Antitrypanosomal and Antileishmanial Activities

  • Andrés Sánchez Alberti
  • Natacha Cerny
  • Augusto Bivona
  • Silvia I. CazorlaEmail author


The so-called neglected tropical diseases, which are endemic in 149 tropical and subtropical countries, affect more than 1 billion people annually, including 875 million children in developing economies. These diseases are responsible for over 500,000 deaths per year and are characterized by long-term disability and severe pain. Neglected tropical diseases include Chagas’ disease, human African trypanosomiasis, and leishmaniasis, among others. The current chemotherapeutic treatments are clearly out-of-date and inadequate because of the toxic effects, the generation of resistance, and frequent inefficacy and because the route and long-term schedules of administration are not adapted to the field conditions. Taken these drawbacks into account, the search for active compounds that provide the basis for the development of new therapies capable of generating curing against T. cruzi and Leishmania spp. infections is highly desirable.

Natural products are an increasing source of new drugs. In recent decades, the Asteraceae family has been extensively studied due to the large number and variety of active compounds that can be extracted from each species. Among them, sesquiterpene lactones are characteristic phytochemicals within this family. The antiprotozoal activity against Trypanosoma cruzi, Leishmania spp., and Plasmodium spp. has been reported for these compounds, making them interesting leads for future drug design.


Trypanosoma cruzi Trypanosoma brucei Leishmania spp. Sesquiterpene lactones Neglected tropical diseases Chemotherapy Active compounds Natural products 


  1. Akhoundi M, Kuhls K, Cannet A et al (2016) A historical overview of the classification, evolution, and dispersion of Leishmania parasites and sandflies. PLoS Negl Trop Dis 10(3):e0004349. Erratum in: PLoS Negl Trop Dis 10(6):e0004770CrossRefPubMedPubMedCentralGoogle Scholar
  2. Aksoy S, Buscher P, Lehane M et al (2017) Human African trypanosomiasis control: achievements and challenges. PLoS Negl Trop Dis 11(4):e0005454. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Avolio F, Rimando AM, Cimmino A et al (2014) Inuloxins A-D and derivatives as antileishmanial agents: structure-activity relationship study. J Antibiot 67(8):597–601. CrossRefPubMedGoogle Scholar
  4. Barrera PA, Jimenez-Ortiz V, Tonn C et al (2008) Natural sesquiterpene lactones are active against Leishmania mexicana. J Parasitol 94(5):1143–1149. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Barrera P, Sülsen VP, Lozano E et al (2013) Natural sesquiterpene lactones induce oxidative Stress in Leishmania mexicana. Evid Based Complement Alternat Med 163404.
  6. Barrett MP, Croft SL (2012) Management of trypanosomiasis and leishmaniasis. Br Med Bull 104:175–196. CrossRefPubMedPubMedCentralGoogle Scholar
  7. Barros de Alencar MV, de Castro E, Sousa JM et al (2017) Diterpenes as lead molecules against neglected tropical diseases. Phytother Res 31(2):175–201. CrossRefPubMedGoogle Scholar
  8. Belo VS, Struchiner CJ, Barbosa DS et al (2014) Risk factors for adverse prognosis and death in American visceral leishmaniasis: a meta-analysis. PLoS Negl Trop Dis 8(7):e2982. CrossRefPubMedPubMedCentralGoogle Scholar
  9. Branquinho RT, Mosqueira VC, de Oliveira-Silva JC et al (2014) Sesquiterpene lactone in nanostructured parenteral dosage form is efficacious in experimental Chagas disease. Antimicrob Agents Chemother 58(4):2067–2075. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Castillo C, Ramírez G, Valck C et al (2013) The interaction of classical complement component C1 with parasite and host calreticulin mediates Trypanosoma cruzi infection of human placenta. PLoS Negl Trop Dis 7(8):e2376. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Castro JA, de Mecca MM, Bartel LC (2006) Toxic side effects of drugs used to treat Chagas’ disease (American trypanosomiasis). Hum Exp Toxicol 25(8):471–479CrossRefPubMedGoogle Scholar
  12. Chatelain E (2016) Chagas disease research and development: is there light at the end of the tunnel? Comput Struct Biotechnol J 15:98–103. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Cheuka PM, Mayoka G, Mutai P et al (2016) The role of natural products in drug discovery and development against Neglected Tropical Diseases. Molecules 22(1). CrossRefGoogle Scholar
  14. Cogo J, De Oliveira Caleare A, Ueda-Nakamura T et al (2012) Trypanocidal activity of guaianolide obtained from Tanacetum Parthenium (L.) Schultz-Bip. and its combinational effect with benznidazole. Phytomedicine 20(1):59–66. CrossRefPubMedGoogle Scholar
  15. Coura JR (2015) The main sceneries of Chagas disease transmission. The vectors, blood and oral transmissions – a comprehensive review. Mem Inst Oswaldo Cruz 110(3):277–282. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Croft SL, Vivas L, Brooker S (2003) Recent advances in research and control of malaria, leishmaniasis, trypanosomiasis and schistosomiasis. East Mediterr Health J 9(4):518–533PubMedGoogle Scholar
  17. De Mieri M, Monteleone G, Ismajili I et al (2017) Antiprotozoal activity-based profiling of a dichloromethane extract from Anthemis nobilis flowers. J Nat Prod 80(2):459–470. CrossRefPubMedGoogle Scholar
  18. Fenwick A (2012) The global burden of neglected tropical diseases. Public Health 126(3):233–236. CrossRefPubMedGoogle Scholar
  19. Frank FM, Fernández MM, Taranto NJ et al (2003) Characterization of human infection by Leishmania spp. in the Northwest of Argentina: immune response, double infection with Trypanosoma cruzi and species of Leishmania involved. Parasitology 126(Pt 1):31–39CrossRefPubMedGoogle Scholar
  20. Frank FM, Ulloa J, Cazorla SI et al (2013) Trypanocidal activity of Smallanthus sonchifolius: identification of active sesquiterpene lactones by bioassay-guided fractionation. Evid Based Complement Alternat Med 627898.
  21. Gazanion E, Vergnes B, Seveno M et al (2011) In vitro activity of nicotinamide/antileishmanial drug combinations. Parasitol Int 60(1):19–24. CrossRefPubMedGoogle Scholar
  22. Girardi C, Fabre N, Paloque L et al (2015) Evaluation of antiplasmodial and antileishmanial activities of herbal medicine Pseudelephantopus spiralis (Less.) Cronquist and isolated hirsutinolide-type sesquiterpenoids. J Ethnopharmacol 170:167–174. CrossRefPubMedGoogle Scholar
  23. Gökbulut A, Kaiser M, Brun R et al (2012) 9β-hydroxyparthenolide esters from Inula montbretiana and their antiprotozoal activity. Planta Med 78(3):225–229. CrossRefPubMedGoogle Scholar
  24. Herrera Acevedo C, Scotti L, Feitosa Alves M et al (2017) Computer-aided drug design using sesquiterpene lactones as sources of new structures with potential activity against Infectious Neglected Diseases. Molecules 22(1):79. CrossRefGoogle Scholar
  25. Hoyos CL, Cajal SP, Juarez M et al (2016) Epidemiology of American Tegumentary Leishmaniasis and Trypanosoma cruzi infection in the Northwestern Argentina. Biomed Res Int 2016:6456031CrossRefPubMedPubMedCentralGoogle Scholar
  26. Izumi E, Ueda-Nakamura T, Dias Filho BP et al (2011) Natural products and Chagas’ disease: a review of plant compounds studied for activity against Trypanosoma cruzi. Nat Prod Rep 28(4):809–823. CrossRefPubMedGoogle Scholar
  27. Jimenez V, Paredes R, Sosa MA et al (2008) Natural programmed cell death in T. cruzi epimastigotes maintained in axenic cultures. J Cell Biochem 105(3):688–698. CrossRefPubMedGoogle Scholar
  28. Jimenez V, Kemmerling U, Paredes R et al (2014) Natural sesquiterpene lactones induce programmed cell death in Trypanosoma Cruzi: a new therapeutic target? Phytomedicine 21(11):1411–1418. CrossRefPubMedGoogle Scholar
  29. Jimenez-Ortiz V, Brengio SD, Giordano O et al (2005) The Trypanocidal effect of Sesquiterpene lactones Helenalin and Mexicanin on cultured Epimastigotes. J Parasitol 91(1):170–174. CrossRefPubMedGoogle Scholar
  30. Julianti T, Hata Y, Zimmermann S et al (2011) Antitrypanosomal sesquiterpene lactones from Saussurea costus. Fitoterapia 82(7):955–959. CrossRefPubMedGoogle Scholar
  31. Kang BY, Chung SW, Kim TS (2001) Inhibition of interleukin-12 production in lipopolysaccharide-activated mouse macrophages by parthenolide, a predominant sesquiterpene lactone in Tanacetum parthenium: involvement of nuclear factor-kappaB. Immunol Lett 77(3):159–166CrossRefPubMedGoogle Scholar
  32. Karimkhani C, Wanga V, Naghavi P et al (2017) Global burden of cutaneous leishmaniasis. Lancet Infect Dis 17(3):264. CrossRefPubMedGoogle Scholar
  33. Karioti A, Skaltsa H, Kaiser M et al (2009) Trypanocidal, leishmanicidal and cytotoxic effects of anthecotulide-type linear sesquiterpene lactones from Anthemis auriculata. Phytomedicine 16(8):783–787. CrossRefPubMedGoogle Scholar
  34. Keating J, Yukich JO, Sutherland CS et al (2015) Human African trypanosomiasis prevention, treatment and control costs: a systematic review. Acta Trop 150:4–13. CrossRefPubMedGoogle Scholar
  35. Laurella LC, Frank FM, Sarquiz A et al (2012) In vitro evaluation of antiprotozoal and antiviral activities of extracts from Argentinean Mikania species. ScientificWorldJournal 121253.
  36. Laurella LC, Cerny N, Bivona AE et al (2017) Sesquiterpene lactones from Mikania species display in vitro activity against Trypanosoma cruzi and Leishmania sp. PLoS Negl Trop Dis 11(9):e0005929. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Lozano E, Barrera P, Salinas R et al (2012) Sesquiterpene lactones and the diterpene 5-epi-icetexone affect the intracellular and extracellular stages of Trypanosoma cruzi. Parasitol Int 61(4):628–633. CrossRefPubMedGoogle Scholar
  38. Macharia JC, Bourdichon AJ, Gicheru MM (2004) Efficacy of Trypan: a diminazene based drug as antileishmanial agent. Acta Trop 92(3):267–272CrossRefPubMedGoogle Scholar
  39. Manyando C, Kayentao K, D'Alessandro U et al (2012) A systematic review of the safety and efficacy of artemether-lumefantrine against uncomplicated Plasmodium falciparum malaria during pregnancy. Malar 11:141. CrossRefGoogle Scholar
  40. Mokoka TA, Xolani PK, Zimmermann S et al (2013) Antiprotozoal screening of 60 south African plants, and the identification of the antitrypanosomal germacranolides schkuhrin I and II. Planta Medm 79(14):1380–1384. CrossRefGoogle Scholar
  41. Molina-Berríos A, Campos-Estrada C, Henriquez N et al (2013) Protective role of acetylsalicylic acid in experimental Trypanosoma cruzi infection: evidence of a 15-epi-lipoxin A4-mediated effect. PLoS Negl Trop Dis 7(4):e2173. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Molyneux D, Savioli L, Engels D (2017) Neglected tropical diseases: progress towards addressing the chronic pandemic. Lancet 389(10066):312–325. CrossRefGoogle Scholar
  43. Mukhopadhyay R, Mukherjee S, Mukherjee B et al (2011) Characterisation of antimony-resistant Leishmania donovani isolates: biochemical and biophysical studies and interaction with host cells. Int J Parasitol 41(13–14):1311–1321. CrossRefPubMedGoogle Scholar
  44. Muschietti L, Ulloa J (2016) Natural sesquiterpene lactones as potential trypanocidal therapeutic agents: a review. Nat Prod Comm 11(10):1569–1578Google Scholar
  45. Mutiso JM, Macharia JC, Barasa M et al (2011) In vitro and in vivo antileishmanial efficacy of a combination therapy of diminazene and artesunate against Leishmania donovani in BALB/c mice. Rev Inst Med Trop Sao Paulo 53(3):129–132CrossRefPubMedGoogle Scholar
  46. Mwololo SW, Mutiso JM, Macharia JC et al (2015) In vitro activity and in vivo efficacy of a combination therapy of diminazene and chloroquine against murine visceral leishmaniasis. J Biomed Res 29(3):214–223. CrossRefPubMedPubMedCentralGoogle Scholar
  47. Nour AM, Khalid SA, Kaiser M et al (2009) The antiprotozoal activity of sixteen asteraceae species native to Sudan and bioactivity-guided isolation of xanthanolides from Xanthium brasilicum. Planta Med 75(12):1363–1368. CrossRefPubMedGoogle Scholar
  48. Olliaro PL, Nair NK, Sathasivam K et al (2001) Pharmacokinetics of artesunate after single oral administration to rats. BMC Pharmacol 1:12CrossRefPubMedPubMedCentralGoogle Scholar
  49. Paucar R, Moreno-Viguri E, Pérez-Silanes S (2016) Challenges in Chagas disease drug discovery: a review. Curr Med Chem 23(28):3154–3170CrossRefPubMedGoogle Scholar
  50. Piela-Smith TH, Liu X (2001) Feverfew extracts and the sesquiterpene lactone parthenolide inhibit intercellular adhesion molecule-1 expression in human synovial fibroblasts. Cell Immunol 209(2):89–96CrossRefPubMedGoogle Scholar
  51. Pink R, Hudson A, Mouriès MA et al (2005) Opportunities and challenges in Antiparasitic drug discovery. Nat Rev Drug Discov 4:727–740CrossRefPubMedGoogle Scholar
  52. Prajapati VK, Sharma S, Rai M et al (2013) In vitro susceptibility of Leishmania donovani to miltefosine in Indian visceral leishmaniasis. Am J Trop Med Hyg 89(4):750–754. CrossRefPubMedPubMedCentralGoogle Scholar
  53. Prokop A, Davidson JM (2008) Nanovehicular intracellular delivery systems. J Pharm Sci 97(9):3518–3590. CrossRefPubMedPubMedCentralGoogle Scholar
  54. Rabito MF, Britta EA, Pelegrini BL et al (2014) In vitro and in vivo antileishmanial activity of sesquiterpene lactone-rich dichloromethane fraction obtained from Tanacetum parthenium (L.) Schultz-Bip. Exp Parasitol 143:18–23. CrossRefPubMedGoogle Scholar
  55. Sacks D, Noben-Trauth N (2002) The immunology of susceptibility and resistance to Leishmania major in mice. Nat Rev Immuno 2(11):845–858CrossRefGoogle Scholar
  56. Sánchez LV, Ramírez JD (2013) Congenital and oral transmission of American trypanosomiasis: an overview of physiopathogenic aspect. Parasitology 140(2):147–159. CrossRefPubMedGoogle Scholar
  57. Sato T, Hara S, Sato M et al (2015) Synthesis of cynaropicrin-d(4). Bioorg Med Chem Lett1 25(23):5504–5507. CrossRefGoogle Scholar
  58. Schmidt TJ, Brun R, Willuhn G et al (2002) Anti-Trypanosomal activity of Helenalin and some structurally related Sesquiterpene lactones. Planta Med 68(8):750–751. CrossRefPubMedPubMedCentralGoogle Scholar
  59. Schmidt TJ, Da Costa FB, Lopes NP et al (2014) In Silico prediction and experimental evaluation of furanoheliangolide sesquiterpene lactones as potent agents against Trypanosoma brucei rhodesiense. Antimicrob Agents Chemother 58(1):325–332. CrossRefPubMedPubMedCentralGoogle Scholar
  60. da Silva CF, Batista Dda G, De Araújo JS et al (2013) Activities of psilostachyin A and cynaropicrin against Trypanosoma cruzi in vitro and in vivo. Antimicrob Agents Chemother 57(11):5307–5314. CrossRefPubMedPubMedCentralGoogle Scholar
  61. da Silva EB, Oliveira E, Silva DA, Oliveira AR et al (2017) Design and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death. Eur J Med Chem 130:39–50. CrossRefPubMedGoogle Scholar
  62. Singh OP, Singh B, Chakravarty J et al (2016) Current challenges in treatment options for visceral leishmaniasis in India: a public health perspective. Infect Dis Poverty 5:19. CrossRefPubMedPubMedCentralGoogle Scholar
  63. Sosa AM, Amaya S, Salamanca Capusiri E et al (2016) Active sesquiterpene lactones against Leishmania amazonensis and Leishmania braziliensis. Nat Prod Res 12:1–5Google Scholar
  64. Srivastava S, Shankar P, Mishra J et al (2016) Possibilities and challenges for developing a successful vaccine for leishmaniasis. Parasit Vectors 9(1):277. CrossRefPubMedPubMedCentralGoogle Scholar
  65. von Stebut E, Udey MC (2004) Requirements for Th1-dependent immunity against infection with Leishmania major. Microbes Infect 6(12):1102–1109CrossRefGoogle Scholar
  66. Steverding D (2017) The history of leishmaniasis. Parasit Vectors 10(1):82. CrossRefPubMedPubMedCentralGoogle Scholar
  67. Sülsen VP, Frank FM, Cazorla SI et al (2008) Trypanocidal and leishmanicidal activities of sesquiterpene lactones from Ambrosia tenuifolia Sprengel (Asteraceae). Antimicrob Agents Chemother 52(7):2415–2419. CrossRefPubMedPubMedCentralGoogle Scholar
  68. Sülsen VP, Frank FM, Cazorla SI et al (2011) Psilostachyin C: a natural compound with trypanocidal activity. Int J Antimicrob Agents 37(6):536–543. CrossRefPubMedGoogle Scholar
  69. Sülsen VP, Cazorla SI, Frank FM et al (2013) Natural terpenoids from Ambrosia species are active in vitro and in vivo against human pathogenic trypanosomatids. PLoS Negl Trop Dis 7(10):e2494. CrossRefPubMedPubMedCentralGoogle Scholar
  70. Sülsen VP, Puente V, Papademetrio D et al (2016) Mode of action of the Sesquiterpene lactones Psilostachyin and Psilostachyin C on Trypanosoma cruzi. PLoS One 11(3):e0150526. CrossRefPubMedPubMedCentralGoogle Scholar
  71. Sundar S, Chakravarty J (2013) Leishmaniasis: an update of current pharmacotherapy. Expert Opin Pharmacother 14(1):53–63. CrossRefPubMedGoogle Scholar
  72. Sundar S, Rai M (2002) Advances in the treatment of leishmaniasis. Curr Opin Infect Dis 15(6):593–598CrossRefPubMedGoogle Scholar
  73. Teixeira AR, Hecht MM, Guimaro MC et al (2011) Pathogenesis of Chagas’ disease: parasite persistence and autoimmunity. Clin Microbiol Rev 24(3):592–630. CrossRefPubMedPubMedCentralGoogle Scholar
  74. Thiem DA, Sneden AT, Khan SI et al (2005) Bisnortriterpenes from Salacia madagascariensis. J Nat Prod 68(2):251–254CrossRefPubMedGoogle Scholar
  75. Tiuman TS, Ueda-Nakamura T, Garcia Cortez DA et al (2005) Antileishmanial activity of parthenolide, a sesquiterpene lactone isolated from Tanacetum parthenium. Antimicrob Agents Chemother 49(1):176–182CrossRefPubMedPubMedCentralGoogle Scholar
  76. Tiuman TS, Ueda-Nakamura T, Alonso A et al (2014) Cell death in amastigote forms of Leishmania amazonensis induced by parthenolide. BMC Microbiol 14:152. CrossRefPubMedPubMedCentralGoogle Scholar
  77. de Toledo JS, Ambrósio SR, Borges CH et al (2014) In vitro leishmanicidal activities of sesquiterpene lactones from Tithonia diversifolia against Leishmania braziliensis promastigotes and amastigotes. Molecules 19(5):6070–6079. doi: CrossRefPubMedGoogle Scholar
  78. Vasconcellos Ede C, Pimentel MI, Schubach Ade O et al (2006) Intralesional meglumine antimoniate for treatment of cutaneous leishmaniasis patients with contraindication to systemic therapy from Rio de Janeiro (2000 to 2006). Am J Trop Med Hyg 87(2):257–260CrossRefGoogle Scholar
  79. Veiga-Santos P, Li K, Lameira L et al (2015) SQ109, a new drug lead for Chagas disease. Antimicrob Agents Chemother 59(4):1950–1961. CrossRefPubMedPubMedCentralGoogle Scholar
  80. World Health Organization (WHO) (2017a) Control of Neglected Tropical Diseases. Accessed 31 July 2017
  81. World Health Organization (WHO) (2017b). Leishmaniasis. Fact sheet Updated April 2017. Accessed 31 July 2017
  82. Wu H, Fronczek FR, Burandt CL Jr et al (2011) Antileishmanial germacranolides from Calea zacatechichi. Planta Med 77(7):749–453. CrossRefPubMedGoogle Scholar
  83. Zahari Z, Jani NA, Amanah A et al (2014) Bioassay-guided isolation of a sesquiterpene lactone of deoxyelephantopin from Elephantopus scaber Linn active on Trypanosoma brucei rhodesiense. Phytomedicine 21(3):282–285. CrossRefPubMedGoogle Scholar
  84. Zimmermann S, Kaiser M, Brun R et al (2012) Cynaropicrin: the first plant natural product with in vivo activity against Trypanosoma brucei. Planta Med 78(6):553–556. CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Andrés Sánchez Alberti
    • 1
    • 2
  • Natacha Cerny
    • 1
    • 2
  • Augusto Bivona
    • 1
    • 2
  • Silvia I. Cazorla
    • 2
    • 3
    Email author
  1. 1.Cátedra de Inmunología, IDEHU (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos AiresBuenos AiresArgentina
  2. 2.Instituto de Microbiología y Parasitología Médica, IMPaM (UBA-CONICET), Facultad de Medicina, Universidad de Buenos AiresBuenos AiresArgentina
  3. 3.Laboratorio de Inmunología, Centro de Referencia para Lactobacilos (CERELA-CONICET)TucumánArgentina

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