Subscribe to RSS
DOI: 10.1055/a-1179-1003
Prospecting and Identifying Phyllanthus amarus Lignans with Antileishmanial and Antitrypanosomal Activity
Supported by: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior 1481071Supported by: Fundação de Amparo à Pesquisa do Estado de São Paulo 2009/16858-9
Supported by: Fundação de Amparo à Pesquisa do Estado do Amazonas 002/2015
Publication History
received 14 January 2020
revised 28 April 2020
accepted 11 May 2020
Publication Date:
08 June 2020 (online)
Abstract
Ten lignans (1 – 10) were isolated from the hexane-ethyl acetate extract of Phyllanthus amarus leaves. Three of them, cubebin dimethyl ether (3), urinatetralin (4), and lintetralin (7) are described for the first time in this species, while phyllanthin (1), niranthin (2), 5-demethoxyniranthin (5), isolintetralin (6), hypophyllanthin (8), nirtetralin (9), and phyltetralin (10) have been already reported from P. amarus. Among the lignans tested against Trypanosoma cruzi intracellular amastigotes, 2 was the most active with an EC50 of 35.28 µM. Lignans 2, 5, 7, and 9 showed inhibitory effects against Leishmania amazonensis promastigotes with EC50 of 56.34, 51.86, 23.57, and 43.27 µM, respectively. During in vitro infection assays, 5 reduced amastigotes by 91% at 103.68 µM concentration, whereas 7 and 9 reduced amastigotes by approximately 84% at 47.5 and 86.04 µM, respectively. Lignans 5, 7, and 9 were more potent in intracellular amastigotes with EC50 of 2.76, 8.30, and 15.83 µM, respectively, than in promastigotes. CC50 for all samples was > 100 µg/mL, thus revealing low cytotoxicity against macrophages, and selectivity against the parasite. L. amazonensis promastigotes treated with compounds 2 and 9 showed decreased respiratory control of 38% and 25%, respectively, suggesting a change in mitochondrial membrane potential and lower ATP production.
Key words
Phyllanthus amarus - Euphorbiaceae - lignans - Leishmania amazonensis - Trypanosoma cruzi - amastigotesSupporting Information
- Supporting Information
1H, 13C, COSY, HSQC, and HMBC NMR spectra of compounds 3, 4, and 7, as well as 1H and 13C NMR and GC-MS data of compounds 1 – 10 and concentration-response curves are available as Supporting Information.
-
References
- 1 World Health Organization: WHO. Neglected tropical diseases. Available at: https://www.who.int/neglected_diseases/diseases/en/ Accessed December 16, 2019
- 2 Drugs for Neglected Diseases initiative: DNDi. About Chagas disease. Available at: https://www.dndi.org/diseases-projects/chagas/ Accessed December 16, 2019
- 3 Drugs for Neglected Diseases initiative: DNDi. About leishmaniasis. Availabe at. https://www.dndi.org/diseases-projects/leishmaniasis/ Accessed December 16, 2019
- 4 World Health Organization: WHO. Leishmaniasis. Available at: https://www.who.int/leishmaniasis/burden/en/ Accessed October 16, 2019
- 5 Salomao K, Menna-Barreto RFS, de Castro SL. Stairway to heaven or hell? Perspectives and limitations of Chagas disease chemotherapy. Curr Top Med Chem 2016; 16: 2266-2289
- 6 Alcântara LM, Ferreira TCS, Gadelha FR, Miguel DC. Challenges in drug discovery targeting TriTryp diseases with an emphasis on leishmaniasis. Int J Parasitol Drugs Drug Resist 2018; 8: 430-439
- 7 Sarin B, Verma N, Martín JP, Mohanty A. An overview of important ethnomedicinal herbs of Phyllanthus species: present status and future prospects. Sci World J 2014; 2014: 1-12
- 8 Qi W, Hua L, Gao K. Chemical constituents of the plants from the genus Phyllanthus . Chem Biodivers 2014; 11: 181-196
- 9 van Andel T, Carvalheiro LG. Why urban citizens in developing countries use traditional medicines: the case of Suriname. Evid Based Complement Alternat Med 2013; 2013: 687197
- 10 Kassuya CAL, Silvestre AA, Rehder VLG, Calixto JB. Anti-allodynic and anti-oedematogenic properties of the extract and lignans from Phyllanthus amarus in models of persistent inflammatory and neuropathic pain. Eur J Pharmacol 2003; 478: 145-153
- 11 Harikrishnan H, Jantan I, Haque MA, Kumolosasi E. Anti-inflammatory effects of Phyllanthus amarus Schum. & Thonn. through inhibition of NF-ΚB, MAPK, and PI3K-Akt signaling pathways in LPS-induced human macrophages. BMC Complement Altern Med 2018; 18: 1-13
- 12 Roengrit T, Wannanon P, Prasertsri P, Kanpetta Y, Sripanidkulchai BO, Leelayuwat N. Antioxidant and anti-nociceptive effects of Phyllanthus amarus on improving exercise recovery in sedentary men: a randomized crossover (double-blind) design. J Int Soc Sports Nutr 2014; 11: 1-9
- 13 Putakala M, Gujjala S, Nukala S, Bongu SBR, Chintakunta N, Desireddy S. Cardioprotective effect of Phyllanthus amarus against high fructose diet induced myocardial and aortic stress in rat model. Biomed Pharmacother 2017; 95: 1359-1368
- 14 Sethiya NK, Shah P, Rajpara A, Nagar PA, Mishra SH. Antioxidant and hepatoprotective effects of mixed micellar lipid formulation of phyllanthin and piperine in carbon tetrachloride-induced liver injury in rodents. Food Funct 2015; 6: 3593-3603
- 15 Akporowhe S, Onyesom I. Phyllathus amarus augments the serum antioxidant capacity and invigorates the blood in experimental mice. Biosci Biotechnol Researsch Commun 2016; 9: 15-18
- 16 Lim WC, Kim H, Kim YJ, Choi KC, Lee IH, Lee KH, Kim MK, Ko H. Dioscin suppresses TGF-β1-induced epithelial-mesenchymal transition and suppresses A549 lung cancer migration and invasion. Bioorganic Med Chem Lett 2017; 27: 3342-3348
- 17 Nguyen VT, Sakoff JA, Scarlett CJ. Physicochemical properties, antioxidant and cytotoxic activities of crude extracts and fractions from Phyllanthus amarus . Medicines 2017; 4: 57-72
- 18 Ilangkovan M, Jantan I, Mesaik MA, Bukhari SNA. Immunosuppressive effects of the standardized extract of Phyllanthus amarus on cellular immune responses in Wistar-Kyoto rats. Drug Des Devel Ther 2015; 9: 4917-4930
- 19 Ilangkovan M, Jantan I, Nasir S, Bukhari A. Phytomedicine phyllanthin from Phyllanthus amarus inhibits cellular and humoral immune responses in balb/c mice. Phytomedicine 2016; 23: 1441-1450
- 20 Chowdhury S, Mukherjee T, Mukhopadhyay R, Mukherjee B, Sengupta S, Chattopadhyay S, Jaisankar P, Roy S, Majumder HK. The lignan niranthin poisons Leishmania donovani topoisomerase IB and favours a Th1 immune response in mice. EMBO Mol Med 2012; 4: 1126-1143
- 21 de Oliveira CNF, Frezza TF, Garcia VL, Figueira GM, Mendes TMF, Allegretti SM. Schistosoma mansoni: in vivo evaluation of Phyllanthus amarus hexanic and ethanolic extracts. Exp Parasitol 2017; 183: 56-63
- 22 Tang YQ, Jaganath I, Manikam R, Sekaran SD. Phyllanthus suppresses prostate cancer cell, PC-3, proliferation and induces apoptosis through multiple signalling pathways (MAPKs, PI3K/Akt, NF κB, and Hypoxia). Evid Based Complement Alternat Med 2013; 2013: 1-13
- 23 Reddy BU, Mullick R, Kumar A, Sharma G, Bag P, Srinivasan P, Nandhitha M, Srinivasan N, Das S. A natural small molecule inhibitor corilagin blocks HCV replication and modulates oxidative stress to reduce liver damage. Antiviral Res 2018; 150: 47-59
- 24 Singh K, Panghal M, Kadyan S, Chaudhary U, Yadav JP. Green silver nanoparticles of Phyllanthus amarus: as an antibacterial agent against multi drug resistant clinical isolates of Pseudomonas aeruginosa . J Nanobiotechnology 2014; 12: 1-9
- 25 Ajitha B, Kumar YA, Jeon H, Won C. Synthesis of silver nanoparticles in an eco-friendly way using Phyllanthus amarus leaf extract: antimicrobial and catalytic activity. Adv Powder Technol 2018; 29: 86-93
- 26 Adeneye AA. The leaf and seed aqueous extract of Phyllanthus amarus improves insulin resistance diabetes in experimental animal studies. J Ethnopharmacol 2012; 144: 705-711
- 27 Yoa NA, Rasul Z, Najmanová I, Kamagaté M, Said A, Chabert P, Auger C, Die-Kakou H, Schini-Kerth V. O10 Beneficial effect of Phyllanthus amarus (Euphorbiaceae) on DOCA-salt-induced left ventricle cardiac hypertrophy and endothelial dysfunction in rats. Biochem Pharmacol 2017; 139: 112-113
- 28 Pradit W, Chomdej S, Nganvongpanit K, Ongchai S. Chondroprotective potential of Phyllanthus amarus Schum & Thonn in experimentally induced cartilage degradation in the explants culture model. Vitr Cell Dev Biol 2015; 51: 336-344
- 29 Mo J, Yang R, Li F, He B, Zhang X, Zhao Y, Shen Z, Chen P. Geraniin promotes osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) via activating β-catenin: a comparative study between BMSCs from normal and osteoporotic rats. J Nat Med 2019; 73: 262-272
- 30 Yao AN, Kamagaté M, Amonkan AK, Chabert P, Kpahé F, Koffi C, Kouamé MN, Auger C, Kati-Coulibaly S, Schini-Kerth V, Die-Kakou H. The acute diuretic effect of an ethanolic fraction of Phyllanthus amarus (Euphorbiaceae) in rats involves prostaglandins. BMC Complement Altern Med 2018; 1-7
- 31 Kumar M, Sheikh MA, Bussmann RW. Ethnomedicinal and ecological status of plants in Garhwal Himalaya, India. J Ethnobiol Ethnomed 2011; 7: 32-45
- 32 Sprenger R da F, Cass QB. Characterization of four Phyllanthus species using liquid chromatography coupled to tandem mass spectrometry. J Chromatogr A 2013; 1291: 97-103
- 33 Elfahmi. Batterman S, Koulman A, Hackl T, Bos R, Kayser O, Woerdenbag HJ, Quax WJ. Lignans from cell suspension cultures of Phyllanthus niruri, an Indonesian medicinal plant. J Nat Prod 2006; 69: 55-58
- 34 Chang CC, Lien YC, Liu KC, Lee SS. Lignans from Phyllanthus urinaria . Phytochemistry 2003; 63: 825-833
- 35 Wang CY, Lee SS. Analysis and identification of lignans in Phyllanthus urinaria by HPLC-SPE-NMR. Phytochem Anal 2005; 16: 120-126
- 36 Leite DFP, Kassuya CAL, Mazzuco TL, Silvestre A, de Melo LV, Rehder VLG, Rumjanek VM, Calixto JB. The cytotoxic effect and the multidrug resistance reversing action of lignans from Phyllanthus amarus . Planta Med 2006; 72: 1353-1358
- 37 Kassuya CAL, Leite DFP, De Melo LV, Rehder VLC, Calixto JB. Anti-inflammatory properties of extracts, fractions and lignans isolated from Phyllanthus amarus . Planta Med 2005; 71: 721-726
- 38 Pereira RG, Nakamura RN, Rodrigues MVN, Osorio-Tobón JF, Garcia VL, Martinez J. Supercritical fluid extraction of phyllanthin and niranthin from Phyllanthus amarus Schum & Thonn. J Supercrit Fluids 2017; 127: 23-32
- 39 Global Health Innovative Technology Fund: GHIT Fund. Hit-to-Lead Platform. Available at: https://.ghitfund.org/ Accessed December 18, 2019
- 40 Lee N, Bertholet S, Debrabant A, Muller J, Duncan R, Nakhasi HL. Programmed cell death in the unicellular protozoan parasite Leishmania . Cell Death Differ 2002; 9: 53-64
- 41 Franco CH, Alcântara LM, Chatelain E, Freitas-Junior L, Moraes CB. Drug discovery for Chagas disease: impact of different host cell lines on assay performance and hit compound selection. Trop Med Infect Dis 2019; 4: 82
- 42 Silva TM, Peloso EF, Vitor SC, Ribeiro LHG, Gadelha FR. O2 consumption rates along the growth curve: new insights into Trypanosoma cruzi mitochondrial respiratory chain. J Bioenerg Biomembr 2011; 43: 409-417
- 43 Miguel DC, Zauli-Nascimento RC, Yokoyama-Yasunaka JKU, Pereira LIA, Jerônimo SMB, Ribeiro-Dias F, Dorta ML, Uliana SRB. Clinical isolates of New World Leishmania from cutaneous and visceral leishmaniasis patients are uniformly sensitive to tamoxifen. Int J Antimicrob Agents 2011; 38: 93-94