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Ethyl nitrobenzoate: A novel scaffold for cholinesterase inhibition

Yeong KY, Liew WL, Murugaiyah V, Ang CW, Osman H, Tan SC

Bioorg Chem, 2017 02;70:27-33.
PMID: 27863748 DOI: 10.1016/j.bioorg.2016.11.005

A series of novel cholinesterase inhibitors containing nitrobenzoate core structure were synthesized by a facile and efficient method. The structure of the novel compounds were fully characterized and confirmed by analytical as well as spectroscopic methods. Compound indicated as 2f was found to possess the best cholinesterase inhibitory activities of all the evaluated compounds. Results suggest that 2f is a selective acetylcholinesterase inhibitor, although it also inhibits butyrylcholinesterase at higher concentration. Kinetics inhibition result suggest that 2f is a mixed-mode inhibitor of acetylcholinesterase. In addition, it was found to have low cytotoxicity. Molecular docking on compound 2f was carried out to rationalize the observed in vitro enzymatic assay results. Most importantly, the potential of nitrobenzoate derivatives as cholinesterase inhibitor was shown through this study. In summary, we discovered nitrobenzoates as a new scaffold that may eventually yield useful compounds in treatment of Alzheimer's disease.
Anticancer activities of a benzimidazole compound through sirtuin inhibition in colorectal cancer

Tan YJ, Lee YT, Yeong KY, Petersen SH, Kono K, Tan SC, et al.

Future Med Chem, 2018 Sep 01;10(17):2039-2057.
PMID: 30066578 DOI: 10.4155/fmc-2018-0052

AIM: This study aims to investigate the mode of action of a novel sirtuin inhibitor (BZD9L1) and its associated molecular pathways in colorectal cancer (CRC) cells.
MATERIALS & METHODS: BZD9L1 was tested against metastatic CRC cell lines to evaluate cytotoxicity, cell cycle and apoptosis, senescence, apoptosis related genes and protein expressions, as well as effect against major cancer signaling pathways.
RESULTS & CONCLUSION: BZD9L1 reduced the viability, cell migration and colony forming ability of both HCT 116 and HT-29 metastatic CRC cell lines through apoptosis. BZD9L1 regulated major cancer pathways differently in CRC with different mutation profiles. BZD9L1 exhibited anticancer activities as a cytotoxic drug in CRC and as a promising therapeutic strategy in CRC treatment.
Discovery of gamma-mangostin from Garcinia mangostana as a potent and selective natural SIRT2 inhibitor

Yeong KY, Khaw KY, Takahashi Y, Itoh Y, Murugaiyah V, Suzuki T

Bioorg Chem, 2020 01;94:103403.
PMID: 31711765 DOI: 10.1016/j.bioorg.2019.103403

Studies have suggested that sirtuin inhibition may have beneficial effects on several age-related diseases such as neurodegenerative disorders and cancer. Garcinia mangostana is a well-known tropical plant found mostly in South East Asia with several positive health effects. Some of its phytochemicals such as α-mangostin was found to be able to modulate sirtuin activity in mice and was implicated with inflammation, diabetes and obesity. However, comprehensive studies on sirtuin activity by the prenylated xanthones extracted from Garcinia mangostana have yet to be reported. The present study led to the discovery and identification of γ-mangostin as a potent and selective SIRT2 inhibitor. It was demonstrated that γ-mangostin was able to increase the α-tubulin acetylation in MDA-MD-231 and MCF-7 breast cancer cells. It was also found to possess potent antiproliferative activity against both cell lines. In addition, it was able to induce neurite outgrowth in the N2a cells.
Method validation in quantitative analysis of phase I and phase II metabolites of mitragynine in human urine using liquid chromatography-tandem mass spectrometry

Lee MJ, Ramanathan S, Mansor SM, Yeong KY, Tan SC

Anal Biochem, 2018 02 15;543:146-161.
PMID: 29248503 DOI: 10.1016/j.ab.2017.12.021

A method using solid phase extraction and liquid chromatography-tandem mass spectrometry to quantitatively detect mitragynine, 16-carboxy mitragynine, and 9-O-demethyl mitragynine in human urine samples was developed and validated. The relevant metabolites were identified using multiple reaction monitoring in positive ionization mode using nalorphine as an internal standard. The method was validated for accuracy, precision, recovery, linearity, and lower limit of quantitation. The intra- and inter-day accuracy and precision were found in the range of 83.6-117.5% with coefficient of variation less than 13%. The percentage of recovery for mitragynine, 16-carboxy mitragynine, and 9-O-demethyl mitragynine was within the range of 80.1-118.9%. The lower limit of quantification was 1 ng/mL for mitragynine, 2 ng/mL for 16-carboxy mitragynine, and 50 ng/mL for 9-O-demethyl mitragynine. The developed method was reproducible, high precision and accuracy with good linearity and recovery for mitragynine, 16-carboxy mitragynine, and 9-O-demethyl mitragynine in human urine.
Fulltext The Role of Interferon-α in Neurodegenerative Diseases: A Systematic Review

Hui BSM, Zhi LR, Retinasamy T, Arulsamy A, Law CSW, Shaikh MF, et al.

J Alzheimers Dis, 2023;94(s1):S45-S66.
PMID: 36776068 DOI: 10.3233/JAD-221081

BACKGROUND: Neurodegenerative diseases (NDs) impose significant financial and healthcare burden on populations all over the world. The prevalence and incidence of NDs have been observed to increase dramatically with age. Hence, the number of reported cases is projected to increase in the future, as life spans continues to rise. Despite this, there is limited effective treatment against most NDs. Interferons (IFNs), a family of cytokines, have been suggested as a promising therapeutic target for NDs, particularly IFN-α, which governs various pathological pathways in different NDs.
OBJECTIVE: This systematic review aimed to critically appraise the currently available literature on the pathological role of IFN-α in neurodegeneration/NDs.
METHODS: Three databases, Scopus, PubMed, and Ovid Medline, were utilized for the literature search.
RESULTS: A total of 77 journal articles were selected for critical evaluation, based on the inclusion and exclusion criteria. The studies selected and elucidated in this current systematic review have showed that IFN-α may play a deleterious role in neurodegenerative diseases through its strong association with the inflammatory processes resulting in mainly neurocognitive impairments. IFN-α may be displaying its neurotoxic function via various mechanisms such as abnormal calcium mineralization, activation of STAT1-dependent mechanisms, and increased quinolinic acid production.
CONCLUSION: The exact role IFN-α in these neurodegenerative diseases have yet to be determine due to a lack in more recent evidence, thereby creating a variability in the role of IFN-α. Future investigations should thus be conducted, so that the role played by IFN-α in neurodegenerative diseases could be delineated.
Sirtuin inhibition and anti-cancer activities of ethyl 2-benzimidazole-5-carboxylate derivatives

Yeong KY, Nor Azizi MIH, Berdigaliyev N, Chen WN, Lee WL, Shirazi AN, et al.

Medchemcomm, 2019 Dec 01;10(12):2140-2145.
PMID: 32904142 DOI: 10.1039/c9md00323a

New benzimidazoles were synthesized based on the previously identified sirtuin inhibitor BZD9L1. The compounds were screened for their sirtuin (SIRT1, SIRT2 and SIRT3) inhibitory activities. Compound BZD9Q1 was determined to be a pan-SIRT1-3 inhibitor. Furthermore, the proliferation of various cancer cells was inhibited by BZD9Q1. It was shown that BZD9Q1 elicits a cytostatic effect by inducing cell cycle arrest at the G2/M phase while also showing a prominent induction of apoptosis against oral cancer cells.
Fulltext Linking Diabetes to Alzheimer's Disease: Potential Roles of Glucose Metabolism and Alpha-Glucosidase

Wee AS, Nhu TD, Khaw KY, Tang KS, Yeong KY

Curr Neuropharmacol, 2023;21(10):2036-2048.
PMID: 36372924 DOI: 10.2174/1570159X21999221111102343

Alzheimer's disease (AD) and type 2 diabetes mellitus (DM) are more prevalent with ageing and cause a substantial global socio-economic burden. The biology of these two conditions is well elaborated, but whether AD and type 2 DM arise from coincidental roots in ageing or are linked by pathophysiological mechanisms remains unclear. Research findings involving animal models have identified mechanisms shared by both AD and type 2 DM. Deposition of β-amyloid peptides and formation of intracellular neurofibrillary tangles are pathological hallmarks of AD. Type 2 DM, on the other hand, is a metabolic disorder characterised by hyperglycaemia and insulin resistance. Several studies show that improving type 2 DM can delay or prevent the development of AD, and hence, prevention and control of type 2 DM may reduce the risk of AD later in life. Alpha-glucosidase is an enzyme that is commonly associated with hyperglycaemia in type 2 DM. However, it is uncertain if this enzyme may play a role in the progression of AD. This review explores the experimental evidence that depicts the relationship between dysregulation of glucose metabolism and AD. We also delineate the links between alpha-glucosidase and AD and the potential role of alpha-glucosidase inhibitors in treating AD.
Repurposing Anakinra for Alzheimer's Disease: The In Vitro and In Vivo Effects of Anakinra on LPS- and AC-Induced Neuroinflammation

Retinasamy T, Lee ALY, Lee HS, Lee VLL, Shaikh MF, Yeong KY

ACS Chem Neurosci, 2024 Aug 30.
PMID: 39213521 DOI: 10.1021/acschemneuro.4c00205

Alzheimer's disease is a significant global health issue, and studies suggest that neuroinflammation plays a vital role in the advancement of this disease. In this study, anakinra has been shown to display a time- and concentration-dependent antineuroinflammatory effect. In the in vitro studies, it diminished the gene expressions of tumor necrosis factor-alpha (TNF-α) and nitric oxide (NO) synthase 2 stimulated by lipopolysaccharide (LPS). Anakinra also reduced the LPS-induced production of NO and reactive oxygen species. Thus, the hypertrophic state of LPS-activated BV2 microglial cells was reversed by anakinra. Furthermore, acrylamide (ACR)-induced activation of nuclear transcription factor-κB, TNF-α, and interleukin-1β was downregulated, while cAMP response element binding protein and brain-derived neurotrophic factor expression levels were markedly enhanced in ACR-treated zebrafish larvae. It was also observed that anakinra improved the uncoordinated swimming behaviors in ACR-exposed zebrafish larvae. Overall, anakinra demonstrated potential antineuroinflammatory and antioxidative effects.
Monitoring of heavy metal pollution in urban and rural environments across Pakistan using House crows (Corvus splendens) as bioindicator

Iqbal F, Ayub Q, Wilson R, Song BK, Talei A, Yeong KY, et al.

Environ Monit Assess, 2021 Mar 30;193(4):237.
PMID: 33783594 DOI: 10.1007/s10661-021-08966-7

A widely distributed urban bird, the house crow (Corvus splendens), was used to assess bioavailable heavy metals in urban and rural environments across Pakistan. Bioaccumulation of arsenic (As), zinc (Zn), lead (Pb), cadmium (Cd), nickel (Ni), iron (Fe), manganese (Mn), chromium (Cr), and copper (Cu) was investigated in wing feathers of 96 crows collected from eight locations and categorized into four groups pertaining to their geographical and environmental similarities. Results revealed that the concentrations of Pb, Ni, Mn, Cu, and Cr were positively correlated and varied significantly among the four groups. Zn, Fe, Cr, and Cu regarded as industrial outputs, were observed in birds both in industrialized cities and in adjoining rural agricultural areas irrigated through the Indus Basin Irrigation System. Birds in both urban regions accrued Pb more than the metal toxicity thresholds for birds. The house crow was ranked in the middle on the metal accumulation levels in feathers between highly accumulating raptor and piscivore and less contaminated insectivore and granivore species in the studied areas,. This study suggests that the house crow is an efficient bioindicator and supports the feasibility of using feathers to discriminate the local pollution differences among terrestrial environments having different levels and kinds of anthropogenic activities.
Contrasting sirtuin and poly(ADP-ribose)polymerase activities of selected 2,4,6-trisubstituted benzimidazoles

Yeong KY, Tan SC, Mai CW, Leong CO, Chung FF, Lee YK, et al.

Chem Biol Drug Des, 2018 01;91(1):213-219.
PMID: 28719017 DOI: 10.1111/cbdd.13072

Both sirtuin and poly(ADP-ribose)polymerase (PARP) family of enzymes utilize NAD+ as co-substrate. Inhibitors of sirtuins and PARPs are important tools in drug discovery as they are reported to be linked to multiple diseases such as cancer. New potent sirtuin inhibitors (2,4,6-trisubstituted benzimidazole) were discovered from reported PARP inhibitor scaffold. Interestingly, the synthesized compounds have contrasting sirtuin and PARP-1 inhibitory activities. We showed that modification on benzimidazoles may alter their selectivity toward sirtuin or PARP-1 enzymes. This offers an opportunity for further discovery and development of new promising sirtuin inhibitors. Molecular docking studies were carried out to aid the rationalization of these observations. Preliminary antiproliferative studies of selected compounds against nasopharyngeal cancer cells also showed relatively promising results.