Mode of Action on Trypanosoma and Leishmania spp.

  • María E. LombardoEmail author
  • Alcira Batlle


In this chapter, the most common molecular targets and mechanisms of action of anti-trypanosomatid drugs are described: biosynthesis of sterols, trypanothione pathway, purine salvage pathway, cysteine proteinases, trans-sialidase, metallocarboxypeptidases, tubulin, calcium homeostasis and pyrophosphate metabolism, heme uptake and degradation, glycolytic pathway, DNA interaction, oxidative stress and apoptosis. Interaction of the sesquiterpene lactones with hemin, the induction of oxidative stress, the inhibition of enzymes as cruzipain and trypanothione reductase, the apoptosis induction and the ability of this type of compounds to inhibit sterol biosynthesis will be also discussed.


Anti-trypanosomatid drugs Drug targets Sterol biosynthesis Trypanothione pathway Proteinases Trans-sialidase Tubulin Heme Oxidative stress Apoptosis 


  1. Alvarez VE, Niemirowicz GT, Cazzulo JJ (2012) The peptidases of Trypanosoma cruzi: digestive enzymes, virulence factors, and mediators of autophagy and programmed cell death. Biochim Biophys Acta 1824:195–206CrossRefPubMedGoogle Scholar
  2. Alvarez VE, Niemirowicz GT, Cazzulo JJ (2013) Metacaspases, autophagins and metallocarboxypeptidases: potential new targets for chemotherapy of the trypanosomiases. Curr Med Chem 20:3069–3077. ReviewCrossRefPubMedGoogle Scholar
  3. Amin D, Cornell SA, Gustafson SK et al (1992) Bisphosphonates used for the treatment of bone disorders inhibit squalene synthase and cholesterol biosynthesis. J Lipid Res 33:1657–1663PubMedGoogle Scholar
  4. Assíria Fontes Martins T, de Figueiredo Diniz L, Mazzeti AL et al (2015) Benznidazole/itraconazole combination treatment enhances anti-Trypanosoma cruzi activity in experimental Chagas disease. PLoS One 10:e0128707CrossRefPubMedPubMedCentralGoogle Scholar
  5. Babokhov P, Sanyaolu AO, Oyibo WA et al (2013) A current analysis of chemotherapy strategies for the treatment of human African trypanosomiasis. Pathog Glob Health 107:242–252CrossRefPubMedPubMedCentralGoogle Scholar
  6. Barrera P, Sülsen VP, Lozano E et al (2013) Natural sesquiterpene lactones induce oxidative stress in Leishmania mexicana. Evid Based Complement Alternat Med 2013:163404CrossRefPubMedPubMedCentralGoogle Scholar
  7. Baum SG, Wittner M, Nadler JP et al (1981) Taxol, a microtubule stabilizing agent, blocks the replication of Trypanosoma cruzi. Proc Natl Acad Sci U S A 78:4571–4575CrossRefPubMedPubMedCentralGoogle Scholar
  8. Benaim B, Garcia CR (2011) Targeting calcium homeostasis as the therapy of Chagas’ disease and leishmaniasis – a review. Trop Biomed 28:471–481PubMedGoogle Scholar
  9. Benaim G, Paniz Mondolfi AE (2012) The emerging role of amiodarone and dronedarone in Chagas disease. Nat Rev Cardiol 9:605–609CrossRefPubMedGoogle Scholar
  10. Benaim G, Hernandez-Rodriguez V, Mujica-Gonzalez S et al (2012) In vitro anti-Trypanosoma cruzi activity of dronedarone, a novel amiodarone derivative with an improved safety profile. Antimicrob Agents Chemother 56:3720–3725CrossRefPubMedPubMedCentralGoogle Scholar
  11. Benaim G, Casanova P, Hernandez-Rodriguez V et al (2014) Dronedarone, an amiodarone analog with improved anti-Leishmania mexicana efficacy. Antimicrob Agents Chemother 58:2295–2303CrossRefPubMedPubMedCentralGoogle Scholar
  12. Brener Z, Cançado JR, Galvão LM et al (1993) An experimental and clinical assay with ketoconazole in the treatment of Chagas disease. Mem Inst Oswaldo Cruz 88:149–153CrossRefPubMedGoogle Scholar
  13. Brengio S, Belmonte S, Guerreiro E et al (2000) The sesquiterpene lactone dehydroleucodine (DhL) affects the growth of cultured epimastigotes of Trypanosoma cruzi. J Parasitol 86:407–412CrossRefPubMedGoogle Scholar
  14. Bryson K, Besteiro S, McGachy HA et al (2009) Overexpression of the natural inhibitor of cysteine peptidases in Leishmania mexicana leads to reduced virulence and a Th1 response. Infect Immun 77:2971–2978CrossRefPubMedPubMedCentralGoogle Scholar
  15. Buckner FS (2008) Sterol 14-demethylase inhibitors for Trypanosoma cruzi infections. Adv Exp Med Biol 625:61–80CrossRefPubMedGoogle Scholar
  16. Burtoloso AC, de Albuquerque S, Furber M et al (2017) Anti-trypanosomal activity of non-peptidic nitrile-based cysteine protease inhibitors. PLoS Negl Trop Dis 11:e0005343CrossRefPubMedPubMedCentralGoogle Scholar
  17. Campos-Salinas J, Cabello-Donayre M, García-Hernández R et al (2011) A new ATP-binding cassette protein is involved in intracellular haem trafficking in Leishmania. Mol Microbiol 79:1430–1444CrossRefPubMedGoogle Scholar
  18. Caputto ME, Fabian LE, Benítez D et al (2011) Thiosemicarbazones derived from 1-indanones as new anti-Trypanosoma cruzi agents. Bioorg Med Chem 19:6818–6826CrossRefPubMedGoogle Scholar
  19. Chakraborti S, Das L, Kapoor N et al (2011) Curcumin recognizes a unique binding site of tubulin. J Med Chem 54:6183–6196CrossRefPubMedGoogle Scholar
  20. Chatelain E (2015) Chagas disease drug discovery: toward a new era. J Biomol Screen 20:22–35CrossRefPubMedGoogle Scholar
  21. Chawla B, Madhubala R (2010) Drug targets in Leishmania. J Parasit Dis 34:1–13CrossRefPubMedPubMedCentralGoogle Scholar
  22. Ciccarelli A, Araujo L, Batlle A et al (2007) Effect of haemin on growth, protein content and the antioxidant defence system in Trypanosoma cruzi. Parasitology 134:959–965CrossRefPubMedGoogle Scholar
  23. Ciccarelli AB, Frank FM, Puente V et al (2012) Antiparasitic effect of vitamin B12 on Trypanosoma cruzi. Antimicrob Agents Chemother 56:5315–5320CrossRefPubMedPubMedCentralGoogle Scholar
  24. Cupello MP, Souza CF, Buchensky C et al (2011) The heme uptake process in Trypanosoma cruzi epimastigotes is inhibited by heme analogues and by inhibitors of ABC transporters. Acta Trop 120:211–218CrossRefPubMedGoogle Scholar
  25. Dc-Rubin SS, Schenkman S (2012) Trypanosoma crWuzi trans-sialidase as a multifunctional enzyme in Chagas’ disease. Cell Microbiol 14:1522–1530CrossRefPubMedGoogle Scholar
  26. Fernandes Rodrigues JC, Concepcion JL, Rodrigues C et al (2008) In vitro activities of ER-119884 and E5700, two potent squalene synthase inhibitors, against Leishmania amazonensis: antiproliferative, biochemical, and ultrastructural effects. Antimicrob Agents Chemother 52:4098–4114CrossRefPubMedPubMedCentralGoogle Scholar
  27. Ferreira RS, Simeonov A, Jadhav A et al (2010) Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors. J Med Chem 53:4891–4905CrossRefPubMedPubMedCentralGoogle Scholar
  28. Frasch AP, Carmona AK, Juliano L et al (2012) Characterization of the M32 metallocarboxypeptidase of Trypanosoma brucei: differences and similarities with its orthologue in Trypanosoma cruzi. Mol Biochem Parasitol 184:63–70CrossRefPubMedPubMedCentralGoogle Scholar
  29. Freire-de-Lima L, Ribeiro TS, Rocha GM et al (2011) The toxic effects of piperine against Trypanosoma cruzi: ultrastructural alterations and reversible blockage of cytokinesis in epimastigote forms. Parasitol Res 102:1059–1067CrossRefGoogle Scholar
  30. Galaka T, Ferrer Casal M, Storey M et al (2017) Antiparasitic activity of sulfur- and fluorine-containing bisphosphonates against trypanosomatids and apicomplexan parasites. Molecules 22(1):82. CrossRefGoogle Scholar
  31. Heby O, Persson L, Rentala M (2007) Targeting the polyamine biosynthetic enzymes: a promising approach to therapy of African sleeping sickness, Chagas’ disease, and leishmaniasis. Amino Acids 33:359–366CrossRefPubMedGoogle Scholar
  32. Huynh C, Yuan X, Miguel DC et al (2012) Heme uptake by Leishmania amazonensis is mediated by the transmembrane protein LHR1. PLoS Pathog 8:e1002795CrossRefPubMedPubMedCentralGoogle Scholar
  33. Jiang Z, Zhou Y (2005) Using bioinformatics for drug target identification from the genome. Am J Pharmacogenomics 5:387–396. ReviewCrossRefPubMedGoogle Scholar
  34. Jimenez V, Kemmerling U, Paredes R et al (2014) Natural sesquiterpene lactones induce programmed cell death in Trypanosoma cruzi: a new therapeutic target? Phytomedicine 21:1411–1418CrossRefPubMedGoogle Scholar
  35. Jimenez-Ortiz V, Brengio SD, Giordano O et al (2005) The trypanocidal effect of sesquiterpene lactones helenalin and mexicanin on cultured epimastigotes. J Parasitol 91:170–174CrossRefPubMedGoogle Scholar
  36. Karioti A, Skaltsa H, Kaiser M et al (2009) Trypanocidal, leishmanicidal and cytotoxic effects of anthecotulide-type linear sesquiterpene lactones from Anthemis auriculata. Phytomedicine 16:783–787CrossRefPubMedGoogle Scholar
  37. Katsila T, Spyroulias GA, Patrinos GP et al (2016) Computational approaches in target identification and drug discovery. Comput Struct Biotechnol J 14:177–184. ReviewCrossRefPubMedPubMedCentralGoogle Scholar
  38. Kavanagh KL, Guo K, Dunford JE et al (2006) The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Proc Natl Acad Sci 103:7829–7834CrossRefPubMedGoogle Scholar
  39. Kerr ID, Lee JH, Farady CJ et al (2009) Vinyl sulfones as antiparasitic agents and a structural basis for drug design. J Biol Chem 284:25697–25703CrossRefPubMedPubMedCentralGoogle Scholar
  40. Kerr ID, Wu P, Marion-Tsukamaki R et al (2010) Crystal structures of TbCatB and rhodesain, potential chemotherapeutic targets and major cysteine proteases of Trypanosoma brucei. PLoS Negl Trop Dis 4:e701CrossRefPubMedPubMedCentralGoogle Scholar
  41. Lechuga GC, Borges JC, Calvet CM et al (2016) Interactions between 4-aminoquinoline and heme: promising mechanism against Trypanosoma cruzi. Int J Parasitol Drugs Drug Resist 6:154–164CrossRefPubMedPubMedCentralGoogle Scholar
  42. Leroux AE, Krauth-Siegel RL (2016) Thiol redox biology of trypanosomatids and potential targets for chemotherapy. Mol Biochem Parasitol 206:67–74CrossRefPubMedGoogle Scholar
  43. Manta B, Comini M, Medeiros A et al (2013) Trypanothione: a unique bis-glutathionyl derivative in trypanosomatids. Biochim Biophys Acta 1830:3199–3216CrossRefPubMedGoogle Scholar
  44. Maya JD, Cassels BK, Iturriaga-Vásquez P et al (2007) Mode of action of natural and synthetic drugs against Trypanosoma cruzi and their interaction with the mammalian host. Comp Biochem Physiol A Mol Integr Physiol 146:601–620CrossRefPubMedGoogle Scholar
  45. McCabe R (1988) Failure of ketoconazole to cure chronic murine Chagas’ disease. J Infect Dis 158:1408–1409CrossRefPubMedGoogle Scholar
  46. McCall LI, El Aroussi A, Choi JY et al (2015) Targeting ergosterol biosynthesis in Leishmania donovani: essentiality of sterol 14 alpha-demethylase. PLoS Negl Trop Dis 9:e0003588CrossRefPubMedPubMedCentralGoogle Scholar
  47. Merli ML, Pagura L, Hernández J et al (2016) The Trypanosoma cruzi protein TcHTE is critical for heme uptake. PLoS Negl Trop Dis 10:e0004359CrossRefPubMedPubMedCentralGoogle Scholar
  48. Miller BR, Roitberg AE (2013) Trypanosoma cruzi trans-sialidase as a drug target against Chagas disease (American trypanosomiasis). Future Med Chem 5:1889–1900CrossRefPubMedGoogle Scholar
  49. Moreira AA, de Souza HB, Amato Neto V et al (1992) Evaluation of the therapeutic activity of itraconazole in chronic infections, experimental and human, by Trypanosoma cruzi. Rev Inst Med Trop Sao Paulo 34:177–180CrossRefPubMedGoogle Scholar
  50. Mukherjee S, Huang C, Guerra F et al (2009) Thermodynamics of bisphosphonates binding to human bone: a two-site model. J Am Chem Soc 131:8374–8375CrossRefPubMedPubMedCentralGoogle Scholar
  51. Nowicki MW, Tulloch LB, Worralll L et al (2008) Design, synthesis and trypanocidal activity of lead compounds based on inhibitors of parasite glycolysis. Bioorg Med Chem 16:5050–5061CrossRefPubMedGoogle Scholar
  52. Paniz-Mondolfi AE, Pérez-Alvarez AM, Lanza G et al (2009) Amiodarone and itraconazole: a rational therapeutic approach for the treatment of chronic Chagas’ disease. Chemotherapy 55:228–233CrossRefPubMedGoogle Scholar
  53. Proto WR, Coombs GH, Mottram JC (2013) Cell death in parasitic protozoa: regulated or incidental? Nat Rev Microbiol 11:58–66CrossRefPubMedGoogle Scholar
  54. Raviolo MA, Solana ME, Novoa MM et al (2013) Synthesis, physicochemical properties of allopurinol derivatives and their biological activity against Trypanosoma cruzi. Eur J Med Chem 69:455–464CrossRefPubMedGoogle Scholar
  55. Rodenko B, van der Burg AM, Wanner MJ et al (2007) 2,N 6-disubstituted adenosine analogs with antitrypanosomal and antimalarial activities. Antimicrob Agents Chemother 51:3796–3802CrossRefPubMedPubMedCentralGoogle Scholar
  56. San Francisco J, Barría I, Gutiérrez B et al (2017) Decreased cruzipain and gp85/trans-sialidase family protein expression contributes to loss of Trypanosoma cruzi trypomastigote virulence. Microbes Infect 19:55–61CrossRefPubMedGoogle Scholar
  57. Saúde-Guimarães DA, Perry KS, Raslan DS et al (2007) Complete assignments of 1H and 13C NMR data for trypanocidal eremantholide C oxide derivatives. Magn Reson Chem 45:1084–1087CrossRefPubMedGoogle Scholar
  58. Sbaraglini ML, Bellera CL, Fraccaroli L et al (2016) Novel cruzipain inhibitors for the chemotherapy of chronic Chagas disease. Int J Antimicrob Agents 48:91–95CrossRefPubMedGoogle Scholar
  59. Schmidt TJ, Brun R, Willuhn G et al (2002) Anti-trypanosomal activity of helenalin and some structurally related sesquiterpene lactones. Planta Med 68:750–751CrossRefPubMedGoogle Scholar
  60. Schmidt TJ, Khalid SA, Romanha AJ et al (2012) The potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases - part I. Curr Med Chem 19:2128–2175CrossRefPubMedGoogle Scholar
  61. Scory S, Stierhof YD, Caffrey CR et al (2007) The cysteine proteinase inhibitor Z-Phe-Ala-CHN2 alters cell morphology and cell division activity of Trypanosoma brucei bloodstream forms in vivo. Kinetoplastid Biol Dis 6:2. CrossRefPubMedPubMedCentralGoogle Scholar
  62. Serrano-Martín X, García-Marchan Y, Fernandez A et al (2009) Amiodarone destabilizes intracellular Ca2+ homeostasis and biosynthesis of sterols in Leishmania mexicana. Antimicrob Agents Chemother 53:1403–1410CrossRefPubMedPubMedCentralGoogle Scholar
  63. Shang N, Li Q, Ko TP et al (2014) Squalene synthase as target for Chagas disease therapeutics. PLoS Pathog 10:e1004114CrossRefPubMedPubMedCentralGoogle Scholar
  64. Silva-Jardim I, Thiemann OH, Anibal F de F (2014) Leishmaniasis and Chagas disease chemotherapy: a critical review. J Braz Chem Soc 25:1810–1823Google Scholar
  65. Smirlis D, Duszenko M, Ruiz AJ (2010) Targeting essential pathways in trypanosomatids gives insights into protozoan mechanisms of cell death. Parasit Vectors 3:107. ReviewCrossRefPubMedPubMedCentralGoogle Scholar
  66. Steenkamp DJ (2002) Thiol metabolism of the trypanosomatids as potential drug targets. IUBMB Life 53:243–248CrossRefPubMedGoogle Scholar
  67. Sueth-Santiago V, Moraes JB, Sobral Alves ES et al (2016) The effectiveness of natural diarylheptanoids against Trypanosoma cruzi: cytotoxicity, ultrastructural alterations and molecular modeling studies. PLoS One 11:e0162926CrossRefPubMedPubMedCentralGoogle Scholar
  68. Sueth-Santiago V, Decote-Ricardo D, Morrot A et al (2017) Challenges in the chemotherapy of Chagas disease: looking for possibilities related to the differences and similarities between the parasite and host. World J Biol Chem 8:57–80CrossRefPubMedPubMedCentralGoogle Scholar
  69. Sülsen VP, Frank FM, Cazorla SI et al (2008) Trypanocidal and leishmanicidal activities of sesquiterpene lactones from Ambrosia tenuifolia Sprengel (Asteraceae). Antimicrob Agents Chemother 52:2415–2419CrossRefPubMedPubMedCentralGoogle Scholar
  70. Sülsen VP, Frank FM, Cazorla SI et al (2011) Psilostachyin C: a natural compound with trypanocidal activity. Int J Antimicrob Agents 37:536–543CrossRefPubMedGoogle Scholar
  71. 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:e2494CrossRefPubMedPubMedCentralGoogle Scholar
  72. 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:e0150526CrossRefPubMedPubMedCentralGoogle Scholar
  73. Tripodi KE, Menendez Bravo SM, Cricco JA (2011) Role of heme and heme-proteins in trypanosomatid essential metabolic pathways. Enzyme Res 201:873230. CrossRefGoogle Scholar
  74. Turrens JF (2004) Oxidative stress and antioxidant defences: a target for the treatment of diseases caused by parasitic protozoa. Mol Asp Med 25:211–220CrossRefGoogle Scholar
  75. Urbina JA (2001) Specific treatment of Chagas disease: current status and new developments. Curr Opin Infect Dis 14:733–741CrossRefPubMedGoogle Scholar
  76. Urbina JA (2010) Specific chemotherapy of Chagas disease: relevance, current limitations and new approaches. Acta Trop 115:55–68CrossRefPubMedGoogle Scholar
  77. Urbina JA, Concepcion JL, Caldera A et al (2004) In vitro and in vivo activities of E5700 and ER-119884, two novel orally active squalene synthase inhibitors, against Trypanosoma cruzi. Antimicrob Agents Chemother 48:2379–2387CrossRefPubMedPubMedCentralGoogle Scholar
  78. Vannier-Santos MA, Urbina JA, Martiny A et al (1995) Alterations induced by the antifungal compounds ketoconazole and terbinafine in Leishmania. J Eukaryot Microbiol 42:337–346CrossRefPubMedGoogle Scholar
  79. Veiga-Santos P, Barrias ES, Santos JF et al (2012) Effects of amiodarone and posaconazole on the growth and ultrastructure of Trypanosoma cruzi. Int J Antimicrob Agents 40:61–71CrossRefPubMedGoogle Scholar
  80. Vieira PM, Francisco AF, Machado EM et al (2012) Different infective forms trigger distinct immune response in experimental Chagas disease. PLoS One 7:e32912CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química BiológicaBuenos AiresArgentina
  2. 2.CONICET – Universidad de Buenos Aires, Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP)Buenos AiresArgentina

Personalised recommendations