Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

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

  • 373 Accesses

  • 9 Citations

Abstract

Leishmaniasis has become a significant public health issue in several countries in the world. New products have been identified to treat against the disease; however, toxicity and/or high cost is a limitation. The present work evaluated the antileishmanial activity of a new naphthoquinone derivate, Flau-A [2-(2,3,4-tri-O-acetyl-6-deoxy-β-L-galactopyranosyloxy)-1,4-naphthoquinone], against promastigote and amastigote-like stages of Leishmania amazonensis and L. infantum. In addition, the cytotoxicity in murine macrophages and human red cells was also investigated. The mechanism of action of Flau-A was assessed in L. amazonensis as well as its efficacy in treating infected macrophages and inhibiting infection of pretreated parasites. Results showed that Flau-A was effective against promastigotes and amastigote-like forms of both parasite species, as well as showed low toxicity in mammalian cells. Results also highlighted the morphological and biochemical alterations induced by Flau-A in L. amazonensis, including loss of mitochondrial membrane potential, as well as increased reactive oxygen species production, cell shrinkage, and alteration of the plasma membrane integrity. The present study demonstrates for the first time the antileishmanial activity of Flau-A against two Leishmania species and suggests that the mitochondria of the parasites may be the main target organelle. Data shown here encourages the use of this molecule in new studies concerning treatment against Leishmania infection in mammalian hosts.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. Andrade MA, Azevedo CD, Motta FN, Santos ML, Silva CL, Santana JM, Bastos IM (2016) Essential oils: in vitro activity against Leishmania amazonensis, cytotoxicity and chemical composition. BMC Complement Altern Med 16(1):444. https://doi.org/10.1186/s12906-016-1401-9

  2. Antinarelli LM, Dias RM, Souza IO, Lima WP, Gameiro J, da Silva AD, Coimbra ES (2015) 4-Aminoquinoline derivatives as potential antileishmanial agents. Chem Biol Drug Des 86(4):704–714. https://doi.org/10.1111/cbdd.12540

  3. Araújo MV, David CC, Neto JC, Oliveira LA, Silva KC, Santos JM, Silva JK, Brandão AVB, Silva TM, Camara CA, Alexandre-Moreira MS (2017) Evaluation on the leishmanicidal activity of 2-N,N’-dialkylamino-1,4-naphthoquinone derivatives. Exp Parasitol 176:46–51. https://doi.org/10.1016/j.exppara.2017.02.004

  4. Asad M, Bhattacharya P, Banerjee A, Ali N (2015) Therapeutic and immunomodulatory activities of short-course treatment of murine visceral leishmaniasis with KALSOME™10, a new liposomal amphotericin B. BMC Infect Dis 15(1):188. https://doi.org/10.1186/s12879-015-0928-6

  5. Camara CA, Silva TM, Silva TG, Martins RM, Barbosa TP, Pinto AC, Vargas MD (2008) Molluscicidal activity of 2-hydroxy-[1,4]naphthoquinone and derivatives. Na Acad Bras Cienc 80(2):329–334. https://doi.org/10.1590/S0001-37652008000200011

  6. Chakravarty J, Sundar S (2010) Drug resistance in leishmaniasis. J Glob Infect Dis 167:176

  7. Chandrasekaran S, Dayakar A, Veronica J, Sundar S, Maurya R (2013) An in vitro study of apoptotic like death in Leishmania donovani promastigotes by withanolides. Parasitol Intern 62(3):253–261. https://doi.org/10.1016/j.parint.2013.01.007

  8. Chávez-Fumagalli MA, Ribeiro TG, Castilho RO, Fernandes SO, Cardoso VN, Coelho CS, Mendonça DV, Soto M, Tavares CA, Faraco AA, Coelho EA (2015) New delivery systems for amphotericin B applied to the improvement of leishmaniasis treatment. Rev Soc Bras Med Trop 48(3):235–242. https://doi.org/10.1590/0037-8682-0138-2015

  9. Cheuka PM, Mayoka G, Mutai P, Chibale K (2016) The role of natural products in drug discovery and development against neglected tropical diseases. Molecules 22:E58

  10. Coelho EAF, Tavares CAP, Carvalho FAA, Chaves KF, Teixeira KN, Rodrigues RC, Charest H, Matlashewski G, Gazzinelli RT, Fernandes AP (2003) Immune responses induced by the Leishmania (Leishmania) donovani A2 antigen, but not by the LACK antigen, are protective against experimental Leishmania (Leishmania) amazonensis infection. Infect Immun 71(7):3988–3994. https://doi.org/10.1128/IAI.71.7.3988-3994.2003

  11. Coimbra ES, Antinarelli LM, Silva NP, Souza IO, Meinel RS, Rocha MN, Soares RP, Silva AD (2016) Quinoline derivatives: synthesis, leishmanicidal activity and involvement of mitochondrial oxidative stress as mechanism of action. Chem Biol Interact 260:50–57. https://doi.org/10.1016/j.cbi.2016.10.017

  12. Copeland NK, Aronson NE (2015) Leishmaniasis: treatment updates and clinical practice guidelines review. Curr Opin Infect Dis 28(5):426–437. https://doi.org/10.1097/QCO.0000000000000194

  13. Costa L, Pinheiro RO, Dutra PM, Santos RF, Cunha-Júnior EF, Torres-Santos EC, Silva AJ, Costa PR, Silva AS (2014) Pterocarpanquinone LQB-118 induces apoptosis in Leishmania (Viannia) braziliensis and controls lesions in infected hamsters. PLoS One 9(10):e109672. https://doi.org/10.1371/journal.pone.0109672

  14. Deray G (2002) Amphotericin B nephrotoxicity. J Antimicrob Chemother 49(suppl 1):37–41. https://doi.org/10.1093/jac/49.suppl_1.37

  15. Duarte MC, Pimenta DC, Menezes-Souza D, Magalhães RD, Diniz JL, Costa LE, Chávez-Fumagalli MA, Lage PS, Bartholomeu DC, Alves MJ, Fernandes AP, Soto M, Tavares CA, Gonçalves DU, Rocha MO, Coelho EA (2015) Proteins selected in Leishmania (Viannia) braziliensis by an immunoproteomic approach with potential serodiagnosis applications for tegumentary leishmaniasis. Clin Vaccine Immunol 22(11):1187–1196. https://doi.org/10.1128/CVI.00465-15

  16. Duarte MC, Lage LM, Lage DP, Martins VT, Carvalho AM, Roatt BM, Menezes-Souza D, Tavares CA, Alves RJ, Barichello JM, Coelho EA (2016) Treatment of murine visceral leishmaniasis using an 8-hydroxyquinoline-containing polymeric micelle system. Parasitol Int 65(6):728–736. https://doi.org/10.1016/j.parint.2016.07.005

  17. El-Hani CN, Borges VM, Wanderley JL, Barcinski MA (2012) Apoptosis and apoptotic mimicry in Leishmania: an evolutionary perspective. Front Cell Infect Microbiol 2:96

  18. Fernandes AP, Coelho EA, Machado-Coelho GL, Grimaldi G Jr, Gazzinelli RT (2012) Making an anti-amastigote vaccine for visceral leishmaniasis: rational, update and perspectives. Curr Opin Microbiol 15(4):476–485. https://doi.org/10.1016/j.mib.2012.05.002

  19. Ferreira SB, Carvalho-da-Silva F, Bezerra FA, Lourenço MC, Kaiser CR, Pinto AC, Ferreira VF (2010) Synthesis of alpha- and beta-pyran naphthoquinones as a new class of antitubercular agents. Arch Pharm (Weinheim) 343(2):81–90. https://doi.org/10.1002/ardp.200900162

  20. Forkink M, Smeitink JA, Brock R, Willems PH, Koopman WJ (2010) Detection and manipulation of mitochondrial reactive oxygen species in mammalian cells. Biochim Biophys Acta 97:1034–1044

  21. Fumarola L, Spinelli R, Brandonisio O (2004) In vitro assays for evaluation of drug activity against Leishmania spp. Res Microbiol 155(4):224–230. https://doi.org/10.1016/j.resmic.2004.01.001

  22. Gao J, Radwan MM, León F, Wang X, Jacob MR, Tekwani BL, Khan SI, Lupien S, Hill RA, Dugan FM, Cutler HG, Cutler SJ (2012) Antimicrobial and antiprotozoal activities of secondary metabolites from the fungus Eurotium repens. Med Chem Res 21(10):3080–3086. https://doi.org/10.1007/s00044-011-9798-7

  23. 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(12):4625–4635. https://doi.org/10.1007/s00436-015-4708-4

  24. Lezama-Dávila CM, Isaac-Márquez AP, Kapadia G, Owens K, Oghumu S, Beverley S, Satoskar AR (2012) Leishmanicidal activity of two naphthoquinones against Leishmania donovani. Biol Pharm Bull 35(10):1761–1764. https://doi.org/10.1248/bpb.b12-00419

  25. Mendonça DV, Lage LM, Lage DP, Chávez-Fumagalli MA, Ludolf F, Roatt BM, Menezes-Souza D, Faraco AA, Castilho RO, Tavares CA, Barichello JM, Duarte MC, Coelho EA (2016) Poloxamer 407 (Pluronic® F127)-based polymeric micelles for amphotericin B: in vitro biological activity, toxicity and in vivo therapeutic efficacy against murine tegumentary leishmaniasis. Exp Parasitol 169:34–42. https://doi.org/10.1016/j.exppara.2016.07.005

  26. Menna-Barreto RF, Castro SL (2014) The double-edged sword in pathogenic trypanosomatids: the pivotal role of mitochondria in oxidative stress and bioenergetics. Biomed Res Int 2014:614014

  27. Mishra J, Dey A, Singh N, Somvanshi R, Singh S (2013) Evaluation of toxicity & therapeutic efficacy of a new liposomal formulation of amphotericin B in a mouse model. Indian J Med Res 137(4):767–776

  28. Muylder G, Ang KKH, Chen S, Arkin MR, Engel JC, Mc Kerrow JH (2011) A screen against Leishmania intracellular amastigotes: comparison to a promastigote screen and identification of a host cell-specific hit. PLoS Negl Trop Dis 5(7):e1253. https://doi.org/10.1371/journal.pntd.0001253

  29. Pinto EG, Santos IO, Schmidt TJ, Borborema SE, Ferreira VF, Rocha DR, Tempone AG (2014) Potential of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones against Leishmania (L.) infantum: biological activity and structure-activity relationships. PLoS One 9(8):e105127. https://doi.org/10.1371/journal.pone.0105127

  30. Proto WR, Coombs GH, Mottram JC (2013) Cell death in parasitic protozoa: regulated or incidental? Nat Rev Microbiol 11(1):58–66. https://doi.org/10.1038/nrmicro2929

  31. Rezende LC, Fumagalli F, Bortolin MS, Oliveira MG, Paula MH, Andrade-Neto VF, Emery FS (2013) In vivo antimalarial activity of novel 2-hydroxy-3-anilino-1,4-naphthoquinones obtained by epoxide ring-opening reaction. Bioorg Med Chem Lett 23(16):4583–4586. https://doi.org/10.1016/j.bmcl.2013.06.033

  32. Ribeiro GA, Cunha-Júnior EF, Pinheiro RO, Da-Silva SA, Canto-Cavalheiro MM, 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 Chemoth 68(4):789–799. https://doi.org/10.1093/jac/dks498

  33. Ribeiro TG, Chávez-Fumagall MA, Valadares DG, França JR, Rodrigues LB, Duarte MC, Lage PS, Andrade PH, Lage DP, Arruda LV, Abánades DR, Costa LE, Martins VT, Tavares CA, Castilho RO, Coelho EA, Faraco AA (2014) Novel targeting using nanoparticles: an approach to the development of an effective antileishmanial drug-delivery system. Int J Nanomedicine 9:877–890. https://doi.org/10.2147/IJN.S55678

  34. Riffel A, Medina LF, Stefani V, Santos RC, Bizani D, Brandelli A (2002) In vitro antimicrobial activity of a new series of 1,4-naphthoquinones. Braz J Med Biol Res 35(7):811–818. https://doi.org/10.1590/S0100-879X2002000700008

  35. Santos MG, Muxel SM, Zampieri RA, Pomorski TG, Floeter-Winter LM (2013) Transbilayer dynamics of phospholipids in the plasma membrane of the Leishmania genus. PLoS One 8:e55604. https://doi.org/10.1371/journal.pone.0055604

  36. Saraiva EM, Pinto-da-Silva LH, Wanderley JL, Bonomo AC, Barcinski MA, Moreira ME (2005) Flow cytometric assessment of Leishmania spp metacyclic differentiation: validation by morphological features and specific markers. Exp Parasitol 110(1):39–47. https://doi.org/10.1016/j.exppara.2005.01.004

  37. Sazgarnia A, Zabolinejad N, Layegh P, Rajabi O, Berenji F, Javidi Z, Salari R (2012) Antileishmanial activity of liposomal clarithromycin against Leishmania major promastigotes. Iran J Basic Med Sci 15(6):1210–1214

  38. Scariot DB, Britta EA, Moreira AL, Falzirolli H, Silva CC, Ueda-Nakamura T, Dias-Filho BP, Nakamura CV (2017) Induction of early autophagic process on Leishmania amazonensis by synergistic effect of miltefosine and innovative semi-synthetic thiosemicarbazone. Front Microbiol 8:1–16

  39. Schuck DC, Ferreira SB, Cruz LN, Rocha DR, Moraes M, Nakabashi M, Rosenthal PJ, Ferreira VF, Garcia CR (2013) Biological evaluation of hydroxynaphthoquinones as anti-malarials. Malar J 12(1):234. https://doi.org/10.1186/1475-2875-12-234

  40. Sharma A, Santos IO, Gaur P, Ferreira VF, Garcia CR, Rocha DR (2013) Addition of thiols to o-quinone methide: new 2-hydroxy-3-phenylsulfanylmethyl[1,4]-naphthoquinones and their activity against the human malaria parasite Plasmodium falciparum (3D7). Eur J Med Chem 59:48–53. https://doi.org/10.1016/j.ejmech.2012.10.052

  41. Smith RA, Hartley RC, Cochemé HM, Murphy MP (2012) Mitochondrial pharmacology. Trends Pharmacol Sci 33(6):341–352. https://doi.org/10.1016/j.tips.2012.03.010

  42. Souza W, Attias M, Rodrigues JC (2009) Particularities of mitochondrial structure in parasitic protists (Apicomplexa and Kinetoplastida). Int J Biochem Cell Biol 41(10):2069–2080. https://doi.org/10.1016/j.biocel.2009.04.007

  43. Stroppa PHF, Antinarelli LMR, Carmo AML, Gameiro J, Coimbra ES, Silva AD (2017) Effect of 1,2,3-triazole salts, non-classical bioisosteres of miltefosine, on Leishmania amazonensis. Bioorg Med Chem 25(12):3034–3045. https://doi.org/10.1016/j.bmc.2017.03.051

  44. Su JC, Lin KL, Chien CM, Tseng CH, Chen YL, Chang LS, Lin SR (2010) Furano-1,2- naphthoquinone inhibits EGFR signaling associated with G2/M cell cycle arrest and apoptosis in A549 cells. Cell Biochem Funct 28:695–705

  45. Sundar S, Chakravarty J (2013) Leishmaniasis: an update of current pharmacotherapy. Expert Opin Pharmacother 14(1):53–63. https://doi.org/10.1517/14656566.2013.755515

  46. Tempone AG, Martins-de-Oliveira C, Berlinck RG (2011) Current approaches to discover marine antileishmanial natural products. Planta Med 77(06):572–585. https://doi.org/10.1055/s-0030-1250663

  47. Ullah N, Nadhman A, Siddiq S, Mehwish S, Islam A, Jafri L, Hamayun M (2016) Plants as antileishmanial agents: current scenario. Phytother Res 30(12):1905–1925. https://doi.org/10.1002/ptr.5710

  48. Wanderley JL, Barcinski MA (2010) Apoptosis and apoptotic mimicry: the Leishmania connection. Cell Mol Life Sci 67(10):1653–1659. https://doi.org/10.1007/s00018-010-0291-0

  49. Winkler JD, Londregan AT, Hamann MT (2007) Synthetic modification of Manzamine A via Grubbs metathesis. Novel structures with enhanced antibacterial and antiprotozoal properties. Org Lett 9(22):4467–4469. https://doi.org/10.1021/ol701799c

  50. World Health Organization (2010) Control of the leishmaniases. World Health Organ Tech Rep Ser 949:22–26

Download references

Author information

Correspondence to Eduardo Antonio Ferraz Coelho.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mendonça, D.V.C., Lage, D.P., Calixto, S.L. et al. 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, 391–403 (2018). https://doi.org/10.1007/s00436-017-5713-6

Download citation

Keywords

  • Leishmania spp.
  • Antileishmanial activity
  • Treatment
  • Naphthoquinones
  • Mechanism of action
  • Mitochondrial dysfunction