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Natural Sirtuin Modulators in Drug Discovery: A Review (2010 -2020)

Chang Y, Yeong KY

Curr Med Chem, 2021 Mar 29.
PMID: 33781187 DOI: 10.2174/0929867328666210329124415

There have been intense research interests in sirtuins since the establishment of their regulatory roles in a myriad of pathological processes. In the last two decades, much research efforts have been dedicated to the development of sirtuin modulators. Although synthetic sirtuin modulators are the focus, natural modulators remain an integral part to be further explored in this area as they are found to possess therapeutic potential in various diseases including cancers, neurodegenerative diseases, and metabolic disorders. Owing to the importance of this cluster of compounds, this review gives a current stand on the naturally occurring sirtuin modulators, , associated molecular mechanisms and their therapeutic benefits.. Furthermore, comprehensive data mining resulted in detailed statistical data analyses pertaining to the development trend of sirtuin modulators from 2010-2020. Lastly, the challenges and future prospect of natural sirtuin modulators in drug discovery will also be discussed.
Repurposing Antihypertensive Drugs for the Management of Alzheimer's Disease

Law CSW, Yeong KY

Curr Med Chem, 2021;28(9):1716-1730.
PMID: 32164502 DOI: 10.2174/0929867327666200312114223

Alzheimer's disease (AD) is a neurodegenerative disorder that has affected millions of people worldwide. However, currently, there is no treatment to cure the disease. The AD drugs available in the market only manage the disease symptomatically and the effects are usually short-term. Thus, there is a need to look at alternatives AD therapies. This literature review aims to shed some light on the potential of repurposing antihypertensives to treat AD. Mid-life hypertension has not only been recognised as a risk factor for AD, but its relation with AD has also been well established. Hence, antihypertensives were postulated to be beneficial in managing AD. Four classes of antihypertensives, as well as their potential limitations and prospects in being utilised as AD therapeutics, were discussed in this review.
Scopolamine, a Toxin-Induced Experimental Model, Used for Research in Alzheimer's Disease

Chen WN, Yeong KY

CNS Neurol Disord Drug Targets, 2020;19(2):85-93.
PMID: 32056532 DOI: 10.2174/1871527319666200214104331

Scopolamine as a drug is often used to treat motion sickness. Derivatives of scopolamine have also found applications as antispasmodic drugs among others. In neuroscience-related research, it is often used to induce cognitive disorders in experimental models as it readily permeates the bloodbrain barrier. In the context of Alzheimer's disease, its effects include causing cholinergic dysfunction and increasing amyloid-β deposition, both of which are hallmarks of the disease. Hence, the application of scopolamine in Alzheimer's disease research is proven pivotal but seldom discussed. In this review, the relationship between scopolamine and Alzheimer's disease will be delineated through an overall effect of scopolamine administration and its specific mechanisms of action, discussing mainly its influences on cholinergic function and amyloid cascade. The validity of scopolamine as a model of cognitive impairment or neurotoxin model will also be discussed in terms of advantages and limitations with future insights.
From Nucleic Acids to Drug Discovery: Nucleobases as Emerging Templates for Drug Candidates

Wong XK, Yeong KY

Curr Med Chem, 2021 Oct 27;28(34):7076-7121.
PMID: 33588718 DOI: 10.2174/0929867328666210215113828

Nucleobases represent key structural motifs in biologically active molecules, including synthetic and natural products. Molecular modifications made on nucleobases or their isolation from natural sources are being widely investigated for the development of drugs with improved potency for the treatment of different diseases, such as cancer, as well as viral and bacterial infections. This review article focuses on the nucleobase analogue drug developments of the past 20 years (2000-2020). Various pharmacological and medicinal aspects of nucleobases and their analogues are discussed. The current state and limitations are also highlighted.
Benzimidazoles in Drug Discovery: A Patent Review

Law CSW, Yeong KY

ChemMedChem, 2021 06 17;16(12):1861-1877.
PMID: 33646618 DOI: 10.1002/cmdc.202100004

Benzimidazole is a heterocyclic ring system that has been widely studied in the pharmaceutical field. For the past decade, numerous benzimidazole derivatives have been synthesized and evaluated for their wide range of pharmacological activities, which are beneficial for drug development. This article presents the biological effects of benzimidazole derivatives in each invention from 2015 to 2020. Two patent databases, Google Patents and Lens, were used to locate relevant granted patent applications. Specifically, this review delineates the role of patented benzimidazoles from a disease-centric perspective and examines the mechanisms of action of these compounds in related diseases. Most of the benzimidazoles have shown good activities against various target proteins. Whilst several of them have progressed into clinical trials, most patents presented novel therapeutic approaches for respective target diseases. Hence, their potential in being developed into clinical drugs are also discussed.
A Patent Review on the Current Developments of Benzoxazoles in Drug Discovery

Wong XK, Yeong KY

ChemMedChem, 2021 11 05;16(21):3237-3262.
PMID: 34289258 DOI: 10.1002/cmdc.202100370

The benzoxazole moiety is widely found in various natural compounds, which are often found to be biologically active. Due to its versatile biological properties, benzoxazole has been incorporated as an essential pharmacophore and substructure in many medicinal compounds. In the past years, numerous benzoxazole derivatives have been synthesised and evaluated for their biological potential. The wide range in therapeutic potential of benzoxazole derivatives is related to the favourable interactions of the benzoxazole moiety with different protein targets. Herein we review the biological activities of benzoxazole derivatives patented within the past six years. Using the Lens database, granted patents issued from 2015 to 2020 were retrieved. The patented benzoxazole derivatives demonstrated excellent activity against various protein targets and diseases, with some reaching clinical trial stage. Pharmacological and medicinal aspects of patented benzoxazole derivatives are discussed. The recent development and drawbacks are also reviewed.
Current trends of benzothiazoles in drug discovery: a patent review (2015-2020)

Law CSW, Yeong KY

Expert Opin Ther Pat, 2022 Jan 17.
PMID: 34986720 DOI: 10.1080/13543776.2022.2026327

INTRODUCTION: Benzothiazole is a bicyclic ring system composed of thiazole and benzene rings. It is present as an important pharmacophore in many marketed drugs. The notable potential of benzothiazoles as therapeutic agent for different target diseases has prompted a growing interest in benzothiazole-based drug development in recent years.
AREAS COVERED: This review of 55 benzothiazole-related patents, filed from 2015 to 2020, covers a wide range of pharmacological activities. These patents were collated from Google Patents and Lens search engines. The inventions were categorized and discussed based on their respective group of target diseases, including metabolic diseases, cancer, inflammation, neurodegeneration, viral diseases, bacterial infections, fibrosis and thrombosis.
EXPERT OPINION: Benzothiazole has shown to be a scaffold with great pharmacological importance and thus, serves as a building block for the development of derivatives having high therapeutic activity. Benzothiazole derivatives were patented for a range of therapeutic applications, with a special focus on cancer research. Several compounds have the potential to progress into the market, given that they exert both selectivity and in vivo efficacy. Others require a more thorough study to obtain adequate information on the compounds.
Sirtuins and Their Implications in Neurodegenerative Diseases from a Drug Discovery Perspective

Yeong KY, Berdigaliyev N, Chang Y

ACS Chem Neurosci, 2020 12 16;11(24):4073-4091.
PMID: 33280374 DOI: 10.1021/acschemneuro.0c00696

Sirtuins are class III histone deacetylase (HDAC) enzymes that target both histone and non-histone substrates. They are linked to different brain functions and the regulation of different isoforms of these enzymes is touted to be an emerging therapy for the treatment of neurodegenerative diseases (NDs), including Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). The level of sirtuins affects brain health as many sirtuin-regulated pathways are responsible for the progression of NDs. Certain sirtuins are also implicated in aging, which is a risk factor for many NDs. In addition to SIRT1-3, it has been suggested that the less studied sirtuins (SIRT4-7) also play critical roles in brain health. This review delineates the role of each sirtuin isoform in NDs from a disease centric perspective and provides an up-to-date overview of sirtuin modulators and their potential use as therapeutics in these diseases. Furthermore, the future perspectives for sirtuin modulator development and their therapeutic application in neurodegeneration are outlined in detail, hence providing a research direction for future studies.
Butyrylcholinesterase: A Multifaceted Pharmacological Target and Tool

Ha ZY, Mathew S, Yeong KY

Curr Protein Pept Sci, 2020;21(1):99-109.
PMID: 31702488 DOI: 10.2174/1389203720666191107094949

Butyrylcholinesterase is a serine hydrolase that catalyzes the hydrolysis of esters in the body. Unlike its sister enzyme acetylcholinesterase, butyrylcholinesterase has a broad substrate scope and lower acetylcholine catalytic efficiency. The difference in tissue distribution and inhibitor sensitivity also points to its involvement external to cholinergic neurotransmission. Initial studies on butyrylcholinesterase showed that the inhibition of the enzyme led to the increment of brain acetylcholine levels. Further gene knockout studies suggested its involvement in the regulation of amyloid-beta, a brain pathogenic protein. Thus, it is an interesting target for neurological disorders such as Alzheimer's disease. The substrate scope of butyrylcholinesterase was recently found to include cocaine, as well as ghrelin, the "hunger hormone". These findings led to the development of recombinant butyrylcholinesterase mutants and viral gene therapy to combat cocaine addiction, along with in-depth studies on the significance of butyrylcholinesterase in obesity. It is observed that the pharmacological impact of butyrylcholinesterase increased in tandem with each reported finding. Not only is the enzyme now considered an important pharmacological target, it is also becoming an important tool to study the biological pathways in various diseases. Here, we review and summarize the biochemical properties of butyrylcholinesterase and its roles, as a cholinergic neurotransmitter, in various diseases, particularly neurodegenerative disorders.
Fulltext Potential Roles of α-amylase in Alzheimer's Disease: Biomarker and Drug Target

Chen WN, Tang KS, Yeong KY

Curr Neuropharmacol, 2022;20(8):1554-1563.
PMID: 34951390 DOI: 10.2174/1570159X20666211223124715

Alzheimer's disease (AD), the most common form of dementia, is pathologically characterized by the deposition of amyloid-β plaques and the formation of neurofibrillary tangles. In a neurodegenerative brain, glucose metabolism is also impaired and considered as one of the key features in AD patients. The impairment causes a reduction in glucose transporters and the uptake of glucose as well as alterations in the specific activity of glycolytic enzymes. Recently, it has been reported that α-amylase, a polysaccharide-degrading enzyme, is present in the human brain. The enzyme is known to be associated with various diseases such as type 2 diabetes mellitus and hyperamylasaemia. With this information at hand, we hypothesize that α-amylase could have a vital role in the demented brains of AD patients. This review aims to shed insight into the possible link between the expression levels of α-amylase and AD. Lastly, we also cover the diverse role of amylase inhibitors and how they could serve as a therapeutic agent to manage or stop AD progression.
Modern vaccine development via reverse vaccinology to combat antimicrobial resistance

Tobuse AJ, Ang CW, Yeong KY

Life Sci, 2022 Aug 01;302:120660.
PMID: 35642852 DOI: 10.1016/j.lfs.2022.120660

With the continuous evolution of bacteria, the global antimicrobial resistance health threat is causing millions of deaths yearly. While depending on antibiotics as a primary treatment has its merits, there are no effective alternatives thus far in the pharmaceutical market against some drug-resistant bacteria. In recent years, vaccinology has become a key topic in scientific research. Combining with the growth of technology, vaccine research is seeing a new light where the process is made faster and more efficient. Although less discussed, bacterial vaccine is a feasible strategy to combat antimicrobial resistance. Some vaccines have shown promising results with good efficacy against numerous multidrug-resistant strains of bacteria. In this review, we aim to discuss the findings from studies utilizing reverse vaccinology for vaccine development against some multidrug-resistant bacteria, as well as provide a summary of multi-year bacterial vaccine studies in clinical trials. The advantages of reverse vaccinology in the generation of new bacterial vaccines are also highlighted. Meanwhile, the limitations and future prospects of bacterial vaccine concludes this review.
Anti-Amyloid β Aggregation Activity and Cell Viability Effect of Betacyanins from Red Pitahaya (Hylocereus polyrhizus) for Alzheimer's Disease

Thwe PN, Yeong KY, Choo WS

Plant Foods Hum Nutr, 2023 Sep;78(3):613-619.
PMID: 37466824 DOI: 10.1007/s11130-023-01081-7

Betacyanin-rich extract from red beet (Beta vulgaris) was recently reported to inhibit amyloid β (Aβ) aggregation, a main pathological event in Alzheimer's disease. However, the anti-Aβ aggregation effect of individual betacyanin isolates has not been reported before. This study investigated the anti-Aβ aggregation activity and cytotoxicity of betacyanins from red pitahaya or red dragon fruit (Hylocereus polyrhizus). Betacyanin fraction (IC50 = 16.02 ± 1.15 µg/mL) and individual betacyanin isolates exhibited anti-Aβ aggregation activity in a concentration-dependent manner using a thioflavin T fluorescence assay. The highest to lowest IC50 was in the order of betanin (426.30 ± 29.55 µM), phyllocactin (175.22 ± 1.52 µM), and hylocerenin (131.73 ± 5.58 µM), following a trend of increase in functional groups of carboxyl, hydroxyl, and/or carbonyl. Further, the betacyanin fraction of 135.78 µg/mL and below, which were concentrations with an anti-Aβ aggregation effect, were validated as non-neurotoxic based on an in vitro cytotoxicity assay using human neuroblastoma (SH-SY5Y) cells. These findings highlight the potential neuroprotective activity of betacyanins for Alzheimer's disease.
Fulltext Shaping the future of antiviral Treatment: Spotlight on Nucleobase-Containing drugs and their revolutionary impact

Wong XK, Ng CS, Yeong KY

Bioorg Chem, 2024 Mar;144:107150.
PMID: 38309002 DOI: 10.1016/j.bioorg.2024.107150

Nucleobases serve as essential molecular frameworks present in both natural and synthetic compounds that exhibit notable antiviral activity. Through molecular modifications, novel nucleobase-containing drugs (NCDs) have been developed, exhibiting enhanced antiviral activity against a wide range of viruses, including the recently emerged SARS‑CoV‑2. This article provides a detailed examination of the significant advancements in NCDs from 2015 till current, encompassing various aspects concerning their mechanisms of action, pharmacology and antiviral properties. Additionally, the article discusses antiviral prodrugs relevant to the scope of this review. It fills in the knowledge gap by examining the structure-activity relationship and trend of NCDs as therapeutics against a diverse range of viral diseases, either as approved drugs, clinical candidates or as early-stage development prospects. Moreover, the article highlights on the status of this field of study and addresses the prevailing limitations encountered.
SIRT1 inhibition in pancreatic cancer models: contrasting effects in vitro and in vivo

Oon CE, Strell C, Yeong KY, Östman A, Prakash J

Eur J Pharmacol, 2015 Jun 15;757:59-67.
PMID: 25843411 DOI: 10.1016/j.ejphar.2015.03.064

Gemcitabine remains the standard treatment for pancreatic cancer, although most patients acquire resistance to the therapy. Up-regulated in pancreatic cancer, SIRT1 is involved in tumorigenesis and drug resistance. However the mechanism through which SIRT1 regulates drug sensitivity in cancer cells is mainly unknown. We hypothesise that inhibiting SIRT1 activity may increase sensitivity of pancreatic cancer cells to gemcitabine treatment through the regulation of apototic cell death, cell cycle, epithelial-mesenschymal-transition (EMT) and senescence. We demonstrate that gemcitabine or 6-Chloro-2,3,4,9-tetrahydro-1 H-Carbazole-1-carboxamide (EX527) SIRT1 inhibitor reduces PANC-1 cell proliferation in vitro. EX527 enhanced sensitivity of PANC-1 cells to gemcitabine treatment through increased apoptosis. However, EX527 displayed no beneficial effect either as a monotreatment or in combination with gemcitabine in the modulation of cell cycle progression. Combination treatment did not reverse the two phenomena known to affect drug sensitivity, namely EMT and senescence, which are both induced by gemcitabine. Unexpectedly, EX527 promoted PANC-1 xenograft tumour growth in SCID mice compared to control group. Dual tX527 and gemcitabine displayed no synergistic effect compared to gemcitabine alone. The study reveals that SIRT1 is involved in chemoresistance and that inhibiting SIRT1 activity with EX527 sensitised PANC-1 cells to gemcitabine treatment in vitro. Sensitisation of cells is shown to be mainly through induction of micronuclei formation as a result of DNA damage and apoptosis in vitro. However, the absence of positive combinatorial effects in vivo indicates possible effects on cells of the tumor microenvironment and suggests caution regarding the clinical relevance of tissue culture findings with EX527.
Synthesis, Molecular Docking, and Biological Evaluation of Benzimidazole Derivatives as Selective Butyrylcholinesterase Inhibitors

Ha ZY, Ong HC, Oo CW, Yeong KY

Curr Alzheimer Res, 2020;17(13):1177-1185.
PMID: 33602088 DOI: 10.2174/1567205018666210218151228

BACKGROUND: Benzimidazole is an interesting pharmacophore which has been extensively studied in medicinal chemistry due to its high affinity towards various enzymes and receptors. Its derivatives have been previously shown to possess a wide range of biological activities including anthelmintic, antihypertensive, antiulcer, as well as anticholinesterase activity.
OBJECTIVE: The objective of this study is to search for more potent benzimidazole-based cholinesterase inhibitors, through the modification of the 1- and 2-positions of the benzimidazole core.
METHODS: Synthesis of compounds were carried out via a 4-step reaction scheme following a previously reported protocol. Structure-activity relationship of the compounds are established through in vitro cholinesterase assays and in silico docking studies. Furthermore, cytotoxicity and blood brain barrier (BBB) permeability of the compounds were also investigated.
RESULTS: Among the synthesised compounds, three of them (5IIa, 5IIb, and 5IIc) exhibited potent selective butyrylcholinesterase inhibition at low micromolar level. The compounds did not show any significant cytotoxicity when tested against a panel of human cell lines. Moreover, the most active compound, 5IIc, was highly permeable across the blood brain barrier.
CONCLUSION: In total 10 benzimidazole derivatives were synthesized and screened for their AChE and BuChE inhibitory activities. Lead compound 5Iic, represents a valuable compound for further development as potential AD therapeutics.
In silico studies, synthesis and pharmacological evaluation to explore multi-targeted approach for imidazole analogues as potential cholinesterase inhibitors with neuroprotective role for Alzheimer's disease

Gurjar AS, Darekar MN, Yeong KY, Ooi L

Bioorg Med Chem, 2018 05 01;26(8):1511-1522.
PMID: 29429576 DOI: 10.1016/j.bmc.2018.01.029

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with multiple factors associated with its pathogenesis. Our strategy against AD involves design of multi-targeted 2-substituted-4,5-diphenyl-1H-imidazole analogues which can interact and inhibit AChE, thereby, increasing the synaptic availability of ACh, inhibit BuChE, relieve induced oxidative stress and confer a neuroprotective role. Molecular docking was employed to study interactions within the AChE active site. In silico ADME study was performed to estimate pharmacokinetic parameters. Based on computational studies, some analogues were synthesized and subjected to pharmacological evaluation involving antioxidant activity, toxicity and memory model studies in animals followed by detailed mechanistic in vitro cholinesterase inhibition study. Amongst the series, analogue 13 and 20 are the most promising multi-targeted candidates which can potentially increase memory, decrease free radical levels and protect neurons against cognitive deficit.
Ringing medicinal chemistry: The importance of 3-membered rings in drug discovery

Uthumange SS, Liew AJH, Chee XW, Yeong KY

Bioorg Med Chem, 2024 Oct 31;116:117980.
PMID: 39536361 DOI: 10.1016/j.bmc.2024.117980

Scaffold-based drug design has become increasingly prominent in the pharmaceutical field due to the systematic and effective approach through which it facilitates the development of novel drugs. The identification of key scaffolds provides medicinal chemists with a fundamental framework for subsequent research. With mounting evidence suggesting that increased aromaticity could impede the chances of developmental success for oral drug candidates, there is an imperative need for a more thorough exploration of alternative ring systems to mitigate attrition risks. The unique characteristics exhibited by three-membered rings have led to their application in medicinal chemistry. This review explores the use of cyclopropane-, aziridine-, thiirane-, and epoxide-containing compounds in drug discovery, focusing on their roles in approved medicines and drug candidates. Specifically, the importance of the three-membered ring systems in rending biological activity for each drug molecule was highlighted. The undeniable therapeutic value and intriguing features presented by these compounds suggest significant pharmacological potential, providing justification for their incorporation into the design of novel drug candidates.
Fulltext Ethyl 2-[5-(4-fluoro-phen-yl)pyridin-3-yl]-1-[3-(2-oxopyrrolidin-1-yl)prop-yl]-1H-benzimidazole-5-carboxyl-ate

Yeong KY, Ali MA, Choon TS, Rosli MM, Razak IA

Acta Crystallogr Sect E Struct Rep Online, 2013;69(Pt 7):o1013-4.
PMID: 24046597 DOI: 10.1107/S1600536813014177

In the title compound, C28H27FN4O3·H2O, the benzimidazole ring system is essentially planar with a maximum deviation of 0.028 (1) Å. It makes dihedral angles of 47.59 (5) and 60.31 (5)°, respectively, with the pyridine and benzene rings, which make a dihedral angle of 22.58 (6)° with each other. The pyrrolidine ring shows an envelope conformation with one of the methyl-ene C atoms as the flap. In the crystal, the components are connected into a tape along the b-axis direction through O-H⋯O and O-H⋯N hydrogen bonds and a π-π inter-action between the pyridine and benzene rings [centroid-centroid distance of 3.685 (8) Å]. The tapes are further linked into layers parallel to the ab plane by C-H⋯O and C-H⋯F inter-actions.
Fulltext Ethyl 2-[4-(di-methyl-amino)-phen-yl]-1-phenyl-1H-benzimidazole-5-carboxyl-ate

Yeong KY, Ali MA, Choon TS, Rosli MM, Razak IA

Acta Crystallogr Sect E Struct Rep Online, 2013 Jun 1;69(Pt 6):o886.
PMID: 23795062 DOI: 10.1107/S1600536813012440

In the title compound, C24H23N3O2, the benzimidazole ring system makes dihedral angles of 7.28 (5) and 67.17 (5)°, respectively, with the planes of the benzene and phenyl rings, which in turn make a dihedral angle of 69.77 (6)°. In the crystal, mol-ecules are connected by C-H⋯N and C-H⋯O inter-actions, forming a layer parallel to the bc plane. A π-π inter-action, with a centroid-centroid distance of 3.656 (1) Å, is observed in the layer.
A rhodamine based chemosensor for solvent dependent chromogenic sensing of cobalt (II) and copper (II) ions with good selectivity and sensitivity: Synthesis, filter paper test strip, DFT calculations and cytotoxicity

Chan WC, Saad HM, Sim KS, Lee VS, Ang CW, Yeong KY, et al.

Spectrochim Acta A Mol Biomol Spectrosc, 2021 Jun 23;262:120099.
PMID: 34198119 DOI: 10.1016/j.saa.2021.120099

A new chemosensor 1 was synthesized by reacting rhodamine B hydrazide and 2,3,4-trihydroxybenzaldehyde, which was then characterized by spectroscopic techniques and single crystal X-ray crystallography. Sensor 1 has the ability to sense Co2+/Cu2+ ions by "naked-eye" with an apparent colour change from colourless to pink in different solvent system, MeCN and DMF respectively. Furthermore, it can selectively detect Co2+/Cu2+ among wide range of different metal ions, and it exhibits low detection limit of 4.425 × 10-8 M and 1.398 × 10-7 M respectively. Binding mode of the two complexes were determined to be 1:1 stoichiometry for Co2+ complex and 1:2 stoichiometry for Cu2+ complex through Job's plot, IR spectroscopy, mass spectrometry and 1H NMR spectroscopy. Moreover, reversibility of the sensor 1 as copper (II) ion detector was determined by using EDTA and the results showed that sensor 1 can be reused for at least 6 cycles. Other than that, a low cost chemosensor test strips were fabricated for the convenient "naked-eye" detection of Co2+ and Cu2+ in pure aqueous media. The MTT assay was conducted in order to determine the cytotoxicity of sensor 1 towards human cell lines.

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