367781

Two naturally occurring xanthones, ananixanthone (1) and β-mangostin (2), were isolated using column chromatographic method from the n-hexane and methanol extracts of Calophyllum teysmannii, respectively. The major constituent, ananixanthone (1), was subjected to structural modifications via acetylation, methylation and benzylation yielding four new xanthone derivatives, ananixanthone monoacetate (3), ananixanthone diacetate (4), 5-methoxyananixanthone (5) and 5-O-benzylananixanthone (6). Compound 1 together with its four new derivatives were subjected to MTT assay against three cancer cell lines; SNU-1, K562 and LS174T. The results indicated that the parent compound has greater cytotoxicity capabilities against SNU-1 and K562 cell lines with IC50 values of 8.97 ± 0.11 and 2.96 ± 0.06 μg/mL, respectively. Compound 5 on the other hand exhibited better cytotoxicity against LS174T cell line with an IC50 value of 5.76 ± 1.07 μg/mL.
Fulltext Impact of Storage Conditions on the Stability of Predominant Phenolic Constituents and Antioxidant Activity of Dried Piper betle Extracts

Ali A, Chong CH, Mah SH, Abdullah LC, Choong TSY, Chua BL

Molecules, 2018 Feb 23;23(2).
PMID: 29473847 DOI: 10.3390/molecules23020484

The phenolic constituents in Piper betle are well known for their antioxidant potential; however, current literature has very little information on their stability under the influence of storage factors. Present study evaluated the stability of total phenolic content (TPC) and antioxidant activity together with individual phenolic constituents (hydroxychavicol, eugenol, isoeugenol and allylpyrocatechol 3,4-diacetate) present in dried Piper betle's extract under different storage temperature of 5 and 25 °C with and without light for a period of six months. Both light and temperature significantly influenced TPC and its corresponding antioxidant activity over time. More than 95% TPC and antioxidant activity was retained at 5 °C in dark condition after 180 days of storage. Hydroxychavicol demonstrated the best stability with no degradation while eugenol and isoeugenol displayed moderate stability in low temperature (5 °C) and dark conditions. 4-allyl-1,2-diacetoxybenzene was the only compound that underwent complete degradation. A new compound, 2,4-di-tert-butylphenol, was detected after five weeks of storage only in the extracts exposed to light. Both zero-order and first-order kinetic models were adopted to describe the degradation kinetics of the extract's antioxidant activity. Zero-order displayed better fit with higher correlation coefficients (R² = 0.9046) and the half-life was determined as 62 days for the optimised storage conditions (5 °C in dark conditions).

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