Skip to main content
NCBI home page
Elsevier - PMC COVID-19 Collection logoLink to Elsevier - PMC COVID-19 Collection
. 2023 Jan 13;21(1):65–80. doi: 10.1016/S1875-5364(23)60386-3

Flavonoids from the roots and rhizomes of Sophoratonkinensis and their in vitro anti-SARS-CoV-2 activity

Zhuo LI a,b,Δ, Hang XIE a,d,Δ, Chunping TANG b, Lu FENG b, Changqiang KE b, Yechun XU c,d,e, Haixia SU d,*, Sheng YAO b,*, Yang YE a,b,c,*
PMCID: PMC9836829  PMID: 36641234

Abstract

Acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had caused a global pandemic since 2019, and posed a serious threat to global health security. Traditional Chinese medicine (TCM) has played an indispensable role in the battle against the epidemic. Many components originated from TCMs were found to inhibit the production of SARS-CoV-2 3C-like protease (3CLpro) and papain-like protease (PLpro), which are two promising therapeutic targets to inhibit SARS-CoV-2. This study describes a systematic investigation of the roots and rhizomes of Sophora tonkinensis, which results in the characterization of 12 new flavonoids, including seven prenylated flavanones (1–7), one prenylated flavonol (8), two prenylated chalcones (9–10), one isoflavanone (11), and one isoflavan dimer (12), together with 43 known compounds (13–55). Their structures including the absolute configurations were elucidated by comprehensive analysis of MS, 1D and 2D NMR data, and time-dependent density functional theory electronic circular dichroism (TDDFT ECD) calculations. Compounds 12 and 51 exhibited inhibitory effects against SARS-CoV-2 3CLpro with IC50 values of 34.89 and 19.88 μmol·L−1, repectively while compounds 9, 43 and 47 exhibited inhibitory effects against PLpro with IC50 values of 32.67, 79.38, and 16.74 μmol·L−1, respectively.

Key Words: Sophora tonkinensis, Flavonoid, Anti-SARS-CoV-2 activity, SARS-CoV-2 3CLpro, SARS-CoV-2 PLpro

Biographies

SU Haixia received her B.S. degree (2016) from East China University of Science and Technology and Ph.D. degree from Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences (CAS). She is interested in the determination of crystal structures of drug targeted proteins, and structure-based drug design.

YAO Sheng was graduated with his Ph.D. degree of Medicinal Chemistry from Shanghai Institute of Materia Medica, Chinese Academy of Sciences in 2008. He currently serves as professor of Natural Product Research Center in Shanghai Institute of Materia Medica. His research mainly focuses on the discovery of natural products with novel structures and potential bioactivities from Chinese herbal medicines or plants. To date, he has published over 70 SCI papers with over 900 citations.

YE Yang, the full professor of Shanghai Institute of Materia Medica, CAS, was awarded the National Science Fund for Distinguished Young Scholars in 2009, and the special government allowance in 2016. He was selected as a leading talent of Shanghai in 2020. Professor YE leads a research group focusing on isolation and structural elucidation of bioactive secondary metabolites from medicinal plant resources by establishing a multi-technology platform for quick analysis and separation of natural products. He conducted systematic investigations of commonly used medicinal, and provided scientific evidence to explain their traditional therapeutic effects.

Footnotes

Available online 20 Jan., 2023

[Research funding] This work was supported from the National Natural Science Foundation of China (Nos. 82173696 and 21920102003), the Science and Technology Commission of Shanghai Municipality (Nos. 20431900200 and 20430780300), the Strategic Priority Research Program of Chinese Academy of Sciences (Nos. SIMM010110 and SIMM040302) and the Sustainable Development of Precious Traditional Chinese Medicine Resources (No. 2060302-2001-01)

These authors have no conflict of interest to declare.

References

  • 1.Hasoksuz M, Kilic S, Sarac F. Coronaviruses and SARS-COV-2. Turk J Med Sci. 2020;50(SI-1):549–556. doi: 10.3906/sag-2004-127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Zumla A, Chan J F, Azhar E I, et al. Coronaviruses: drug discovery and therapeutic options. Nat Rev Drug Discov. 2016;15(5):327–347. doi: 10.1038/nrd.2015.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Pillaiyar T, Manickam M, Namasivayam V, et al. An overview of severe acute respiratory syndrome-coronavirus (SARS-CoV) 3CL protease inhibitors: peptidomimetics and small molecule chemotherapy. J Med Chem. 2016;59(14):6595–6628. doi: 10.1021/acs.jmedchem.5b01461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Dai WH, Zhang B, Jiang XM, et al. Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science. 2020;368(6497):1331–1335. doi: 10.1126/science.abb4489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Shagufta AI. An update on pharmacological relevance and chemical synthesis of natural products and derivatives with anti SARS-CoV-2 activity. ChemistrySelect. 2021;6(42):11502–11527. doi: 10.1002/slct.202103301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Liu W, Huang J, Zhang F, et al. Comprehensive profiling and characterization of the absorbed components and metabolites in mice serum and tissues following oral administration of Qing-Fei-Pai-Du decoction by UHPLC-Q-Exactive-Orbitrap HRMS [J] Chin J Nat Med. 2021;19(4):305–320. doi: 10.1016/S1875-5364(21)60031-6. [DOI] [PubMed] [Google Scholar]
  • 7.Wei WL, Wu SF, Li HJ, et al. Chemical profiling of Huashi Baidu prescription, an effective anti-COVID-19 TCM formula, by UPLC-Q-TOF/MS. Chin J Nat Med. 2021;19(6):473–480. doi: 10.1016/S1875-5364(21)60046-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Su HX, Yao S, Zhao WF, et al. Anti-SARS-CoV-2 activities in vitro of Shuanghuanglian preparations and bioactive ingredients. Acta Pharmacol Sin. 2020;41(9):1167–1177. doi: 10.1038/s41401-020-0483-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Zhang JJ, Chen BS, Dai HQ, et al. Sesquiterpenes and polyphenols with glucose-uptake stimulatory and antioxidant activities from the medicinal mushroom Sanghuangporus sanghuang. Chin J Nat Med. 2021;19(9):693–699. doi: 10.1016/S1875-5364(21)60101-2. [DOI] [PubMed] [Google Scholar]
  • 10.Goswami D, Kumar M, Ghosh S, et al. Natural product compounds in Alpinia officinarum and ginger are potent SARS-CoV-2 papain-like protease inhibitors [Z] ChemRxiv. 2020 doi: 10.26434/chemrxiv.12071997.v1. [DOI] [Google Scholar]
  • 11.Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020;14(1):72–73. doi: 10.5582/bst.2020.01047. [DOI] [PubMed] [Google Scholar]
  • 12.Chrzanowski J, Chrzanowska A, Graboń W. Glycyrrhizin: an old weapon against a novel coronavirus. Phytother Res. 2021;35(2):629–636. doi: 10.1002/ptr.6852. [DOI] [PubMed] [Google Scholar]
  • 13.Su HX, Yao S, Zhao WF, et al. Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease. Nat Commun. 2021;12(1) doi: 10.1038/s41467-021-23751-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Zhu DF, Su HX, Ke CQ, et al. Efficient discovery of potential inhibitors for SARS-CoV-2 3C-like protease from herbal extracts using a native MS-based affinity-selection method. J Pharm Biomed Anal. 2022;209 doi: 10.1016/j.jpba.2021.114538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.The Chinese Pharmacopoeia Commission . China Medical Science and Technology Press; Beijing: 2020. Pharmacopoeia of the People's Republic of China, Vol. 1 [M] [Google Scholar]
  • 16.Zhang SN, Li XZ, Tan LY, et al. A review of pharmacological and toxicological effects of Sophora tonkinensis with bioinformatics prediction. Am J Chinese Med. 2021;49(02):359–389. doi: 10.1142/S0192415X21500178. [DOI] [PubMed] [Google Scholar]
  • 17.Zhang W, Wei X, Zhang LY, et al. Chemical constituents of Sophora tonkinensis. Chem Nat Compd. 2020;56(6):1140–1142. doi: 10.1007/s10600-020-03248-z. [DOI] [Google Scholar]
  • 18.Ahn J, Kim YM, Chae HS, et al. Prenylated flavonoids from the roots and rhizomes of Sophora tonkinensis and their effects on the expression of inflammatory mediators and proprotein convertase subtilisin/kexin type 9. J Nat Prod. 2019;82(2):309–317. doi: 10.1021/acs.jnatprod.8b00748. [DOI] [PubMed] [Google Scholar]
  • 19.Wu C, He LJ, Yi X, et al. Three new alkaloids from the roots of Sophora tonkinensis. J Nat Med. 2019;73(3):667–671. doi: 10.1007/s11418-019-01313-8. [DOI] [PubMed] [Google Scholar]
  • 20.He LJ, Liu JS, Luo D, et al. Quinolizidine alkaloids from Sophora tonkinensis and their anti-inflammatory activities. Fitoterapia. 2019;139 doi: 10.1016/j.fitote.2019.104391. [DOI] [PubMed] [Google Scholar]
  • 21.Pan QM, Zhang GJ, Huang RZ, et al. Cytisine-type alkaloids and flavonoids from the rhizomes of Sophora tonkinensis. J Asian Nat Prod Res. 2016;18(5):429–435. doi: 10.1080/10286020.2015.1131680. [DOI] [PubMed] [Google Scholar]
  • 22.Duchemin I, Guido CA, Jacquemin D, et al. The Bethe-Salpeter formalism with polarisable continuum embedding: reconciling linear-response and state-specific features [J] Chem Sci. 2018;9(19):4430–4443. doi: 10.1039/c8sc00529j. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Goto H, Osawa E. Corner flapping: a simple and fast algorithm for exhaustive generation of ring conformations [J] J Am Chem Soc. 1989;111(24):8950–8951. [Google Scholar]
  • 24.Bruhn T, Schaumloffel A, Hemberger Y, et al. SpecDis: quantifying the comparison of calculated and experimental electronic circular dichroism spectra. Chirality. 2013;25(4):243–249. doi: 10.1002/chir.22138. [DOI] [PubMed] [Google Scholar]
  • 25.Pescitelli G, Bruhn T. Good computational practice in the assignment of absolute configurations by TDDFT calculations of ECD spectra. Chirality. 2016;28(6):466–474. doi: 10.1002/chir.22600. [DOI] [PubMed] [Google Scholar]
  • 26.Grimblat N, Zanardi MM, Sarotti AM. Beyond DP4: an improved probability for the stereochemical assignment of isomeric compounds using quantum chemical calculations of nmr shifts. J Org Chem. 2015;80(24):12526–12534. doi: 10.1021/acs.joc.5b02396. [DOI] [PubMed] [Google Scholar]
  • 27.Zanardi MM, Sarotti AM. Sensitivity analysis of DP4+ with the probability distribution terms: development of a universal and customizable method. J Org Chem. 2021;86(12):8544–8548. doi: 10.1021/acs.joc.1c00987. [DOI] [PubMed] [Google Scholar]
  • 28.Ghosh AK, Takayama J, Aubin Y, et al. Structure-based design, synthesis, and biological evaluation of a series of novel and reversible inhibitors for the severe acute respiratory syndrome–coronavirus papain-like protease. J Med Chem. 2009;52(16):5228–5240. doi: 10.1021/jm900611t. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Owen DR, Allerton CMN, Anderson AS, et al. An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for the treatment of COVID-19. Science. 2021;374(6575):1586–1593. doi: 10.1126/science.abl4784. [DOI] [PubMed] [Google Scholar]
  • 30.Fu Z, Huang B, Tang J, et al. The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery. Nat Commun. 2021;12(1):488. doi: 10.1038/s41467-020-20718-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Xu RS. Science Press; Beijing: 1993. The Chemistry of Natural Products [M] [Google Scholar]
  • 32.Luo GY, Yang Y, Zhou M, et al. Novel 2-arylbenzofuran dimers and polyisoprenylated flavanones from Sophora tonkinensis. Fitoterapia. 2014;99:21–27. doi: 10.1016/j.fitote.2014.08.019. [DOI] [PubMed] [Google Scholar]
  • 33.Slade D, Ferreira D, Marais JP. Circular dichroism, a powerful tool for the assessment of absolute configuration of flavonoids. Phytochemistry. 2005;66(18):2177–2215. doi: 10.1016/j.phytochem.2005.02.002. [DOI] [PubMed] [Google Scholar]
  • 34.Li P, Chai WC, Wang ZY, et al. Bioactivity-guided isolation of compounds from Sophora flavescens with antibacterial activity against Acinetobacter baumannii. Nat Prod Res. 2022;36(17):4340–4348. doi: 10.1080/14786419.2021.1983570. [DOI] [PubMed] [Google Scholar]
  • 35.Li XN, Lu ZQ, Chen GT, et al. NMR spectral assignments of isoprenylated flavanones from Sophora tonkinensis. Magn Reson Chem. 2008;46(9):898–902. doi: 10.1002/mrc.2274. [DOI] [PubMed] [Google Scholar]
  • 36.Chen ZA, Ke CQ, Zhou S, et al. Ten undescribed cadinane-type sesquiterpenoids from Eupatorium chinense. Fitoterapia. 2022;156 doi: 10.1016/j.fitote.2021.105091. [DOI] [PubMed] [Google Scholar]
  • 37.Kyogoku K, Hatayama K, Yokomori S, et al. Studies on the constituents of Sophora species. VI. Constituents of the root of Sophora subprostrata CHUN et T. CHEN. (4) Chem Pharm Bull. 1973;21(6):1192–1197. doi: 10.1248/cpb.21.1192. [DOI] [Google Scholar]
  • 38.Guan LP, Peng DX, Zhang L, et al. Design, synthesis, and cholinesterase inhibition assay of liquiritigenin derivatives as anti-Alzheimer's activity. Bioorganic Med Chem Lett. 2021;52 doi: 10.1016/j.bmcl.2021.128306. [DOI] [PubMed] [Google Scholar]
  • 39.Yoo H, Chae HS, Kim YM, et al. Flavonoids and arylbenzofurans from the rhizomes and roots of Sophora tonkinensis with IL-6 production inhibitory activity. Bioorganic Med Chem Lett. 2014;24(24):5644–5647. doi: 10.1016/j.bmcl.2014.10.077. [DOI] [PubMed] [Google Scholar]
  • 40.Mizuno M, Tanaka T, Matsuura N, et al. Two flavanones from Euchresta horsfieldii. Phytochemistry. 1990;29(8):2738–2740. doi: 10.1016/0031-9422(90)85236-9. [DOI] [Google Scholar]
  • 41.Xia W, Luo P, Hua P, et al. Discovery of a new pterocarpan-type antineuroinflammatory compound from Sophora tonkinensis through suppression of the TLR4/NFκB/MAPK signaling pathway with PU.1 as a potential target. ACS Chem Neurosci. 2019;10(1):295–303. doi: 10.1021/acschemneuro.8b00243. [DOI] [PubMed] [Google Scholar]
  • 42.Li XN, Yan HX, Pang X, et al. Chemical constituents of flavonoids from rhizome of Sophora tonkinensis. China J Chin Mater Med. 2009;34(3):282–285. [PubMed] [Google Scholar]
  • 43.Meragelman KM, McKee TC, Boyd MR. Anti-HIV prenylated flavonoids from Monotes africanus. J Nat Prod. 2001;64(4):546–548. doi: 10.1021/np0005457. [DOI] [PubMed] [Google Scholar]
  • 44.Sin MG, Li JR, Ding NP, et al. Chemical constituents of Lespedeza davidii. J China Pharm Univ. 1991;22(3):148–149. [Google Scholar]
  • 45.Lin Y, Kuang Y, Li K, et al. Nrf2 activators from Glycyrrhiza inflata and their hepatoprotective activities against CCl4-induced liver injury in mice. Bioorg Med Chem. 2017;25(20):5522–5530. doi: 10.1016/j.bmc.2017.08.018. [DOI] [PubMed] [Google Scholar]
  • 46.Sun XG, Pang X, Liang HZ, et al. New prenylated flavonoid glycosides derived from Epimedium wushanense by β-glucosidase hydrolysis and their testosterone production-promoting effects. Chin J Nat Med. 2022;20(9):712–720. doi: 10.1016/S1875-5364(22)60188-2. [DOI] [PubMed] [Google Scholar]
  • 47.Simões MA, Pinto DC, Neves BM, et al. Flavonoid profile of the Genista tridentata L., a species used traditionally to treat inflammatory processes. Molecules. 2020;25(4):812. doi: 10.3390/molecules25040812. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Yang XZ, Deng SH, Huang M, et al. Chemical constituents from Sophora tonkinensis and their glucose transporter 4 translocation activities. Bioorganic Med Chem Lett. 2017;27(6):1463–1466. doi: 10.1016/j.bmcl.2017.01.078. [DOI] [PubMed] [Google Scholar]
  • 49.Kim JY, Wang Y, Song YH, et al. Antioxidant activities of phenolic metabolites from Flemingia philippinensis Merr. et Rolfe and their application to DNA damage protection. Molecules. 2018;23(4):816. doi: 10.3390/molecules23040816. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Inoue M, Tanabe H, Nakashima KI, et al. Rexinoids isolated from Sophora tonkinensis with a gene expression profile distinct from the synthetic rexinoid bexarotene. J Nat Prod. 2014;77(7):1670–1677. doi: 10.1021/np5002016. [DOI] [PubMed] [Google Scholar]
  • 51.Tahara S, Katagiri Y, Ingham J L, et al. Prenylated flavonoids in the roots of yellow lupin. Phytochemistry. 1994;36(5):1261–1271. doi: 10.1016/S0031-9422(00)89648-X. [DOI] [PubMed] [Google Scholar]
  • 52.Ruangrungsi N, Iinuma M, Tanaka T, et al. Three flavanones with a lavandulyl group in the roots of Sophora exigua. Phytochemistry. 1992;31(3):999–1001. doi: 10.1016/0031-9422(92)80056-K. [DOI] [Google Scholar]
  • 53.Baruah P, Barua NC, Sharma RP, et al. Flavonoids from Millettia pulchra. Phytochemistry. 1984;23(2):443–447. doi: 10.1016/S0031-9422(00)80349-0. [DOI] [Google Scholar]
  • 54.Chepkirui C, Ochieng PJ, Sarkar B, et al. Antiplasmodial and antileishmanial flavonoids from Mundulea sericea. Fitoterapia. 2021;149 doi: 10.1016/j.fitote.2020.104796. [DOI] [PubMed] [Google Scholar]
  • 55.Sutthivaiyakit S, Thongnak O, Lhinhatrakool T, et al. Cytotoxic and antimycobacterial prenylated flavonoids from the roots of Eriosema chinense. J Nat Prod. 2009;72(6):1092–1096. doi: 10.1021/np900021h. [DOI] [PubMed] [Google Scholar]
  • 56.Cheung S, Fang W, Li X, et al. Chemical constituents of Dalbergia odorifera. Chem Nat Compd. 2021;57(6):1122–1124. doi: 10.1007/s10600-021-03565-x. [DOI] [Google Scholar]
  • 57.Ji S, Li Z, Song W, et al. Bioactive constituents of Glycyrrhiza uralensis (Licorice): discovery of the effective components of a traditional herbal medicine. J Nat Prod. 2016;79(2):281–292. doi: 10.1021/acs.jnatprod.5b00877. [DOI] [PubMed] [Google Scholar]
  • 58.Dat LD, Tu NTM, Duc NV, et al. Anti-inflammatory secondary metabolites from the stems of Millettia dielsiana Harms ex Diels. Carbohydr Res. 2019;484 doi: 10.1016/j.carres.2019.107778. [DOI] [PubMed] [Google Scholar]
  • 59.Li Y, Sun B, Zhai J, et al. Synthesis and antibacterial activity of four natural chalcones and their derivatives. Tetrahedron Lett. 2019;60(43) doi: 10.1016/j.tetlet.2019.151165. [DOI] [Google Scholar]
  • 60.Komatsu M, Tomimori T, Hatayama K, et al. Studies on the constituents of Sophora species. I. Constituents of Sophora subprostrata CHUN et T. CHEN. (1). Isolation and structure of new flavonoids, sophoradin and sophoranone. Chem Pharm Bull. 1970;18(3):602–607. doi: 10.1248/cpb.18.602. [DOI] [PubMed] [Google Scholar]
  • 61.Máximo P, Lourenço A, Feio SS, et al. Flavonoids from Ulex species. Z Naturforsch. 2000;55c:506–510. doi: 10.1515/znc-2000-7-804. [DOI] [Google Scholar]
  • 62.Li X, Wang D, Xia MY, et al. Cytotoxic prenylated flavonoids from the stem bark of Maackia amurensis. Chem Pharm Bull. 2009;57(3):302–306. doi: 10.1248/cpb.57.302. [DOI] [PubMed] [Google Scholar]
  • 63.Posri P, Suthiwong J, Thongsri Y, et al. Antifungal activity of compounds from the stems of Dalbergia stipulacea against Pythium insidiosum. Nat Prod Res. 2021;35(17):2823–2830. doi: 10.1080/14786419.2019.1672068. [DOI] [PubMed] [Google Scholar]
  • 64.Erasto P, Bojase-Moleta G, Majinda RRT. Antimicrobial and antioxidant flavonoids from the root wood of Bolusanthus speciosus. Phytochemistry. 2004;65(7):875–880. doi: 10.1016/j.phytochem.2004.02.011. [DOI] [PubMed] [Google Scholar]

Articles from Chinese Journal of Natural Medicines are provided here courtesy of Elsevier

RESOURCES