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Planta Med 2023; 89(12): 1165-1169
DOI: 10.1055/a-2112-6631
Biological and Pharmacological Activity
Original Papers

Bioassay-Guided Isolation and Identification of Antiplasmodial Compounds from the Stem Bark of Clausena excavata

Prapairat Seephonkai
1   Multidisciplinary Research Unit of Pure and Applied Chemistry, Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahasarakham University, Khamriang, Kantarawichai, Maha Sarakham, Thailand
,
Chatthai Kaewtong
1   Multidisciplinary Research Unit of Pure and Applied Chemistry, Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahasarakham University, Khamriang, Kantarawichai, Maha Sarakham, Thailand
,
Phurpa Wangchuk
2   Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns Campus, Smithfield, Queenland, Australia
,
Kedchin Jearawuttanakul
3   Excellent Center for Drug Discovery, Faculty of Science, Mahidol University, Bangkok, Thailand
,
Phongthon Kanjanasirirat
3   Excellent Center for Drug Discovery, Faculty of Science, Mahidol University, Bangkok, Thailand
,
Suparerk Borwornpinyo
3   Excellent Center for Drug Discovery, Faculty of Science, Mahidol University, Bangkok, Thailand
,
Tachin Khulmanee
4   Drug Research Unit for Malaria, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
,
Rapatbhorn Patrapuvich
4   Drug Research Unit for Malaria, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
› Author AffiliationsThis research project was financially supported by Mahasarakham University (grant year 2022).
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Abstract

Clausena excavata is a medicinal plant widely distributed in Southeast Asia. It is used for a variety of indications, including to treat malaria. In our present study, a phytochemical study of the methanol extract from the stem bark of C. excavata led to the isolation of five pyranocoumarins, nordentatin (1), dentatin (2), kinocoumarin (3), clausarin (4), and clausenidin (5), and a coumarin, 8-hydroxy-3″,4″-dihydrocapnolactone-2′,3′-diol (6). The isolation of compound 6 from C. excavata and the antiplasmodial activities against a multidrug-resistant K1 strain of Plasmodium falciparum of 1, 3, and 5 were reported for the first time. Compounds 3 and 4 exhibited potent antiplasmodial activities with EC50 values of 1.10 and 0.58 µM, respectively, while 1 and 5 had EC50 values of 5.62 and 7.15 µM, respectively. A prenyl group attached to the C-3 or C-12 position on the pyranocoumarin ring probably plays an important role on the activity. A hydroxyl group at the C-10 position is also likely to enhance the activity.

Key words

Clausena excavata - Rutaceae - clausarin - kinocoumarin - nordentatin - pyranocoumarins - antiplasmodial compound

Supporting Information

    TLC (Figs. 1S and 3S) and HPLC (Fig. 2S) chromatograms of C. excavata extracts, 1H and 13C NMR spectra (Figs. 6S-14S), antiplasmodial (Fig. 4S and Tables S1-S6) and cytotoxic (Fig. 5S) activities, and NMR spectroscopic data (Tables 6S-12S) of compounds 1 – 6 are available as Supporting Information.

  • Supporting Information


Publication History

Received: 24 March 2023

Accepted after revision: 13 June 2023

Article published online:
06 July 2023

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  • References

  • 1 World Health Organization. World Malaria Report, 2021. Accessed October 26, 2022 at: https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2021
    PubMedGoogle Scholar
  • 2 World Health Organization. World Malaria Report, 2018. Accessed October 26, 2022 at: http://apps.who.int/iris/bitstream/handle/10665/275867/9789241565653-eng.pdf
    PubMedGoogle Scholar
  • 3 Huang SC, Wu PL, Wu TS. Two coumarins from the root bark of Clausena excavata . Phytochemistry 1997; 44: 179-181
    CrossrefPubMedGoogle Scholar
  • 4 Perry LM. Medicinal Plants of East and Southeast Asia: Attributed Properties and Used. Cambridge: The MIT Press; 1980
    Google Scholar
  • 5 Sasaki S. “Khoyo Taiwan Minkun Yakyo Shokubutsu Shi”, Khobunkan. Taipei; 1924: 36
    Google Scholar
  • 6 Wu TS, Furukawa H. Biological and phytochemical investigation of Clausena excavata . J Nat Prod 1982; 45: 718-720
    CrossrefPubMedGoogle Scholar
  • 7 Wu TS, Huang SC, Lai JS, Teng CM, Ko FN, Kuoh CS. Chemical and antiplatelet aggregative investigation of the leaves of Clausena excavata . Phytochemistry 1993; 32: 449-451
    CrossrefPubMedGoogle Scholar
  • 8 Manosroi A, Araphanchotiwitthaya A, Manosroi J. Immunomodulatory activities of fractions from hot aqueous extract of wood from Clausena excavata . Fitoterapia 2004; 75: 302-308
    CrossrefPubMedGoogle Scholar
  • 9 Wu TS, Huang SC, Wu PL. Carbazole-pyranocoumarin dimer and binary carbazole alkaloid from Clausena excavate . Tetrahedron Lett 1996; 37: 7819-7822
    CrossrefPubMedGoogle Scholar
  • 10 Sripisut T, Cheenpracha S, Ritthiwigrom T, Prawat U, Laphookhieo S. Chemical constituents from the roots of Clausena excavata and their cytotoxicity. Rac Nat Prod 2012; 6: 386-389
    PubMedGoogle Scholar
  • 11 Peng WW, Zheng YQ, Chen YS, Zhao SM, Ji CJ, Tan NH. Coumarins from roots of Clausena excavata . J Asian Nat Prod Res 2013; 15: 215-220
    CrossrefPubMedGoogle Scholar
  • 12 Sunthitikawinsakul A, Kongkathip N, Kongkathip B, Phonnakhu S, Daly JW, Spande TF, Nimit Y, Rochanaruangrai S. Coumarins and carbazoles from Clausena excavata exhibited antimycobacterial and antifungal activities. Planta Med 2003; 69: 155-157
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Wu TS, Huang SC, Wu PL, Teng CM. Carbazole alkaloids from Clausena excavata and their biological activity. Phytochemistry 1996; 43: 133-140
    CrossrefPubMedGoogle Scholar
  • 14 Ito C, Katsuno S, Ohta H, Omura M, Kajiura I, Furakawa H. Constituents of Clausena excavata. Isolation and structural elucidation of new carbazole alkaloids. Chem Pharm Bull 1997; 45: 48-52
    CrossrefPubMedGoogle Scholar
  • 15 Sripisut T, Laphookhieo S. Carbazole alkaloids from the stems of Clausena excavata . J Asian Nat Prod Res 2012; 12: 614-617
    CrossrefPubMedGoogle Scholar
  • 16 Peh TH, Lim GK, Taufiq-Yap YH, Ee GCL, Rahmani M, Md Sukari MA. A new cytotoxic carbazole alkaloid isolated from the stem bark of Malaysian Clausena excavata . Can Chem Trans 2013; 1: 165-172
    CrossrefPubMedGoogle Scholar
  • 17 Chakthong S, Bindulem N, Raknai S, Yodwaree S, Kaewsanee S, Kanjana-Opas A. Carbazole-pyranocoumarin conjugate and two carbazole alkaloids from the stems of Clausena excavata . Nat Prod Res 2016; 30: 1690-1697
    CrossrefPubMedGoogle Scholar
  • 18 Lim PC, Ramli H, Kassim NK, Ali Z, Khan IA, Shaari K, Ismail A. Chemical constituents from the stem bark of Clusena excavata Burm. f. Biochem Syst Ecol 2019; 82: 52-55
    CrossrefPubMedGoogle Scholar
  • 19 Ito C, Itoigawa M, Katsuno S, Omura M, Tokuda H, Nishino H, Furukawa H. Chemical constituents of Clausena excavata: isolation and structure elucidation of novel furanone-coumarins with inhibitory effects for tumor-promotion. J Nat Prod 2000; 63: 1218-1224
    CrossrefPubMedGoogle Scholar
  • 20 Kumar R, Saha A, Saha D. A new antifungal coumarin from Clausena excavata . Fitoterapia 2012; 83: 230-233
    CrossrefPubMedGoogle Scholar
  • 21 Santoni A, Ibrahim S, Salim R, Syukri D. Isolation and structure elucidation of coumarin derivate from fruit seed of Clausena excavata . J Chem Pharm Res 2014; 6: 753-757
    PubMedGoogle Scholar
  • 22 Jantamas P, Weerapreeyakul N, Puthongking P. Cytotoxic and apoptosis induction of coumarins and carbazole alkaloids from Clausena harmandiana . Molecules 2019; 24: 3385
    CrossrefPubMedGoogle Scholar
  • 23 Songsiang U, Thongthoom T, Zeekpudsa P, Kukongviriyapan V, Boonyarat C, Wangboonskul J, Yenjai C. Antioxidant activity and cytotoxicity against cholangiocarcinoma of carbazoles and coumarins from Clausena harmandiana . ScienceAsia 2012; 38: 75-81
    CrossrefPubMedGoogle Scholar
  • 24 Waziri PM, Abdullah R, Yeap SW, Omar AR, Abdul AB, Kassim NK, Malami I, Karunakaran T, Imam MU. Clausenidin from Clausena excavata induces apoptosis in hepG2 cells via the mitochondrial pathway. J Ethnopharmacol 2016; 194: 549-558
    CrossrefPubMedGoogle Scholar
  • 25 Rahmani M, Susidarti RA, Ismail HB, Sukari MA, Hin TY, Lian GE, Ali AM, Kulip J, Waterman PG. Coumarins from Malaysian Micromelum minutum . Phytochemistry 2003; 64: 873-877
    CrossrefPubMedGoogle Scholar
  • 26 Govindachari TR, Pai BR, Subramaniam PS. Coumarins of Clausena dentata (Willd.) R. and S. Tetrahedron 1968; 24: 753-757
    CrossrefPubMedGoogle Scholar
  • 27 Anwer F, Shoeb A, Kapil RS, Popli SP. Clausarin – a novel coumarin from Clausena pentaphylla (Roxb.) DC. Experientia 1976; 33: 142-143
    PubMedGoogle Scholar
  • 28 Wu TS, Furukawa H. Biological and phytochemical investigation of Clausena excavata . J Nat Prod 1982; 5: 718-720
    PubMedGoogle Scholar
  • 29 Ito C, Matsuoka M, Mixuno T, Sato K, Kimura Y, Ju-Ichi M, Inoue M, Kajiura I, Omura M, Furukawa H. New coumarins from some Citrus plants. Chem Pharm Bull 1988; 36: 3805-3810
    CrossrefPubMedGoogle Scholar
  • 30 Yenjai C, Sripontan S, Sriprajun P, Kittakoop P, Jintasirikul A, Tanticharoen M, Thebtaranonth Y. Coumarins and carbazoles with antiplasmodial activity from Clausena harmandiana . Planta Med 2000; 66: 277-279
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Songsiang U, Thongthoom T, Boonyarat C, Yenjai C. Claurailas A–D, cytotoxic carbazole alkaloids from the roots of Clausena harmandiana . J Nat Prod 2011; 74: 208-212
    CrossrefPubMedGoogle Scholar
  • 32 Wu TS, Huang SC, Wu PL, Kuoh CS. Alkaloidal and other constituents from the root bark of Clausena excavata . Phytochemistry 1999; 52: 523-527
    CrossrefPubMedGoogle Scholar
  • 33 Seo C, Ahn EK, Kang JS, Lee JH, Oh JS, Hong SS. Excavasides A and B, two new flavonoid glycosides from Clausena excavata Burm. f. (Rutaceae). Phytochem Lett 2017; 20: 93-97
    CrossrefPubMedGoogle Scholar
  • 34 Peng WW, Song WW, Huang MB, Zeng GZ, Tan NH. Twelve benzene derivatives from Clausena excavata . Acta Pharm Sin 2014; 49: 1689-1693
    PubMedGoogle Scholar
  • 35 Peng WW, Song WW, Huang MB, Tan NH. Monoterpenes and sesquiterpenes from Clausena excavata . Zhongguo Zhong Yao Za Zhi 2014; 39: 1620-1624
    PubMedGoogle Scholar
  • 36 Thuy TT, Ripperger H, Porzel A, Van Sung T, Adam G. Coumarins, limonoids and an alkaloid from Clausena excavata . Phytochemistry 1999; 52: 511-516
    CrossrefPubMedGoogle Scholar
  • 37 Susidarti RA, Lusika VP, Astana YN. In vitro antiplasmodial activity of coumarin 8-hydroxyisocapnolactone-2′,3′-diol isolated from Micromelum minutum (G. Forst.) Wight & Arn. Indonesian J Pharm 2014; 25: 44-50
    CrossrefPubMedGoogle Scholar
  • 38 Su CR, Yeh SF, Liu CM, Damu AG, Kuo TH, Chiang PC, Bastow KF, Lee KH, Wu TS. Anti-HBV and cytotoxic activities of pyranocoumarin derivatives. Bioorg Med Chem 2009; 17: 6137-6143
    CrossrefPubMedGoogle Scholar
  • 39 Bennett TN, Paguio M, Gligorijevic B, Seudieu C, Kosar AD, Davidson E, Roepe PD. Novel, rapid, and inexpensive cell-based quantification of antimalarial drug efficacy. Antimicrob Agents Chemother 2004; 48: 1807-1810
    CrossrefPubMedGoogle Scholar
  • 40 Smilkstein M, Sriwilaijaroen N, Kelly JX, Wilairat P, Riscoe M. Simple and inexpensive fluorescence-based technique for high-throughput antimalarial drug screening. Antimicrob Agents Chemother 2004; 48: 1803-1806
    CrossrefPubMedGoogle Scholar
  • 41 Trager W, Jensen JB. Human malaria parasites in continuous culture. 1976. J Parasitol 2005; 91: 484-486
    CrossrefPubMedGoogle Scholar
  • 42 Thaithong S, Beale GH, Chutmongkonkul M. Susceptibility of Plasmodium falciparum to five drugs: An in vitro study of isolates mainly from Thailand. Trans R Soc Trop Med Hyg 1983; 77: 228-231
    CrossrefPubMedGoogle Scholar