Download PDF
Planta Med 2023; 89(11): 1063-1073
DOI: 10.1055/a-2063-5265
Biological and Pharmacological Activity
Original Papers

Anti-viral and Anti-inflammatory Isoflavonoids from Ukrainian Iris aphylla Rhizomes: Structure-Activity Relationship Coupled with ChemGPS-NP Analysis

Olha Mykhailenko‡
1   Department of Pharmaceutical Chemistry, National University of Pharmacy of Ministry of Health of Ukraine, Kharkiv, Ukraine
2   Pharmacognosy and Phytotherapy Group, UCL School of Pharmacy, London, United Kingdom
,
Chung-Fan Hsieh‡
3   Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan
4   Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan City, Taiwan
,
Mohamed El-Shazly
5   Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, African Union Organization Street, Abbassia, Cairo, Egypt
,
Alexander Nikishin
6   V. N. Karazin Kharkiv National University, Organic Chemistry Department, Kharkiv, Ukraine
,
Vladimir Kovalyov
7   Department of Pharmacognosy, National University of Pharmacy of Ministry of Health of Ukraine, Kharkiv, Ukraine
,
Pavlo Shynkarenko
8   Enamine Ltd, Kyiv, Ukraine
,
Liudas Ivanauskas
9   Lithuanian University of Health Sciences, Department of Analytical and Toxicological Chemistry, Kaunas, Lithuania
,
Bing-Hung Chen
10   Department of Biotechnology, College of Life Science, Kaohsiung, Taiwan
11   The Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
,
Jim-Tong Horng
3   Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan
12   Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan
13   Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kweishan, Taoyuan, Taiwan
14   Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan
15   Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan
,
Tsong-Long Hwang
14   Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan
15   Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan
16   Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan
17   Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
,
Victoriya Georgiyants
1   Department of Pharmaceutical Chemistry, National University of Pharmacy of Ministry of Health of Ukraine, Kharkiv, Ukraine
,
Michal Korinek 
10   Department of Biotechnology, College of Life Science, Kaohsiung, Taiwan
16   Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan
18   Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
› Author AffiliationsThe research was supported by grants from the National Science and Technology Council, Taiwan (111-2320-B-037-007 awarded to M. K. for chemical analysis and logistics; 111-2321-B-255-001, 111-2321-B-182 – 001, 109-2320-B-650-001-MY3, 109-2327-B-255-001, and 109-2327-B-182-002 awarded to T.-L. H. for bioactivity assays and instrumentation; 109-2320-B-037-004-MY3 awarded to B.-H. C. for bioactivity assays and analysis). This study was also supported by a grant from the Kaohsiung Medical University Research Foundation (KMU-Q112 006) awarded to M. K. for chemical analysis; Chang Gung Memorial Hospital (CMRPF1M0131-2, CMRPF1M0101-2, CMRPF1L0071, and CORPF1L0011) and Chang Gung University of Science and Technology (ZRRPF3L0091) awarded to T.-L. H. for bioactivity assays and technical support.
› Further Information
    Permissions and Reprints

Abstract

Dried Iris rhizomes have been used in Chinese and European traditional medicine for the treatment of various diseases such as bacterial infections, cancer, and inflammation, as well as for being astringent, laxative, and diuretic agents. Eighteen phenolic compounds including some rare secondary metabolites, such as irisolidone, kikkalidone, irigenin, irisolone, germanaism B, kaempferol, and xanthone mangiferin, were isolated for the first time from Iris aphylla rhizomes. The hydroethanolic Iris aphylla extract and some of its isolated constituents showed protective effects against influenza H1N1 and enterovirus D68 and anti-inflammatory activity in human neutrophils. The promising anti-influenza effect of apigenin (13, almost 100% inhibition at 50 µM), kaempferol (14, 92%), and quercetin (15, 48%) were further confirmed by neuraminidase inhibitory assay. Irisolidone (1, almost 100% inhibition at 50 µM), kikkalidone (5, 93%), and kaempferol (14, 83%) showed promising anti-enterovirus D68 activity in vitro. The identified compounds were plotted using ChemGPS-NP to correlate the observed activity of the isolated phenolic compounds with the in-house database of anti-influenza and anti-enterovirus agents. Our results indicated that the hydroethanolic Iris aphylla extract and Iris phenolics hold the potential to be developed for the management of seasonal pandemics of influenza and enterovirus infections.

Key words

Iris aphylla - Iris hungarica - Iridaceae - isoflavones - enterovirus - influenza - neutrophilic inflammation - ChemGPS-NP

Supporting Information

    The following file is available free of charge.

    Figures and tables describing NMR, spectroscopic, and MS data of isolated compounds, complete anti-viral data (influenza H1N1, enterovirus D68), and ChemGPS-NP in-house database (PDF).

  • Supporting Information


Publication History

Received: 14 July 2022

Accepted after revision: 23 March 2023

Accepted Manuscript online:
28 March 2023

Article published online:
05 June 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Wang C, Wang Z, Wang G, Lau JY, Zhang K, Li W. COVID-19 in early 2021: Current status and looking forward. Signal Transduct Target Ther 2021; 6: 114-128
    CrossrefPubMedGoogle Scholar
  • 2 Woolf SH, Chapman DA, Sabo RT, Zimmerman EB. Excess deaths from COVID-19 and other causes in the US, March 1, 2020, to January 2, 2021. JAMA 2021; 325: 1786-1789
    CrossrefPubMedGoogle Scholar
  • 3 United Nationn. Coronavirus global health emergency. Accessed February 13, 2022 at: https://www.un.org/en/coronavirus
    PubMedGoogle Scholar
  • 4 World Health Organization. Coronavirus disease (COVID-19) pandemic. Accessed February 13, 2022 at: https://www.who.int/
    PubMedGoogle Scholar
  • 5 Khanna M, Kumar P, Choudhary K, Kumar B, Vijayan VK. Emerging influenza virus: A global threat. J Biosci 2008; 33: 475-482
    CrossrefPubMedGoogle Scholar
  • 6 Holm-Hansen CC, Midgley SE, Fischer TK. Global emergence of enterovirus D68: A systematic review. Lancet Infect Dis 2016; 16: e64
    CrossrefPubMedGoogle Scholar
  • 7 Hussain M, Galvin HD, Haw TY, Nutsford AN, Husain M. Drug resistance in influenza A virus: The epidemiology and management. Infect Drug Resist 2017; 10: 121-134
    CrossrefPubMedGoogle Scholar
  • 8 Sethy B, Hsieh CF, Lin TJ, Hu PY, Chen YL, Lin CY, Tseng SN, Horng JT, Hsieh PW. Design, synthesis, and biological evaluation of itaconic acid derivatives as potential anti-influenza agents. J Med Chem 2019; 62: 2390-2403
    CrossrefPubMedGoogle Scholar
  • 9 Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med 2005; 353: 1363-1373
    CrossrefPubMedGoogle Scholar
  • 10 McKimm-Breschkin JL. Influenza neuraminidase inhibitors: Antiviral action and mechanisms of resistance. Influenza Other Respir Viruses 2013; 7: 25-36
    CrossrefPubMedGoogle Scholar
  • 11 Korkmaz B, Horwitz MS, Jenne DE, Gauthier F. Neutrophil elastase, proteinase 3, and cathepsin G as therapeutic targets in human diseases. Pharmacol Rev 2010; 62: 726-759
    CrossrefPubMedGoogle Scholar
  • 12 Chiang CC, Korinek M, Cheng WJ, Hwang TL. Targeting neutrophils to treat acute respiratory distress syndrome in coronavirus disease. Front Pharmacol 2020; 11: 572009-572023
    CrossrefPubMedGoogle Scholar
  • 13 Drugs.com. Find Drugs & Conditions. Accessed February 13, 2022 at: https://www.drugs.com/
    PubMedGoogle Scholar
  • 14 European Medical Agency. Covid-19 pandemic. Accessed February 13, 2022 at: https://www.ema.europa.eu/en
    PubMedGoogle Scholar
  • 15 U.S. Food & Drugs. Accessed February 13, 2022 at: https://www.fda.gov/drugs
    PubMedGoogle Scholar
  • 16 Compendium. Drugs. Accessed February 13, 2022 at: https://compendium.com.ua/
    PubMedGoogle Scholar
  • 17 Wróblewska A, Brzosko E, Czarnecka B, Nowosielski J. High levels of genetic diversity in populations of Iris aphylla L. (Iridaceae), an endangered species in Poland. Bot J Linn Soc 2003; 142: 65-72
    CrossrefPubMedGoogle Scholar
  • 18 Marinescu VM, Alexiu V. Iris aphylla L. ssp. hungarica critically endangered taxon in Europa. CTNS 2013; 2: 96-99
    PubMedGoogle Scholar
  • 19 Mykhailenko O, Ivanauskas L, Bezruk I, Lesyk R, Georgiyants V. Comparative investigation of amino acids content in the dry extracts of Juno bucharica, Gladiolus hybrid zefir, Iris hungarica, Iris variegata and Crocus sativus raw materials of Ukrainian flora. Sci Pharm 2020; 88: 8-21
    CrossrefPubMedGoogle Scholar
  • 20 Mykhailenko O, Gudžinskas Z, Kovalyov V, Desenko V, Ivanauskas L, Bezruk I, Georgiyants V. Effect of ecological factors on the accumulation of phenolic compounds in Iris species from Latvia, Lithuania and Ukraine. Phytochem Anal 2020; 31: 1-19
    CrossrefPubMedGoogle Scholar
  • 21 Mykhailenko O, Korinek M, Ivanauskas L, Bezruk I, Myhal A, Petrikaitė V, El-Shazly M, Yen CH, Chen BH, Georgiyants V, Hwang TL. Qualitative and quantitative analysis of Ukrainian Iris species: A fresh look on their antioxidant content and biological activities. Molecules 2020; 25: 4588
    CrossrefPubMedGoogle Scholar
  • 22 Mykhailenko O, Kovalyov V, Kovalyov S, Krechun A. Isoflavonoids from the rhizomes of Iris hungarica and antibacterial activity of the dry rhizomes extract. Ars Pharm 2017; 58: 39-45
    CrossrefPubMedGoogle Scholar
  • 23 Larsson J, Gottfries J, Muresan S, Backlund A. ChemGPS-NP: Tuned for navigation in biologically relevant chemical space. J Nat Prod 2007; 70: 789-794
    CrossrefPubMedGoogle Scholar
  • 24 Korinek M, Tsai YH, El-Shazly M, Lai KH, Backlund A, Wu SF, Lai WC, Wu TY, Chen SL, Wu YC, Cheng YB, Hwang TL, Chen BH, Chang FR. Anti-allergic hydroxy fatty acids from Typhonium blumei explored through ChemGPS-NP. Front Pharmacol 2017; 8: 356-363
    CrossrefPubMedGoogle Scholar
  • 25 Ibrahim SR, Mohamed GA, Al-Musayeib NM. New constituents from the rhizomes of Egyptian Iris germanica L. Molecules 2012; 17: 2587-2598
    CrossrefPubMedGoogle Scholar
  • 26 Buch SM, Mir FA, Rehman S, Qurishi MA, Banday JA. Irigenin – an isoflavone: A brief study on structural and optical properties. Eur Phys J Appl Phys 2013; 62: 31201-31205
    CrossrefPubMedGoogle Scholar
  • 27 Ayatollahi SAM, Moein MR, Kobarfard F, Nasim S, Choudhary MI. 1-D and 2D-NMR assignments of nigricin from Iris imbricate . Iran J Pharm Sci 2005; 4: 250-254
    PubMedGoogle Scholar
  • 28 Zhou J, Xie G, Yan X. Encyclopedia of Traditional Chinese Medicines. Vol. 3. Berlin, Heidelberg, New York: Springer; 2011
    Google Scholar
  • 29 Qiu QH, Zhang ZG, Wang JH, Lv TS. [Studies on the isoflavonoids of Iris tectorum]. Zhong Yao Cai 2009; 32: 1392-1394 [Article in Chinese]
    PubMedGoogle Scholar
  • 30 Kovalev VN, Zatylʼnikova OA, Kovalev SV. A new isoflavone from Iris pseudacorus . Chem Nat Comp 2013; 49: 34-35
    CrossrefPubMedGoogle Scholar
  • 31 Hsieh CF, Lo C, Liu CH, Lin S, Yen HR, Lin TY, Horng JT. Mechanism by which ma-xing-shi-gan-tang inhibits the entry of influenza virus. J Ethnopharmacol 2012; 143: 57-67
    CrossrefPubMedGoogle Scholar
  • 32 Jeong HJ, Ryu YB, Park SJ, Kim JH, Kwon HJ, Kim JH, Park KH, Rho MC, Lee WS. Neuraminidase inhibitory activities of flavonols isolated from Rhodiola rosea roots and their in vitro anti-influenza viral activities. Bioorg Med Chem 2009; 17: 6816-6823
    CrossrefPubMedGoogle Scholar
  • 33 Liu AL, Liu B, Qin HL, Lee SM, Wang YT, Du GH. Anti-influenza virus activities of flavonoids from the medicinal plant Elsholtzia rugulosa . Planta Med 2008; 74: 847-851
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Alhazmi MI. Molecular docking of selected phytocompounds with H1N1 Proteins. Bioinformation 2015; 11: 196-202
    CrossrefPubMedGoogle Scholar
  • 35 Mehta P, Shah R, Lohidasan S, Mahadik KR. Pharmacokinetic profile of phytoconstituent(s) isolated from medicinal plants-A comprehensive review. J Tradit Complement Med 2015; 5: 207-227
    CrossrefPubMedGoogle Scholar
  • 36 Hsieh CF, Chen YL, Lin CF, Ho JY, Huang CH, Chiu CH, Horng JT. An extract from Taxodium distichum targets hemagglutinin- and neuraminidase-related activities of influenza virus in vitro . Sci Rep 2016; 6: 1-13
    CrossrefPubMedGoogle Scholar
  • 37 Sadati S, Gheibi N, Ranjbar S, Hashemzadeh M. Docking study of flavonoid derivatives as potent inhibitors of influenza H1N1 virus neuraminidase. Biomed Rep 2018; 10: 33-38
    PubMedGoogle Scholar
  • 38 Liu Z, Zhao J, Li W, Wang X, Xu J, Xie J, Tao K, Shen L, Zhang R. Molecular docking of potential inhibitors for influenza H7N9. Comput Math Methods Med 2015; 2015: 480764
    PubMedGoogle Scholar
  • 39 Sethy B, Hsieh CF, Yeh C, Horng JT, Hsieh PW. Design, synthesis & structure-activity relationships of a new class of antihuman enterovirus D68 & A71 agents. Future Med Chem 2018; 10: 1333-1347
    CrossrefPubMedGoogle Scholar
  • 40 Dai W, Bi J, Li F, Wang S, Huang X, Meng X, Sun B, Wang D, Kong W, Jiang C, Su W. Antiviral efficacy of flavonoids against enterovirus 71 infection in vitro and in newborn mice. Viruses 2019; 11: 625
    CrossrefPubMedGoogle Scholar
  • 41 Zumla A, Chan JF, Azhar EI, Hui DS, Yuen KY. Coronaviruses – drug discovery and therapeutic options. Nat Rev Drug Discov 2016; 15: 327-347
    CrossrefPubMedGoogle Scholar
  • 42 Rosen J, Lovgren A, Kogej T, Muresan S, Gottfries J, Backlund A. ChemGPS-NP(Web): chemical space navigation online. J Comput Aided Mol Des 2009; 23: 253-259
    CrossrefPubMedGoogle Scholar
  • 43 Amarelle L, Lecuona E, Sznajder JI. Anti-influenza treatment: Drugs currently used and under development. Arch Bronconeumol 2017; 53: 19-26
    CrossrefPubMedGoogle Scholar
  • 44 Hu Y, Musharrafieh R, Zheng M, Wang J. Enterovirus D68 antivirals: Past, present, and future. ACS Infect Dis 2020; 6: 1572-1586
    CrossrefPubMedGoogle Scholar
  • 45 Hsu JTA, Yeh JY, Lin TJ, Li ML, Wu MS, Hsieh CF, Chou YC, Tang WF, Lau KS, Hung HC, Fang MY, Ko S, Hsieh HP, Horng JT. Identification of BPR3P0128 as an inhibitor of cap-snatching activities of influenza virus. Antimicrob Agents Chemother 2012; 56: 647-657
    CrossrefPubMedGoogle Scholar
  • 46 Hsieh CF, Jheng JR, Lin GH, Chen YL, Ho JY, Liu CJ, Hsu KY, Chen YS, Chan YF, Yu HM, Hsieh PW, Chern JH, Horng JT. Rosmarinic acid exhibits broad anti-enterovirus A71 activity by inhibiting the interaction between the five-fold axis of capsid VP1 and cognate sulfated receptors. Emerg Microbes Infect 2020; 9: 1194-1205
    CrossrefPubMedGoogle Scholar
  • 47 Boyum A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl 1968; 97: 77-89
    PubMedGoogle Scholar
  • 48 Korinek M, Hsieh PS, Chen YL, Hsieh PW, Chang SH, Wu YH, Hwang TL. Randialic acid B and tomentosolic acid block formyl peptide receptor 1 in human neutrophils and attenuate psoriasis-like inflammation in vivo . Biochem Pharmacol 2021; 190: 114596
    CrossrefPubMedGoogle Scholar
  • 49 Yang SC, Chung PJ, Ho CM, Kuo CY, Hung MF, Huang YT, Chang WY, Chang YW, Chan KH, Hwang TL. Propofol inhibits superoxide production, elastase release, and chemotaxis in formyl peptide-activated human neutrophils by blocking formyl peptide receptor 1. J Immunol 2013; 190: 6511-6519
    CrossrefPubMedGoogle Scholar
  • 50 Hwang TL, Su YC, Chang HL, Leu YL, Chung PJ, Kuo LM, Chang YJ. Suppression of superoxide anion and elastase release by C18 unsaturated fatty acids in human neutrophils. J Lipid Res 2009; 50: 1395-1408
    CrossrefPubMedGoogle Scholar