Exploring Endoperoxides as Leishmanicidal Compounds

  • Sritama De Sarkar
  • Mitali ChatterjeeEmail author


With advances in genomics, proteomics, and bioinformatics, identification of unique parasite-specific metabolic pathways has facilitated development of antileishmanial chemotherapeutics. In view of Leishmania parasites having a compromised antioxidant defense mechanism, induction of oxidative stress is a universal strategy adopted by conventional antileishmanial drugs with mitochondrial dysfunction being the major source of free radicals. However, a limitation is that mammalian mitochondria too are inhibited. Therefore, an attractive therapeutic option would be compounds like endoperoxides which owing to their unusual peroxide bridge mediate parasiticidal activity primarily via generation of free radicals. Accordingly, exploring the leishmanicidal potential of endoperoxides like artemisinin and ascaridole having established antimalarial and antihelminthic properties respectively, was the focus of this study. Leishmania proved to be a susceptible target for these free radical generating endoperoxides, making this therapeutic modality worthy of future pharmacological consideration.


Antileishmanial drugs Drug repurposing Endoperoxides Free radicals Mitochondria Oxidative stress 


  1. 1.
    Jin G, Wong ST (2014) Toward better drug repositioning: prioritizing and integrating existing methods into efficient pipelines. Drug Discov Today 19:637–644CrossRefGoogle Scholar
  2. 2.
    Torres-Guerrero E, Quintanilla-Cedillo MR, Ruiz-Esmenjaud J, Arenas R (2017) Leishmaniasis: a review. F1000Res 6:750CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    World Health Organization. Accessed 19 Sept 2018
  4. 4.
    Croft SL, Seifert K, Duchêne M (2003) Antiprotozoal activities of phospholipid analogues. Mol Biochem Parasitol 126:165–172CrossRefGoogle Scholar
  5. 5.
    Dorlo TP, Balasegaram M, Beijnen JH, de Vries PJ (2012) Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. J Antimicrob Chemother 67:2576–2597CrossRefGoogle Scholar
  6. 6.
    Andrade-Neto VV, Cunha-Junior EF, Dos Santos FV, Pereira TM, Silva RL, Leon LL, Torres-Santos EC (2018) Leishmaniasis treatment: update of possibilities for drug repurposing. Front Biosci (Landmark Ed) 23:967–996CrossRefGoogle Scholar
  7. 7.
    Sen R, Bandyopadhyay S, Dutta A, Mandal G, Ganguly S, Saha P, Chatterjee M (2007) Artemisinin triggers induction of cell-cycle arrest and apoptosis in Leishmania donovani promastigotes. J Med Microbiol 56:1213–1218CrossRefPubMedGoogle Scholar
  8. 8.
    Sen R, Ganguly S, Saha P, Chatterjee M (2010a) Efficacy of artemisinin in experimental visceral leishmaniasis. Int J Antimicrob Agents 36:43–49CrossRefPubMedGoogle Scholar
  9. 9.
    Sen R, Saha P, Sarkar A, Ganguly S, Chatterjee M (2010b) Iron enhances generation of free radicals by artemisinin causing a caspase-independent, apoptotic death in Leishmania donovani promastigotes. Free Radic Res 44:1289–1295CrossRefPubMedGoogle Scholar
  10. 10.
    Huang Z, Srinivasan S, Zhang J, Chen K, Li Y, Li W, Quiocho FA, Pan X (2012) Discovering thiamine transporters as targets of chloroquine using a novel functional genomics strategy. PLoS Genet 8:e1003083CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    van Assche T, Deschacht M, da Luz RA, Maes L, Cos P (2011) Leishmania-macrophage interactions: insights into the redox biology. Free Radic Biol Med 51:337–351CrossRefGoogle Scholar
  12. 12.
    Mukbel RM, Patten C Jr, Gibson K, Ghosh M, Petersen C, Jones DE (2007) Macrophage killing of Leishmania amazonensis amastigotes requires both nitric oxide and superoxide. Am J Trop Med Hyg 76:669–675CrossRefGoogle Scholar
  13. 13.
    Courret N, Fréhel C, Gouhier N, Pouchelet M, Prina E, Roux P, Antoine JC (2002) Biogenesis of Leishmania harbouring parasitophorous vacuoles following phagocytosis of the metacyclic promastigote or amastigotes stage of the parasites. J Cell Sci 115:2303–2316PubMedGoogle Scholar
  14. 14.
    Krauth-Siegel RL, Comini MA (2008) Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism. Biochim Biophys Acta 1780:1236–1248CrossRefPubMedGoogle Scholar
  15. 15.
    Dolai S, Yadav RK, Pal S, Adak S (2009) Overexpression of mitochondrial Leishmania major ascorbate peroxidase enhances tolerance to oxidative stress-induced programmed cell death and protein damage. Eukaryot Cell 8:1721–1731CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Fairlamb AH, Blackburn P, Ulrich P, Chait BT, Cerami A (1985) Trypanothione: a novel bis(glutathionyl)spermidine cofactor for glutathione reductase in trypanosomatids. Science 227:1485–1487CrossRefGoogle Scholar
  17. 17.
    Saudagar P, Dubey VK (2011) Cloning, expression, characterization and inhibition studies on trypanothione synthetase, a drug target enzyme, from Leishmania donovani. Biol Chem 392:1113–1122CrossRefPubMedGoogle Scholar
  18. 18.
    Flohé L, Hecht HJ, Steinert P (1999) Glutathione and trypanothione in parasitic hydroperoxide metabolism. Free Radic Biol Med 27:966–984CrossRefPubMedGoogle Scholar
  19. 19.
    Comini MA, Flohé L (2013) Trypanothione-based redox metabolism of trypanosomatids. In: Trypanosomatid diseases: molecular routes to drug discovery. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, pp 167–199CrossRefGoogle Scholar
  20. 20.
    Field MC, Horn D, Fairlamb AH, Ferguson MAJ, Gray DW, Read KD, De Rycker M, Torrie LS, Wyatt PG, Wyllie S, Gilbert IH (2017) Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need. Nat Rev Microbiol 15:217–231CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Leroux AE, Krauth-Siegel RL (2016) Thiol redox biology of trypanosomatids and potential targets for chemotherapy. Mol Biochem Parasitol 206:67–74CrossRefPubMedGoogle Scholar
  22. 22.
    Mookerjee Basu J, Mookerjee A, Sen P, Bhaumik S, Sen P, Banerjee S, Naskar K, Choudhuri SK, Saha B, Raha S, Roy S (2006) Sodium antimony gluconate induces generation of reactive oxygen species and nitric oxide via phosphoinositide 3-kinase and mitogen-activated protein kinase activation in Leishmania donovani-infected macrophages. Antimicrob Agents Chemother 50:1788–1797CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Sundar S, Chatterjee M (2006) Visceral leishmaniasis—current therapeutic modalities. Indian J Med Res 123:345–352PubMedGoogle Scholar
  24. 24.
    Lee N, Bertholet S, Debrabant A, Muller J, Duncan R, Nakhasi HL (2002) Programmed cell death in the unicellular protozoan parasite Leishmania. Cell Death Differ 9:53–64CrossRefPubMedGoogle Scholar
  25. 25.
    Mehta A, Shaha C (2004) Apoptotic death in Leishmania donovani promastigotes in response to respiratory chain inhibition: complex II inhibition results in increased pentamidine cytotoxicity. J Biol Chem 279:11798–11813CrossRefPubMedGoogle Scholar
  26. 26.
    Shaha C (2006) Apoptosis in Leishmania species & its relevance to disease pathogenesis. Indian J Med Res 123:233–244PubMedGoogle Scholar
  27. 27.
    Verma NK, Singh G, Dey CS (2007) Miltefosine induces apoptosis in arsenite-resistant Leishmania donovani promastigotes through mitochondrial dysfunction. Exp Parasitol 116:1–13CrossRefPubMedGoogle Scholar
  28. 28.
    Getachew F, Gedamu L (2012) Leishmania donovani mitochondrial iron superoxide dismutase A is released into the cytosol during miltefosine induced programmed cell death. Mol Biochem Parasitol 183:42–51CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Shadab M, Jha B, Asad M, Deepthi M, Kamran M, Ali N (2017) Apoptosis-like cell death in Leishmania donovani treated with KalsomeTM10, a new liposomal amphotericin B. PLoS One 12:e0171306CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Singh K, Ali V, Pratap Singh K, Gupta P, Suman SS, Ghosh AK, Bimal S, Pandey K, Das P (2017) Deciphering the interplay between cysteine synthase and thiol cascade proteins in modulating amphotericin B resistance and survival of Leishmania donovani under oxidative stress. Redox Biol 12:350–366CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Dembitsky VM (2008) Bioactive peroxides as potential therapeutic agents. Eur J Med Chem 43:223–251CrossRefGoogle Scholar
  32. 32.
    Dörsam B, Fahrer J (2016) The disulfide compound α-lipoic acid and its derivatives: a novel class of anticancer agents targeting mitochondria. Cancer Lett 371:12–19CrossRefGoogle Scholar
  33. 33.
    Dembitsky VM, Gloriozova TA, Poroikov VV (2007) Natural peroxy anticancer agents. Mini-Rev Med Chem 7:571–589CrossRefGoogle Scholar
  34. 34.
    Usman LA, Hamid AA, Muhammad NO, Olawore NO, Edewor TI, Saliu BK (2010) Chemical constituents and anti-inflammatory activity of leaf essential oil of Nigerian grown Chenopodium album L. EXCLI J 9:181–186PubMedPubMedCentralGoogle Scholar
  35. 35.
    Jardim CM, Jham GN, Dhingra OD, Freire MM (2008) Composition and antifungal activity of the essential oil of the Brazilian Chenopodium ambrosioides L. J Chem Ecol 34:1213–1218CrossRefGoogle Scholar
  36. 36.
    Pollack Y, Segal R, Golenser J (1990) The effect of ascaridole on the in vitro development of Plasmodium falciparum. Parasitol Res 76:570–572CrossRefGoogle Scholar
  37. 37.
    Efferth T, Olbrich A, Sauerbrey A, Ross DD, Gebhart E, Neugebauer M (2002) Activity of ascaridole from the anthelmintic herb Chenopodium anthelminticum L. against sensitive and multidrug-resistant tumor cells. Anticancer Res 22:4221–4224PubMedGoogle Scholar
  38. 38.
    Kiuchi F, Itano Y, Uchiyama N, Honda G, Tsubouchi A, Nakajima-Shimada J, Aoki T (2002) Monoterpene hydroperoxides with trypanocidal activity from Chenopodium ambrosioides. J Nat Prod 65:509–512CrossRefGoogle Scholar
  39. 39.
    Monzote L, Montalvo AM, Almanonni S, Scull R, Miranda M, Abreu J (2006) Activity of the essential oil from Chenopodium ambrosioides grown in Cuba against Leishmania amazonensis. Chemotherapy 52:130–136CrossRefGoogle Scholar
  40. 40.
    Meshnick SR (2002) Artemisinin: mechanisms of action, resistance and toxicity. Int J Parasitol 32:1655–1660CrossRefGoogle Scholar
  41. 41.
    Meshnick SR, Thomas A, Ranz A, Xu CM, Pan HZ (1991) Artemisinin (qinghaosu): the role of intracellular hemin in its mechanism of antimalarial action. Mol Biochem Parasitol 49:181–189CrossRefGoogle Scholar
  42. 42.
    Posner GH, Wang D, Cumming JN, Oh CH, French AN, Bodley AL, Shapiro TA (1995) Further evidence supporting the importance of and the restrictions on a carbon-centered radical for high antimalarial activity of 1,2,4-trioxanes like artemisinin. J Med Chem 38:2273–2275CrossRefGoogle Scholar
  43. 43.
    Olliaro P (2001) Mode of action and mechanisms of resistance for antimalarial drugs. Pharmacol Ther 89:207–219CrossRefGoogle Scholar
  44. 44.
    Meshnick SR (1994) Free radicals and antioxidants. Lancet 344:1441–1442PubMedGoogle Scholar
  45. 45.
    O’Neill PM, Barton VE, Ward SA (2010) The molecular mechanism of action of artemisinin—the debate continues. Molecules 15:1705–1721CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Dong Y, Vennerstrom JL (2003) Mechanisms of in situ activation for peroxidic antimalarials. Redox Rep 8:284–288CrossRefGoogle Scholar
  47. 47.
    Biagini GA, O’Neill PM, Nzila A, Ward SA, Bray PG (2003) Antimalarial chemotherapy: young guns or back to the future? Trends Parasitol 19:479–487CrossRefGoogle Scholar
  48. 48.
    O’Neill PM, Posner GH (2004) A medicinal chemistry perspective on artemisinin and related endoperoxides. J Med Chem 47:2945–2964CrossRefGoogle Scholar
  49. 49.
    Cavalli JF, Tomi F, Bernardini AF, Casanova J (2004) Combined analysis of the essential oil of Chenopodium ambrosioides by GC, GC-MS and 13C-NMR spectroscopy: quantitative determination of ascaridole, a heat-sensitive compound. Phytochem Anal 15:275–279CrossRefGoogle Scholar
  50. 50.
    Chittiboyina AG, Avonto C, Khan IA (2016) What happens after activation of ascaridole? Reactive compounds and their implications for skin sensitization. Chem Res Toxicol 29:1488–1492CrossRefGoogle Scholar
  51. 51.
    Geroldinger G, Tonner M, Hettegger H, Bacher M, Monzote L, Walter M, Staniek K, Rosenau T, Gille L (2017) Mechanism of ascaridole activation in Leishmania. Biochem Pharmacol 132:48–62CrossRefGoogle Scholar
  52. 52.
    Ruiz J, Mallet-Ladeira S, Maynadier M, Vial H, André-Barrès C (2014) Design, synthesis and evaluation of new tricyclic endoperoxides as potential antiplasmodial agents. Org Biomol Chem 12:5212–5221CrossRefGoogle Scholar
  53. 53.
    Rudrapal M, Chetia D (2016) Endoperoxide antimalarials: development, structural diversity and pharmacodynamic aspects with reference to 1,2,4-trioxane-based structural scaffold. Drug Des Devel Ther 10:3575–3590CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Monzote L, Geroldinger G, Tonner M, Scull R, De Sarkar S, Bergmann S, Bacher M, Staniek K, Chatterjee M, Rosenau T, Gille L (2018) Interaction of ascaridole, carvacrol, and caryophyllene oxide from essential oil of Chenopodium ambrosioides L. with mitochondria in Leishmania and other eukaryotes. Phytother Res 32:1729–1740CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Blackwell JM, Goswami T, Evans CA, Sibthorpe D, Papo N, White JK, Searle S, Miller EN, Peacock CS, Mohammed H, Ibrahim M (2001) SLC11A1 (formerly NRAMP1) and disease resistance. Cell Microbiol 3:773–784CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Mittra B, Cortez M, Haydock A, Ramasamy G, Myler PJ, Andrews NW (2013) Iron uptake controls the generation of Leishmania infective forms through regulation of ROS levels. J Exp Med 210:401–416CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Monzote L, García M, Pastor J, Gil L, Scull R, Maes L, Cos P, Gille L (2014) Essential oil from Chenopodium ambrosioides and main components: activity against Leishmania, their mitochondria and other microorganisms. Exp Parasitol 136:20–26CrossRefGoogle Scholar
  58. 58.
    Avery MA, Muraleedharan KM, Desai PV, Bandyopadhyaya AK, Furtado MM, Tekwani BL (2003) Structure-activity relationships of the antimalarial agent artemisinin. 8. Design, synthesis, and CoMFA studies toward the development of artemisinin-based drugs against leishmaniasis and malaria. J Med Chem 46:4244–4258CrossRefGoogle Scholar
  59. 59.
    Menon RB, Kannoth MM, Tekwani BL, Gut J, Rosenthal PJ, Avery MA (2006) A new library of C-16 modified artemisinin analogs and evaluation of their anti-parasitic activities. Comb Chem High Throughput Screen 9:729–741CrossRefGoogle Scholar
  60. 60.
    Chollet C, Crousse B, Bories C, Bonnet-Delpon D, Loiseau PM (2008) In vitro antileishmanial activity of fluoro-artemisinin derivatives against Leishmania donovani. Biomed Pharmacother 62:462–465CrossRefGoogle Scholar
  61. 61.
    Raffetin A, Bruneel F, Roussel C, Thellier M, Buffet P, Caumes E, Jauréguiberry S (2018) Use of artesunate in non-malarial indications. Med Mal Infect 48:238–249CrossRefGoogle Scholar
  62. 62.
    Slade D, Galal AM, Gul W, Radwan MM, Ahmed SA, Khan SI, Tekwani BL, Jacob MR, Ross SA, Elsohly MA (2009) Antiprotozoal, anticancer and antimicrobial activities of dihydroartemisinin acetal dimers and monomers. Bioorg Med Chem 17:7949–7957CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Marchi S, Giorgi C, Suski JM, Agnoletto C, Bononi A, Bonora M, De Marchi E, Missiroli S, Patergnani S, Poletti F, Rimessi A, Duszynski J, Wieckowski MR, Pinton P (2012) Mitochondria-ROS crosstalk in the control of cell death and aging. J Signal Transduction 2012:329635CrossRefGoogle Scholar
  64. 64.
    Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552:335–344CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Alvarez-Fortes E, Ruiz-Pérez LM, Bouillaud F, Rial E, Rivas L (1998) Expression and regulation of mitochondrial uncoupling protein 1 from brown adipose tissue in Leishmania major promastigotes. Mol Biochem Parasitol 93:191–202CrossRefGoogle Scholar
  66. 66.
    Gull K (1999) The cytoskeleton of trypanosomatid parasites. Annu Rev Microbiol 53:629–655CrossRefGoogle Scholar
  67. 67.
    Taanman JW (1999) The mitochondrial genome: structure, transcription, translation and replication. Biochim Biophys Acta 1410:103–123CrossRefGoogle Scholar
  68. 68.
    Fidalgo LM, Gille L (2011) Mitochondria and trypanosomatids: targets and drugs. Pharm Res 28:2758–2770CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Opperdoes F, Michels P (2008) The metabolic repertoire of Leishmania and implications for drug discovery. After The Genome, LeishmaniaGoogle Scholar
  70. 70.
    Santhamma KR, Bhaduri A (1995) Characterization of the respiratory chain of Leishmania donovani promastigotes. Mol Biochem Parasitol 75:43–53CrossRefGoogle Scholar
  71. 71.
    Monzote L, Gille L (2010) Mitochondria as a promising antiparasitic target. Curr Clin Pharmacol 5:55–60CrossRefGoogle Scholar
  72. 72.
    Brand MD, Nicholls DG (2011) Assessing mitochondrial dysfunction in cells. Biochem J 435:297–312CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Monzote L, Lackova A, Staniek K, Steinbauer S, Pichler G, Jäger W, Gille L (2016) The antileishmanial activity of xanthohumol is mediated by mitochondrial inhibition. Parasitology 2016:1–13Google Scholar
  74. 74.
    van Hellemond JJ, Opperdoes FR, Tielens AG (1998) Trypanosomatidae produce acetate via a mitochondrial acetate:succinate CoA transferase. Proc Natl Acad Sci U S A 95:3036–3041CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Chen M, Zhai L, Christensen SB, Theander TG, Kharazmi A (2001) Inhibition of fumarate reductase in Leishmania major and L. donovani by chalcones. Antimicrob Agents Chemother 45:2023–2029CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Schneider A (2001) Unique aspects of mitochondrial biogenesis in trypanosomatids. Int J Parasitol 31:1403–1415CrossRefGoogle Scholar
  77. 77.
    Turrens JF, Boveris A (1980) Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria. Biochem J 191:421–427CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Turrens JF, Freeman BA, Levitt JG, Crapo JD (1982) The effect of hyperoxia on superoxide production by lung submitochondrial particles. Arch Biochem Biophys 217:401–410CrossRefGoogle Scholar
  79. 79.
    Dröse S, Brandt U (2008) The mechanism of mitochondrial superoxide production by the cytochrome bc1 complex. J Biol Chem 283:21649–21654CrossRefGoogle Scholar
  80. 80.
    Nohl H, Gille L, Kozlov A, Staniek K (2003) Are mitochondria a spontaneous and permanent source of reactive oxygen species? Redox Rep 8:135–141CrossRefPubMedGoogle Scholar
  81. 81.
    Sen N, Majumder HK (2008) Mitochondrion of protozoan parasite emerges as potent therapeutic target: exciting drugs are on the horizon. Curr Pharm Des 14:839–846CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Luque-Ortega JR, Rivas L (2007) Miltefosine (hexadecylphosphocholine) inhibits cytochrome c oxidase in Leishmania donovani promastigotes. Antimicrob Agents Chemother 51:1327–1332CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Calixto SL, Glanzmann N, Xavier Silveira MM, da Trindade GJ, Gorza Scopel KK, Torres de Aguiar T, DaMatta RA, Macedo GC, da Silva AD, Coimbra ES (2018) Novel organic salts based on quinoline derivatives: the in vitro activity trigger apoptosis inhibiting autophagy in Leishmania spp. Chem Biol Interact 293:141–151CrossRefPubMedGoogle Scholar
  84. 84.
    Mendonça DVC, Lage DP, Calixto SL, Ottoni FM, Tavares GSV, Ludolf F, Chávez-Fumagalli MA, Schneider MS, Duarte MC, Tavares CAP, Alves RJ, Coimbra ES, Coelho EAF (2018) Antileishmanial activity of a naphthoquinone derivate against promastigote and amastigote stages of Leishmania infantum and Leishmania amazonensis and its mechanism of action against L. amazonensis species. Parasitol Res 117:391–403CrossRefGoogle Scholar
  85. 85.
    Geroldinger G, Tonner M, Fudickar W, De Sarkar S, Dighal A, Monzote L, Staniek K, Linker T, Chatterjee M, Gille L (2018 Jul 10) Activation of anthracene Endoperoxides in Leishmania and impairment of mitochondrial functions. Molecules 23(7). pii: E1680).
  86. 86.
    Moreira AL, Scariot DB, Pelegrini BL, Pessini GL, Ueda-Nakamura T, Nakamura CV, Ferreira ICP (2017) Acyclic sesquiterpenes from the fruit pericarp of Sapindus saponaria induce ultrastructural alterations and cell death in Leishmania amazonensis. Evid Based Complement Alternat Med 2017:5620693CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Aliança ASDS, Oliveira AR, Feitosa APS, Ribeiro KRC, de Castro MCAB, Leite ACL, Alves LC, Brayner FA (2017) In vitro evaluation of cytotoxicity and leishmanicidal activity of phthalimido-thiazole derivatives. Eur J Pharm Sci 105:1–10CrossRefPubMedGoogle Scholar
  88. 88.
    Villa-Pulgarín JA, Gajate C, Botet J, Jimenez A, Justies N, Varela-M RE, Cuesta-Marbán Á, Müller I, Modolell M, Revuelta JL, Mollinedo F (2017) Mitochondria and lipid raft-located FOF1-ATP synthase as major therapeutic targets in the antileishmanial and anticancer activities of ether lipid edelfosine. PLoS Negl Trop Dis 11:e0005805CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    López-Arencibia A, Martín-Navarro C, Sifaoui I, Reyes-Batlle M, Wagner C, Lorenzo-Morales J, Maciver SK, Piñero JE (2017) Perifosine mechanisms of action in Leishmania species. Antimicrob Agents Chemother 61(4):e02127-16CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Garcia FP, Henrique da Silva Rodrigues J, Din ZU, Rodrigues-Filho E, Ueda-Nakamura T, Auzély-Velty R, Nakamura CV (2017) A3K2A3-induced apoptotic cell death of Leishmania amazonensis occurs through caspase- and ATP-dependent mitochondrial dysfunction. Apoptosis 22:57–71CrossRefPubMedGoogle Scholar
  91. 91.
    Awasthi BP, Kathuria M, Pant G, Kumari N, Mitra K (2016) Plumbagin, a plant-derived naphthoquinone metabolite induces mitochondria mediated apoptosis-like cell death in Leishmania donovani: an ultrastructural and physiological study. Apoptosis 21:941–953CrossRefPubMedGoogle Scholar
  92. 92.
    Corpas-López V, Merino-Espinosa G, Díaz-Sáez V, Morillas-Márquez F, Navarro-Moll MC, Martín-Sánchez J (2016) The sesquiterpene (−)-α-bisabolol is active against the causative agents of Old World cutaneous leishmaniasis through the induction of mitochondrial-dependent apoptosis. Apoptosis 21:1071–1081CrossRefPubMedGoogle Scholar
  93. 93.
    da Silva JM, Antinarelli LM, Ribeiro A, Coimbra ES, Scio E (2015) The effect of the phytol-rich fraction from Lacistema pubescens against Leishmania amazonensis is mediated by mitochondrial dysfunction. Exp Parasitol 159:143–150CrossRefPubMedGoogle Scholar
  94. 94.
    Fonseca-Silva F, Canto-Cavalheiro MM, Menna-Barreto RF, Almeida-Amaral EE (2015) Effect of apigenin on Leishmania amazonensis is associated with reactive oxygen species production followed by mitochondrial dysfunction. J Nat Prod 78:880–884CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Lage PS, Chávez-Fumagalli MA, Mesquita JT, Mata LM, Fernandes SO, Cardoso VN, Soto M, Tavares CA, Leite JP, Tempone AG, Coelho EA (2015) Antileishmanial activity and evaluation of the mechanism of action of strychnobiflavone flavonoid isolated from Strychnos pseudoquina against Leishmania infantum. Parasitol Res 114:4625–4635CrossRefPubMedGoogle Scholar
  96. 96.
    Monzote L, Lackova A, Staniek K, Cuesta-Rubio O, Gille L (2015) Role of mitochondria in the leishmanicidal effects and toxicity of acyl phloroglucinol derivatives: nemorosone and guttiferone A. Parasitology 142:1239–1248CrossRefPubMedGoogle Scholar
  97. 97.
    Rodrigues IA, Azevedo MM, Chaves FC, Alviano CS, Alviano DS, Vermelho AB (2014) Arrabidaea chica hexanic extract induces mitochondrion damage and peptidase inhibition on Leishmania spp. Biomed Res Int 2014:985171PubMedPubMedCentralGoogle Scholar
  98. 98.
    Elmahallawy EK, Jiménez-Aranda A, Martínez AS, Rodriguez-Granger J, Navarro-Alarcón M, Gutiérrez-Fernández J, Agil A Activity of melatonin against Leishmania infantum promastigotes by mitochondrial dependent pathway. Chem Biol Interact 220:84–93Google Scholar
  99. 99.
    Kathuria M, Bhattacharjee A, Sashidhara KV, Singh SP, Mitra K (2014) Induction of mitochondrial dysfunction and oxidative stress in Leishmania donovani by orally active clerodane diterpene. Antimicrob Agents Chemother 58:5916–5928CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Casanova E, Moreno D, Gigante A, Rico E, Genes CM, Oliva C, Camarasa MJ, Gago F, Jiménez-Ruiz A, Pérez-Pérez MJ (2013) 5′-Trityl-substituted thymidine derivatives as a novel class of antileishmanial agents: Leishmania infantum EndoG as a potential target. ChemMedChem 8:1161–1174CrossRefPubMedGoogle Scholar
  101. 101.
    Mesquita-Rodrigues C, Menna-Barreto RF, Sabóia-Vahia L, Da-Silva SA, de Souza EM, Waghabi MC, Cuervo P, De Jesus JB (2013) Cellular growth and mitochondrial ultrastructure of Leishmania (Viannia) braziliensis promastigotes are affected by the iron chelator 2,2-dipyridyl. PLoS Negl Trop Dis 7:e2481CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Mesquita JT, Pinto EG, Taniwaki NN, Galisteo AJ Jr, Tempone AG (2013) Lethal action of the nitrothiazolyl-salicylamide derivative nitazoxanide via induction of oxidative stress in Leishmania (L.) infantum. Acta Trop 128:666–673CrossRefPubMedGoogle Scholar
  103. 103.
    Ribeiro GA, Cunha-Júnior EF, Pinheiro RO, da-Silva SA, Canto-Cavalheiro MM, da Silva AJ, Costa PR, Netto CD, Melo RC, Almeida-Amaral EE, Torres-Santos EC (2013) LQB-118, an orally active pterocarpanquinone, induces selective oxidative stress and apoptosis in Leishmania amazonensis. J Antimicrob Chemother 68:789–799CrossRefGoogle Scholar
  104. 104.
    de Macedo-Silva ST, Urbina JA, de Souza W, Rodrigues JC (2013) In vitro activity of the antifungal azoles itraconazole and posaconazole against Leishmania amazonensis. PLoS One 8:e83247CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Britta EA, Silva AP, Ueda-Nakamura T, Dias-Filho BP, Silva CC, Sernaglia RL, Nakamura CV (2012) Benzaldehyde thiosemicarbazone derived from limonene complexed with copper induced mitochondrial dysfunction in Leishmania amazonensis. PLoS One 7:e41440CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Lopes MV, Desoti VC, Caleare Ade O, Ueda-Nakamura T, Silva SO, Nakamura CV (2012) Mitochondria superoxide anion production contributes to geranylgeraniol-induced death in Leishmania amazonensis. Evid Based Complement Alternat Med 2012:298320CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Inacio JD, Canto-Cavalheiro MM, Menna-Barreto RF, Almeida-Amaral EE (2012) Mitochondrial damage contribute to epigallocatechin-3-gallate induced death in Leishmania amazonensis. Exp Parasitol 132:151–155CrossRefPubMedGoogle Scholar
  108. 108.
    Medina JM, Rodrigues JC, De Souza W, Atella GC, Barrabin H (2012) Tomatidine promotes the inhibition of 24-alkylated sterol biosynthesis and mitochondrial dysfunction in Leishmania amazonensis promastigotes. Parasitology 139:1253–1265CrossRefPubMedGoogle Scholar
  109. 109.
    Fonseca-Silva F, Inacio JD, Canto-Cavalheiro MM, Almeida-Amaral EE (2011) Reactive oxygen species production and mitochondrial dysfunction contribute to quercetin induced death in Leishmania amazonensis. PLoS One 6:e14666CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Monzote Fidalgo L, Sariego Ramos I, García Parra M, Cuesta-Rubio O, Márquez Hernández I, Campo Fernández M, Piccinelli AL, Rastrelli L (2011) Activity of Cuban propolis extracts on Leishmania amazonensis and Trichomonas vaginalis. Nat Prod Commun 6:973–976PubMedGoogle Scholar
  111. 111.
    Luque-Ortega JR, Reuther P, Rivas L, Dardonville C (2010) New benzophenone-derived bisphosphonium salts as leishmanicidal leads targeting mitochondria through inhibition of respiratory complex II. J Med Chem 53:1788–1798CrossRefGoogle Scholar
  112. 112.
    Carvalho L, Luque-Ortega JR, Manzano JI, Castanys S, Rivas L, Gamarro F (2010) Tafenoquine, an antiplasmodial 8-aminoquinoline, targets Leishmania respiratory complex III and induces apoptosis. Antimicrob Agents Chemother 54:5344–5351CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Saha P, Sen R, Hariharan C, Kumar D, Das P, Chatterjee M (2009) Berberine chloride causes a caspase-independent, apoptotic-like death in Leishmania donovani promastigotes. Free Radic Res 43:1101–1110CrossRefGoogle Scholar
  114. 114.
    Kaur J, Singh BK, Tripathi RP, Singh P, Singh N (2009) Leishmania donovani: a glycosyl dihydropyridine analogue induces apoptosis like cell death via targeting pteridine reductase 1 in promastigotes. Exp Parasitol 123:258–264CrossRefGoogle Scholar
  115. 115.
    Tempone AG, Taniwaki NN, Reimão JQ (2009) Antileishmanial activity and ultrastructural alterations of Leishmania (L.) chagasi treated with the calcium channel blocker nimodipine. Parasitol Res 105:499–505CrossRefGoogle Scholar
  116. 116.
    Sarkar A, Sen R, Saha P, Ganguly S, Mandal G, Chatterjee M (2008) An ethanolic extract of leaves of Piper betle (Paan) Linn mediates its antileishmanial activity via apoptosis. Parasitol Res 102:1249–1255CrossRefGoogle Scholar
  117. 117.
    Roy A, Ganguly A, BoseDasgupta S, Das BB, Pal C, Jaisankar P, Majumder HK (2008) Mitochondria-dependent reactive oxygen species-mediated programmed cell death induced by 3,3′-diindolylmethane through inhibition of F0F1-ATP synthase in unicellular protozoan parasite Leishmania donovani. Mol Pharmacol 74:1292–1307CrossRefGoogle Scholar
  118. 118.
    Luque-Ortega JR, van’t Hof W, Veerman EC, Saugar JM, Rivas L (2008) Human antimicrobial peptide histatin 5 is a cell-penetrating peptide targeting mitochondrial ATP synthesis in Leishmania. FASEB J 22:1817–1828CrossRefGoogle Scholar
  119. 119.
    Dutta A, Bandyopadhyay S, Mandal C, Chatterjee M (2007) Aloe vera leaf exudate induces a caspase-independent cell death in Leishmania donovani promastigotes. J Med Microbiol 56:629–636CrossRefGoogle Scholar
  120. 120.
    Rodrigues JC, Bernardes CF, Visbal G, Urbina JA, Vercesi AE, de Souza W (2007) Sterol methenyl transferase inhibitors alter the ultrastructure and function of the Leishmania amazonensis mitochondrion leading to potent growth inhibition. Protist 158:447–456CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Delfín DA, Bhattacharjee AK, Yakovich AJ, Werbovetz KA (2006) Activity of and initial mechanistic studies on a novel antileishmanial agent identified through in silico pharmacophore development and database searching. J Med Chem 49:4196–4207CrossRefPubMedGoogle Scholar
  122. 122.
    Tempone AG, da Silva AC, Brandt CA, Martinez FS, Borborema SE, da Silveira MA, de Andrade HF Jr (2005) Synthesis and antileishmanial activities of novel 3-substituted quinolines. Antimicrob Agents Chemother 49:1076–1080CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Magán R, Marín C, Rosales MJ, Salas JM, Sánchez-Moreno M (2005) Therapeutic potential of new Pt(II) and Ru(III) triazole-pyrimidine complexes against Leishmania donovani. Pharmacology 73:41–48CrossRefPubMedGoogle Scholar
  124. 124.
    Tavares J, Ouaissi A, Lin PK, Tomás A, Cordeiro-da-Silva A (2005) Differential effects of polyamine derivative compounds against Leishmania infantum promastigotes and axenic amastigotes. Int J Parasitol 35:637–646CrossRefPubMedGoogle Scholar
  125. 125.
    Rodrigues JC, Urbina JA, de Souza W (2005) Antiproliferative and ultrastructural effects of BPQ-OH, a specific inhibitor of squalene synthase, on Leishmania amazonensis. Exp Parasitol 111:230–238CrossRefPubMedGoogle Scholar
  126. 126.
    Luque-Ortega JR, Martínez S, Saugar JM, Izquierdo LR, Abad T, Luis JG, Piñero J, Valladares B, Rivas L (2004) Fungus-elicited metabolites from plants as an enriched source for new leishmanicidal agents: antifungal phenyl-phenalenone phytoalexins from the banana plant (Musa acuminata) target mitochondria of Leishmania donovani promastigotes. Antimicrob Agents Chemother 48:1534–1540CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Delorenzi JC, Attias M, Gattass CR, Andrade M, Rezende C, da Cunha PA, Henriques AT, Bou-Habib DC, Saraiva EM (2001) Antileishmanial activity of an indole alkaloid from Peschiera australis. Antimicrob Agents Chemother 45:1349–1354CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Ott R, Chibale K, Anderson S, Chipeleme A, Chaudhuri M, Guerrah A, Colowick N, Hill GC (2006) Novel inhibitors of the trypanosome alternative oxidase inhibit Trypanosoma brucei brucei growth and respiration. Acta Trop 100:172–184CrossRefPubMedGoogle Scholar
  129. 129.
    Dantas-Leite L, Urbina JA, de Souza W, Vommaro RC (2004) Selective anti-Toxoplasma gondii activities of azasterols. Int J Antimicrob Agents 23:620–626CrossRefPubMedGoogle Scholar
  130. 130.
    Muelas-Serrano S, Le-Senne A, Fernandez-Portillo C, Nogal JJ, Ochoa C, Gomez-Barrio A (2002) In vitro and in vivo anti-Trypanosoma cruzi activity of a novel nitro-derivative. Mem Inst Oswaldo Cruz 97:553–557CrossRefPubMedGoogle Scholar
  131. 131.
    Faccenda D, Campanella M (2012) Molecular regulation of the mitochondrial F(1)F(o)-ATPsynthase: physiological and pathological significance of the inhibitory factor 1 (IF(1)). Int J Cell Biol 2012:367934CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    De Sarkar S, Sarkar D, Sarkar A, Dighal A, Chakrabarti S, Staniek K, Gille L, Chatterjee M (2019) The leishmanicidal activity of artemisinin is mediated by cleavage of the endoperoxide bridge and mitochondrial dysfunction. Parasitology 146:511–520Google Scholar
  133. 133.
    Sen R, Chatterjee M (2011) Plant derived therapeutics for the treatment of leishmaniasis. Phytomedicine 18:1056–1069Google Scholar
  134. 134.
    Jain V, Jain V (2018) Molecular targets and pathways for the treatment of visceral leishmaniasis. Drug Discov Today 23:161–170Google Scholar
  135. 135.
    Chatterjee M, Saha P, Sarkar A, Ghosh S, Mukherjee S, Roy S, Mukhopadhyay D (2012) In: Ray A, Gulati K (eds) Emerging druggable targets in leishmaniasis. Vidyanilyam Prakashan, Delhi. Chapter 18, pp 319–340Google Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of PharmacologyInstitute of Post Graduate Medical Education and ResearchKolkataIndia

Personalised recommendations