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Fulltext Antibiotic resistance modifying ability of phytoextracts in anthrax biological agent Bacillus anthracis and emerging superbugs: a review of synergistic mechanisms

Dassanayake MK, Khoo TJ, An J

Ann Clin Microbiol Antimicrob, 2021 Dec 02;20(1):79.
PMID: 34856999 DOI: 10.1186/s12941-021-00485-0

BACKGROUND AND OBJECTIVES: The chemotherapeutic management of infections has become challenging due to the global emergence of antibiotic resistant pathogenic bacteria. The recent expansion of studies on plant-derived natural products has lead to the discovery of a plethora of phytochemicals with the potential to combat bacterial drug resistance via various mechanisms of action. This review paper summarizes the primary antibiotic resistance mechanisms of bacteria and also discusses the antibiotic-potentiating ability of phytoextracts and various classes of isolated phytochemicals in reversing antibiotic resistance in anthrax agent Bacillus anthracis and emerging superbug bacteria.
METHODS: Growth inhibitory indices and fractional inhibitory concentration index were applied to evaluate the in vitro synergistic activity of phytoextract-antibiotic combinations in general.
FINDINGS: A number of studies have indicated that plant-derived natural compounds are capable of significantly reducing the minimum inhibitory concentration of standard antibiotics by altering drug-resistance mechanisms of B. anthracis and other superbug infection causing bacteria. Phytochemical compounds allicin, oleanolic acid, epigallocatechin gallate and curcumin and Jatropha curcas extracts were exceptional synergistic potentiators of various standard antibiotics.
CONCLUSION: Considering these facts, phytochemicals represents a valuable and novel source of bioactive compounds with potent antibiotic synergism to modulate bacterial drug-resistance.
Antibacterial alkaloids from Artabotrys crassifolius Hook.f. & Thomson

Tan KK, Khoo TJ, Rajagopal M, Wiart C

Nat Prod Res, 2015;29(24):2346-9.
PMID: 25738993 DOI: 10.1080/14786419.2015.1013954

Chloroform extract of bark of Artabotrys crassifolius Hook.f. & Thomson exhibited antibacterial activities against both American Type Culture Collection and clinical bacterial strains in vitro with zones of inhibition ranging from 7 to 14 mm. Further analysis of this extract yielded artabotrine, liridine, lysicamine and atherospermidine. Artabotrine displayed a broad array of antibacterial activity mostly against Gram-positive bacteria with minimum inhibitory concentration (MIC) values ranging from 1.25 μg/mL to 5 μg/mL. Of note, artabotrine, liridine and lysicamine are bactericidal against Gram-negative extended-spectrum beta-lactamase-producing Klebsiella with MIC values equal 2.5, 2.5 and 10 μg/mL, respectively, and minimum bactericidal concentrations values equal to 2.5, 5 and 20 μg/mL.
Fulltext Synthesis, Characterization, and Bioactivity of Schiff Bases and Their Cd(2+), Zn(2+), Cu(2+), and Ni(2+) Complexes Derived from Chloroacetophenone Isomers with S-Benzyldithiocarbazate and the X-Ray Crystal Structure of S-Benzyl- β -N-(4-chlorophenyl)methylenedithiocarbazate

Break MK, Tahir MI, Crouse KA, Khoo TJ

Bioinorg Chem Appl, 2013;2013:362513.
PMID: 24319401 DOI: 10.1155/2013/362513

Two bidentate Schiff base ligands having nitrogen sulphur donor sequence were derived from the condensation of S-benzyldithiocarbazate (SBDTC) with 2-chloroacetophenone and 4-chloroacetophenone to give S-benzyl- β -N-(2-chlorophenyl)methylenedithiocarbazate (NS2) and S-benzyl- β -N-(4-chlorophenyl)methylenedithiocarbazate (NS4) isomers. Each of the ligands was then chelated with Cd(2+), Zn(2+), Cu(2+), and Ni(2+). The compounds were characterized via IR spectroscopy and melting point while the structure of NS4 was revealed via X-ray crystallography. Finally, the compounds were screened for antimicrobial activity to investigate the effect that is brought by the introduction of the chlorine atom to the benzene ring. X-ray crystallographic analysis showed that the structure of NS4 is planar with a phenyl ring that is nearly perpendicular to the rest of the molecules. The qualitative antimicrobial assay results showed that NS4 and its complexes lacked antifungal activity while Gram-positive bacteria were generally inhibited more strongly than Gram-negative bacteria. Furthermore, NS4 metal complexes were inhibited more strongly than the ligand while the opposite was seen with NS2 ligand and its complexes due to the partial solubility in dimethyl sulfoxide (DMSO). It was concluded that generally NS2 derivatives have higher bioactivity than that of NS4 derivatives and that the Cd complexes of both ligands have pronounced activity specifically on K. rhizophila.
Fulltext Crystal structure of benzyl (E)-2-(3,4-di-meth-oxy-benzyl-idene)hydrazine-1-carbodi-thio-ate

Tan YF, Break MK, Tahir MI, Khoo TJ

Acta Crystallogr E Crystallogr Commun, 2015 Feb 1;71(Pt 2):238-40.
PMID: 25878829 DOI: 10.1107/S205698901500095X

The title compound, C17H18N2O2S2, synthesized via a condensation reaction between S-benzyl di-thio-carbazate and 3,4-di-meth-oxy-benzaldehyde, crystallized with two independent mol-ecules (A and B) in the asymmetric unit. Both mol-ecules have an L-shape but differ in the orientation of the benzyl ring with respect to the 3,4-di-meth-oxy-benzyl-idine ring, this dihedral angle is 65.59 (8)° in mol-ecule A and 73.10 (8)° in mol-ecule B. In the crystal, the A and B mol-ecules are linked via pairs of N-H⋯S hydrogen bonds, forming dimers with an R 2 (2)(8) ring motif. The dimers are linked via pairs of C-H⋯O hydrogen bonds, giving inversion dimers of dimers. These units are linked by C-H⋯π inter-actions, forming ribbons propagating in the [100] direction.
Bioengineering of the Plant Culture of Capsicum frutescens with Vanillin Synthase Gene for the Production of Vanillin

Chee MJ, Lycett GW, Khoo TJ, Chin CF

Mol Biotechnol, 2017 Jan;59(1):1-8.
PMID: 27826796 DOI: 10.1007/s12033-016-9986-2

Production of vanillin by bioengineering has gained popularity due to consumer demand toward vanillin produced by biological systems. Natural vanillin from vanilla beans is very expensive to produce compared to its synthetic counterpart. Current bioengineering works mainly involve microbial biotechnology. Therefore, alternative means to the current approaches are constantly being explored. This work describes the use of vanillin synthase (VpVAN), to bioconvert ferulic acid to vanillin in a plant system. The VpVAN enzyme had been shown to directly convert ferulic acid and its glucoside into vanillin and its glucoside, respectively. As the ferulic acid precursor and vanillin were found to be the intermediates in the phenylpropanoid biosynthetic pathway of Capsicum species, this work serves as a proof-of-concept for vanillin production using Capsicum frutescens (C. frutescens or hot chili pepper). The cells of C. frutescens were genetically transformed with a codon optimized VpVAN gene via biolistics. Transformed explants were selected and regenerated into callus. Successful integration of the gene cassette into the plant genome was confirmed by polymerase chain reaction. High-performance liquid chromatography was used to quantify the phenolic compounds detected in the callus tissues. The vanillin content of transformed calli was 0.057% compared to 0.0003% in untransformed calli.
Activity of Pericampylus glaucus and periglaucine A in vitro against nasopharangeal carcinoma and anti-inflammatory activity

Shipton FN, Khoo TJ, Hossan MS, Wiart C

J Ethnopharmacol, 2017 Feb 23;198:91-97.
PMID: 28049063 DOI: 10.1016/j.jep.2016.12.045

ETHNOPHARMACOLOGICAL RELEVANCE: Pericampylus glaucus is a climbing plant found across Asia and used in traditional medicine to treat a number of conditions including splenomegaly, fever, cough, laryngitis, pulmonary disease, asthma, headache, hair loss, snake bite, boar bite, factures, boils, tumours, tetanus, rheumatic pain, itches and eclampsia.
AIM OF THE STUDY: To test extracts of P. glaucus in a number of bioassays and determine the legitimacy of its traditional use.
MATERIALS AND METHODS: The stems, leaves, roots and fruits of P. glaucus were collected and extracted sequentially with hexane, chloroform and ethanol, respectively. The anti-inflammatory activity was assessed by testing the ability of the extracts to inhibit heat induced protein denaturation, stabilise human red blood cells under hypotonic stress and by testing the inhibitory activity of the extracts against cyclooxygenases 1 and 2. Cytotoxicity was tested using the human lung epithelial cell line MRC-5 and nasopharangeal carcinoma cell line HK1 in the MTT assay.
RESULTS: Many of the samples showed an ability to prevent heat induced protein denaturation, as well as prevent lysis of red blood cells. Most of the extracts demonstrated inhibitory activity towards both of the COX enzymes. The ethanol extracts tended to demonstrate greater toxicity than other extracts, with some of the other extracts significantly enhancing growth and metabolism of the cells.
CONCLUSION: The benefit of P. glaucus for the treatment of diseases related to inflammation and cancer was supported by the in vitro assays adopted in this study.
Fulltext A P212121 polymorph of (+)-clusianone

Vaneesa Nagalingam S, Wong Pik Ching J, Khaled Bin Break M, Tahir MI, Khoo TJ

Acta Crystallogr Sect E Struct Rep Online, 2013 Dec 1;69(Pt 12):o1799-800.
PMID: 24860292 DOI: 10.1107/S1600536813031036

The title compound, C33H42O4 [systematic name: (1S,5S,7R)-3-benzoyl-4-hy-droxy-8,8-dimethyl-1,5,7-tris-(3-methyl-but-2--enyl)bi-cyclo-[3.3.1]nona-3-ene-2,9-dione], has a central bi-cyclo-[3.3.1]nonane-2,4,9-trione surrounded by tetra-prenyl-ated and benzoyl groups. The compound was recrystallized several times in methanol using both a slow evaporation method and with a crystal-seeding technique. This subsequently produced diffraction-quality crystals which crystallize in the ortho-rhom-bic space group P212121, in contrast to a previous report of a structure determination in the Pna21 space group [McCandlish et al. (1976 ▶). Acta Cryst. B32, 1793-1801]. The title compound has a melting point of 365-366 K, and a specific rotation [α](20) value of +51.94°. A strong intra-molecular O-H⋯O hydrogen bond is noted. In the crystal, mol-ecules are assembled in the ab plane by weak C-H⋯O inter-actions.
Optimal methods for evaluating antimicrobial activities from plant extracts

Othman M, Loh HS, Wiart C, Khoo TJ, Lim KH, Ting KN

J Microbiol Methods, 2011 Feb;84(2):161-6.
PMID: 21094190 DOI: 10.1016/j.mimet.2010.11.008

The search for antimicrobial agents from plants has been a growing interest in the last few decades. However, results generated from many of these studies cannot be directly compared due to the absence of standardization in particular antimicrobial methods employed. The need for established methods with consistent results for the evaluation of antimicrobial activities from plant extracts has been proposed by many researchers. Nevertheless, there are still many studies reported in the literature describing different methodologies. The aim of this study was to find optimal methods to give consistent quantitative antimicrobial results for studying plant extracts. Three different agar-based assays (pour plate disc diffusion (PPDD), streak plate disc diffusion (SPDD) and well-in agar (WA)) and one broth-based (turbidometric (TB)) assay were used in this study. Extracts from two plant species (Duabanga grandiflora and Acalypha wilkesiana) were tested on two bacterial species, namely Escherichia coli and Staphylococcus aureus. Amongst the agar-based assays, PPDD produced the most reproducible results. TB was able to show the inhibitory effects of the test samples on the growth kinetic of the bacteria including plant extracts with low polarity. We propose that both agar- (i.e PPDD) and broth-based assays should be employed when assessing the antimicrobial activity of plant crude extracts.
Fulltext Benzyl N-[(Z)-(1-methyl-2-sulfanyl-propyl-idene)amino]-carbamodithio-ate

Break MK, Mehta S, Tahir MI, Crouse KA, Khoo TJ

Acta Crystallogr Sect E Struct Rep Online, 2013 Feb 1;69(Pt 2):o178.
PMID: 23424463 DOI: 10.1107/S1600536812051008

The title compound, C(12)H(16)N(2)S(3), was obtained by the condensation reaction of S-benzyl dithio-carbazate and 3-mercaptobutan-2-one. The phenyl ring and thiol (SH) group are approximately perpendicular [S-C-C-C and N-C-C-S torsion angles = 67.8 (3) and 116.9 (2)°, respectively] to the rest of the mol-ecule. In the crystal, mol-ecules are linked by weak S-H⋯S and N-H⋯S hydrogen bonds, π-π inter-actions between the benzene rings [centroid-centroid distance = 3.823 (2) Å] and C-H⋯π inter-actions.
Fulltext Virucidal activity of Garcinia parvifolia leaf extracts in animal cell culture

Adnan A, Allaudin ZN, Hani H, Loh HS, Khoo TJ, Ting KN, et al.

BMC Complement Altern Med, 2019 Jul 10;19(1):169.
PMID: 31291936 DOI: 10.1186/s12906-019-2586-5

BACKGROUND: Garcinia species contain bioactive compounds such as flavonoids, xanthones, triterpernoids, and benzophenones with antibacterial, antifungal, anti-inflammatory, and antioxidant activities. In addition, many of these compounds show interesting biological properties such as anti-human immunodeficiency virus activity. Garcinia parvifolia is used in traditional medicine. Currently, the antiviral activity of G. parvifolia is not known.
METHODS: This study was conducted to determine the effects of ethyl acetate (45 L Ea), ethanol (45 L Et), and hexane (45 L H) leaf extracts of G. parvifolia on the infectivity of pseudorabies virus (PrV) in Vero cells. The antiviral effects of the extracts were determined by cytopathic effect (CPE), inhibition, attachment, and virucidal assays.
RESULTS: The 50% cytotoxicity concentration (CC50) values obtained were 237.5, 555.0, and
Cytotoxic Activity of Boesenbergia rotunda Extracts against Nasopharyngeal Carcinoma Cells (HK1). Cardamonin, a Boesenbergia rotunda Constituent, Inhibits Growth and Migration of HK1 Cells by Inducing Caspase-Dependent Apoptosis and G2/M-Phase Arrest

Break MKB, Chiang M, Wiart C, Chin CF, Khoo ASB, Khoo TJ

Nutr Cancer, 2021;73(3):473-483.
PMID: 32270712 DOI: 10.1080/01635581.2020.1751217

Boesenbergia rotunda (L.) Mansf. is an edible herb that is commonly used in the cuisine of several Asian countries. Studies have shown that it possesses high bioactivity against a variety of cancer cells. In this study, we investigated the cytotoxic activity of Boesenbergia rotunda rhizomes and some of its constituents on nasopharyngeal carcinoma cells (HK1). MTT assay results showed that the methanolic and hexane extracts of Boesenbergia rotunda decreased HK1 cell viability with IC50 values of 136 µg/ml and 66 µg/ml, respectively. Cardamonin, a constituent of Boesenbergia rotunda, exhibited the highest cytotoxic activity with an IC50 value of 27 μg/ml. Further studies on cardamonin revealed that it inhibited the migration of HK1 cells, caused G2/M-phase arrest and induced apoptosis. Apoptosis was induced via activating caspase-8 and caspase-3, but independent of caspase-9. This indicated that cardamonin induced extrinsic apoptosis. Western blot analysis further showed that cardamonin caused extrinsic apoptosis, as the expression levels of intrinsic apoptosis-related proteins (Bcl-XL, Bcl-2 and Bax), were not affected. Finally, JC-1 staining of HK1 cells revealed an increase in the mitochondrial membrane potential after treatment, further proving that cardamonin did not induce apoptosis via the intrinsic pathway. These results reflect cardamonin's potential as an anticancer agent.
Fulltext Novel Semi-Synthetic Cu (II)-Cardamonin Complex Exerts Potent Anticancer Activity against Triple-Negative Breast and Pancreatic Cancer Cells via Inhibition of the Akt Signaling Pathway

Hossan MS, Break MKB, Bradshaw TD, Collins HM, Wiart C, Khoo TJ, et al.

Molecules, 2021 Apr 09;26(8).
PMID: 33918814 DOI: 10.3390/molecules26082166

Cardamonin is a polyphenolic natural product that has been shown to possess cytotoxic activity against a variety of cancer cell lines. We previously reported the semi-synthesis of a novel Cu (II)-cardamonin complex (19) that demonstrated potent antitumour activity. In this study, we further investigated the bioactivity of 19 against MDA-MB-468 and PANC-1 cancer cells in an attempt to discover an effective treatment for triple-negative breast cancer (TNBC) and pancreatic cancer, respectively. Results revealed that 19 abolished the formation of MDA-MB-468 and PANC-1 colonies, exerted growth-inhibitory activity, and inhibited cancer cell migration. Further mechanistic studies showed that 19 induced DNA damage resulting in gap 2 (G2)/mitosis (M) phase arrest and microtubule network disruption. Moreover, 19 generated reactive oxygen species (ROS) that may contribute to induction of apoptosis, corroborated by activation of caspase-3/7, PARP cleavage, and downregulation of Mcl-1. Complex 19 also decreased the expression levels of p-Akt and p-4EBP1, which indicates that the compound exerts its activity, at least in part, via inhibition of Akt signalling. Furthermore, 19 decreased the expression of c-Myc in PANC-1 cells only, which suggests that it may exert its bioactivity via multiple mechanisms of action. These results demonstrate the potential of 19 as a therapeutic agent for TNBC and pancreatic cancer.
Fulltext Synergistic Field Crop Pest Management Properties of Plant-Derived Essential Oils in Combination with Synthetic Pesticides and Bioactive Molecules: A Review

Dassanayake MK, Chong CH, Khoo TJ, Figiel A, Szumny A, Choo CM

Foods, 2021 Aug 27;10(9).
PMID: 34574123 DOI: 10.3390/foods10092016

The management of insect pests and fungal diseases that cause damage to crops has become challenging due to the rise of pesticide and fungicide resistance. The recent developments in studies related to plant-derived essential oil products has led to the discovery of a range of phytochemicals with the potential to combat pesticide and fungicide resistance. This review paper summarizes and interprets the findings of experimental work based on plant-based essential oils in combination with existing pesticidal and fungicidal agents and novel bioactive natural and synthetic molecules against the insect pests and fungi responsible for the damage of crops. The insect mortality rate and fractional inhibitory concentration were used to evaluate the insecticidal and fungicidal activities of essential oil synergists against crop-associated pests. A number of studies have revealed that plant-derived essential oils are capable of enhancing the insect mortality rate and reducing the minimum inhibitory concentration of commercially available pesticides, fungicides and other bioactive molecules. Considering these facts, plant-derived essential oils represent a valuable and novel source of bioactive compounds with potent synergism to modulate crop-associated insect pests and phytopathogenic fungi.
Fulltext Bis{(Z)-[(E)-2-(pyridin-2-yl-methyl-idene)hydrazin-1-yl-idene][(pyridin-2-yl)methyl-sulfan-yl]methane-thiol-ato}nickel(II)

Khoo TJ, Break MK, Tahir MI, Krouse KA, Cowley AR, Watkin DJ

Acta Crystallogr Sect E Struct Rep Online, 2013 Jun 01;69(Pt 6):m323-4.
PMID: 23794987 DOI: 10.1107/S1600536813013032

The title compound, [Ni(C13H11N4S2)2], was obtained by the reaction of S-2-picolyldi-thio-carbazate and pyridine-2-carbaldehyde with nickel(II) acetate. The Ni(II) atom is located on a twofold rotation axis and is bonded to four N atoms at distances of 2.037 (8) and 2.109 (9) Å, and to two S atoms at a distance of 2.406 (3) Å, leading to a distorted octa-hedral coordination. The angle between the mean planes of the coordinating moieties of the two symmetry-related tridentate ligands is 83.3 (2)°. In the crystal, complex mol-ecules are linked by weak C-H⋯S hydrogen bonds, π-π inter-actions between the pyridine rings [centroid-centroid distance = 3.775 (9) Å] and C-H⋯π inter-actions. The hydrogen-bonding inter-actions lead to the formation of layers parallel to (010); π-π inter-actions link these layers into a three-dimensional network.
Fulltext Crude Ethanol Extract of Pithecellobium ellipticum as a Potential Lipid-Lowering Treatment for Hypercholesterolaemia

Wong JP, Wijaya S, Ting KN, Wiart C, Mustafa K, Shipton F, et al.

Evid Based Complement Alternat Med, 2014;2014:492703.
PMID: 24839451 DOI: 10.1155/2014/492703

If left untreated, hypercholesterolaemia can lead to atherosclerosis, given time. Plants from the Fabaceae family have shown the ability to significantly suppress atherosclerosis progression. We selected four extracts from Pithecellobium ellipticum, from the Fabaceae family, to be screened in a 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) assay. The ethanol extract, at a concentration of 500 μ g/mL, exhibited superior inhibition properties over the other extracts by demonstrating 80.9% inhibition, while 0.223 μ g/mL of pravastatin (control) showed 78.1% inhibition towards enzymatic activity. These findings led to the fractionation of the ethanol extract using ethyl acetate : methanol (95 : 5), gradually increasing polarity and produced seven fractions (1A to 7A). Fraction 7A at 150 μ g/mL emerged as being the most promising bioactive fraction with 78.7% inhibition. FRAP, beta carotene, and DPPH assays supported the findings from the ethanol extract as it exhibited good overall antioxidant activity. The antioxidant properties have been said to reduce free radicals that are able to oxidize lipoproteins which are the cause of atherosclerosis. Phytochemical screenings revealed the presence of terpenoid, steroid, flavonoid, and phenolic compounds as the responsible group of compound(s), working individually or synergistically, within the extract to prevent binding of HMG-CoA to HMG-CoA reductase.
Search for antibacterial agents from Malaysian rainforest and tropical plants

Othman M, Genapathy S, Liew PS, Ch'ng QT, Loh HS, Khoo TJ, et al.

Nat Prod Res, 2011 Nov;25(19):1857-64.
PMID: 21838540 DOI: 10.1080/14786419.2010.537274

The world's rainforests hold untold potential for drug discovery. Rainforest plants are thought to contain evolved defensive active metabolites of greater diversity compared to plants from temperate regions. In recent years, the interest and overall output from pharmaceutical companies on novel antibacterial agents has diminished at a time when there is a critical need for them to fight the threat of resistance. In this study, we have investigated the antimicrobial properties of 21 flowering plants from 16 different families against six bacterial strains consisting of two Gram negative and four Gram positive. Using the pour plate disc diffusion technique, almost all extracts from these plants were found to be active against some of the bacterial strains tested. The most interesting and active plants with broad spectrum activities include Duabanga grandiflora, Acalypha wilkesiana and Pseuduvaria macrophylla where the minimum inhibitory concentration, minimum bactericidal concentration and phytochemical analysis were carried out. This is the first report describing the antimicrobial and phytochemical properties of D. grandiflora and P. macrophylla. Our findings support the utilisation of higher plant species in the search for new antimicrobial molecules to combat new emerging infective diseases and the problem of drug resistant pathogens.
Acalypha wilkesiana extracts induce apoptosis by causing single strand and double strand DNA breaks

Lim SW, Ting KN, Bradshaw TD, Zeenathul NA, Wiart C, Khoo TJ, et al.

J Ethnopharmacol, 2011 Nov 18;138(2):616-23.
PMID: 22008878 DOI: 10.1016/j.jep.2011.10.005

The seeds of Acalypha wilkesiana have been used empirically by traditional healers in Southwest Nigeria together with other plants as a powder mixture to treat patients with breast tumours and inflammation.
Cardiac glycoside cerberin exerts anticancer activity through PI3K/AKT/mTOR signal transduction inhibition

Hossan MS, Chan ZY, Collins HM, Shipton FN, Butler MS, Rahmatullah M, et al.

Cancer Lett, 2019 07 01;453:57-73.
PMID: 30930233 DOI: 10.1016/j.canlet.2019.03.034

Natural products possess a significant role in anticancer therapy and many currently-used anticancer drugs are of natural origin. Cerberin (CR), a cardenolide isolated from the fruit kernel of Cerbera odollam, was found to potently inhibit cancer cell growth (GI50 values 60% bioavailability and rapid absorption; doses of 1-10 mg/kg CR were predicted to maintain efficacious unbound plasma concentrations (>GI50 value). CR's potent and selective anti-tumour activity, and its targeting of key signalling mechanisms pertinent to tumourigenesis support further preclinical evaluation of this cardiac glycoside.
Antiviral activity of Embelia ribes Burm. f. against influenza virus in vitro

Hossan MS, Fatima A, Rahmatullah M, Khoo TJ, Nissapatorn V, Galochkina AV, et al.

Arch Virol, 2018 Aug;163(8):2121-2131.
PMID: 29633078 DOI: 10.1007/s00705-018-3842-6

Viral respiratory infections are raising serious concern globally. Asian medicinal plants could be useful in improving the current treatment strategies for influenza. The present study examines the activity of five plants from Bangladesh against influenza virus. MDCK cells infected with influenza virus A/Puerto Rico/8/34 (H1N1) were treated with increasing concentrations of ethyl acetate extracts, and their cytotoxicity (CC50), virus-inhibiting activity (IC50), and selectivity index (SI) were calculated. The ethyl acetate extract of fruits of Embelia ribes Burm. f. (Myrsinaceae) had the highest antiviral activity, with an IC50 of 0.2 µg/mL and a SI of 32. Its major constituent, embelin, was further isolated and tested against the same virus. Embelin demonstrated antiviral activity, with an IC50 of 0.3 µM and an SI of 10. Time-of-addition experiments revealed that embelin was most effective when added at early stages of the viral life cycle (0-1 h postinfection). Embelin was further evaluated against a panel of influenza viruses including influenza A and B viruses that were susceptible or resistant to rimantadine and oseltamivir. Among the viruses tested, avian influenza virus A/mallard/Pennsylvania/10218/84 (H5N2) was the most susceptible to embelin (SI = 31), while A/Aichi/2/68 (H3N2) virus was the most resistant (SI = 5). In silico molecular docking showed that the binding site for embelin is located in the receptor-binding domain of the viral hemagglutinin. The results of this study provide evidence that E. ribes can be used for development of a novel alternative anti-influenza plant-based agent.
Discovery of a highly active anticancer analogue of cardamonin that acts as an inducer of caspase-dependent apoptosis and modulator of the mTOR pathway

Break MKB, Hossan MS, Khoo Y, Qazzaz ME, Al-Hayali MZK, Chow SC, et al.

Fitoterapia, 2018 Mar;125:161-173.
PMID: 29355749 DOI: 10.1016/j.fitote.2018.01.006

Cardamonin is a natural chalcone that has been shown to exhibit high anticancer activity. In an attempt to discover analogues of cardamonin with enhanced anticancer activity, 19 analogues were synthesized and tested against A549 and HK1 cell lines. Results of the MTS cell viability assay showed that several derivatives possessed cytotoxic activities that were several-fold more potent than cardamonin. SAR analysis showed the importance of the ketone and alkene groups for bioactivity, while substituting cardamonin's phenolic groups with more polar moieties resulted in activity enhancement. As part of the SAR study and further exploration of chemical space, the effect of metal coordination on cytotoxicity was also investigated, but it was only possible to successfully obtain the Cu (II) complex of cardamonin (19). Compound 19 was the most active analogue possessing IC50 values of 13.2μM and 0.7μM against A549 and HK1 cells, corresponding to a 5- and 32-fold increase in activity, respectively. It was also able to significantly inhibit the migration of A549 and HK1 cells. Further mode of action studies have shown that the most active analogue, 19, induced DNA damage resulting in G2/M-phase cell- cycle arrest in both cell lines. These events further led to the induction of apoptosis by the compound via caspase-3/7 and caspase-9 activation, PARP cleavage and downregulation of Mcl-1 expression. Moreover, 19 inhibited the expression levels of p-mTOR and p-4EBP1, which indicated that it exerted its anticancer activity, at least in part, via inhibition of the mTOR signalling pathway.

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