Advertisement

Synthesis and evaluation of the antileishmanial activity of silver compounds containing imidazolidine-2-thione

  • Patrícia Ferreira EspuriEmail author
  • Larissa Luiza dos Reis
  • Eduardo de Figueiredo Peloso
  • Vanessa Silva Gontijo
  • Fábio Antônio Colombo
  • Juliana Barbosa Nunes
  • Carine Ervolino de Oliveira
  • Eduardo T. De Almeida
  • Débora E. S. Silva
  • Jessica Bortoletto
  • Daniel Fonseca Segura
  • Adelino V. G. Netto
  • Marcos José MarquesEmail author
Article
  • 72 Downloads

Abstract

A new series of silver compounds could be of interest on designing new drugs for the treatment of leishmaniasis. The compounds [Ag(phen)(imzt)]NO3(1), [Ag(phen)(imzt)]CF3SO3(2), [Ag(phen)2](BF4)·H2O (3), [Ag2(imzt)6](NO3)2(4), and imzt have been synthesized and evaluated in vitro for antileishmanial activity against Leishmania. (L.) amazonensis (La) and L. (L.) chagasi (Lc), and two of them were selected for in vivo studies. In addition to investigating the action on Leishmania, their effects on the hydrogen peroxide production and cysteine protease inhibition have also been investigated. As for antileishmanial activity, compound (4) was the most potent against promastigote and amastigote forms of La (IC50 = 4.67 and 1.88 μM, respectively) and Lc (IC50 = 9.35 and 8.05 μM, respectively); and comparable to that of amphotericin B, reference drug. Beside showing excellent activity, it also showed a low toxicity. In the in vivo context, compound (4) reduced the number of amastigotes in the liver and spleen when compared to the untreated group. In evaluating the effect of the compounds on Leishmania, the level of hydrogen peroxide production was maintained between the lag and log phases; however, in the treatment with compound (4) it was possible to observe a reduction of 25.44 and 49.13%, respectively, in the hydrogen peroxide rates when compared to the lag and log phases. It was noticed that the presence of a nitrate ion and imzt in compound (4) was important for the modulation of the antileishmanial activity. Thus, this compound can represent a potentially new drug for the treatment of leishmaniasis.

Graphical abstract

Keywords

Leishmania Silver compounds Biological effects 

Notes

Acknowledgements

This work was sponsored by Grants from CNPq (proc. 487092/2012-0, INCT-INOFAR), FAPESP (2016/17711-5), CAPES and FAPEMIG.

Supplementary material

775_2019_1657_MOESM1_ESM.pdf (79 kb)
Supplementary material 1 (PDF 78 kb)

References

  1. 1.
    Vijayakumar S, Pradeep DAS (2018) Recent progress in drug targets and inhibitors towards combting leishmaniasis. Acta Trop 181:95–104CrossRefGoogle Scholar
  2. 2.
    World Health Organization (2016) Leishmaniasis, Geneva, p 375. http://who.int/mediacentre/factsheets/fs375/en/. Accessed Dec 2018
  3. 3.
    Akhoundi M, Downing T, Votýpka J, Kuhls K, Luke SJ, Cannet A, Ravel C, Marty P, Delaunay P, Kasbari M, Granouillac B, Gradoni L, Sereno D (2017) Leishmania infections: molecular targets and diagnosis. Mol Asp Med 57:1–29CrossRefGoogle Scholar
  4. 4.
    Ghorbani M, Farhoudi R (2018) Leishmaniasis in humans: drug or vaccine therapy? Drug Des Dev Ther 12:25–40CrossRefGoogle Scholar
  5. 5.
    World Health Organization (2018) WHO, Leishmaniasis. Geneva. http://who.int/leishmaniasis/clinical_forms_leishmaniases/en/index2.html. Accessed Dec 2018
  6. 6.
    Martínez DY, Verdonck K, Kaye PM, Adaui V, Polman K, Llanos-Cuentas A et al (2018) Tegumentary leishmaniasis and coinfections other than HIV. PLoS Negl Trop Dis 12(3):e0006125CrossRefGoogle Scholar
  7. 7.
    Awasthi A, Mathur RK, Saha B (2004) Immune response to Leishmania infection. Indian J Med Res 119:238–258Google Scholar
  8. 8.
    Codonho BS et al (2016) HSP70 of Leishmania amazonensis alters resistance to different stresses and mitochondrial bioenergetics. Memórias do Instituto Oswaldo Cruz Rio de Janeiro 111(7):460–468CrossRefGoogle Scholar
  9. 9.
    Savoia D (2015) Recent updates and perspectives on leishmaniasis. J Infect Dev Ctries 9(6):588–596CrossRefGoogle Scholar
  10. 10.
    Oliveira LF, Schubach AO, Martins MM, Passos SL, Oliveira RV, Marzochi MC et al (2011) Systematic review of the adverse effects of cutaneous leishmaniasis treatment in the New World. Acta Trop 118(2):87–96CrossRefGoogle Scholar
  11. 11.
    Gontijo VS, Espuri PF, Alves RB, Camargos LF, Santos FV, Judice WAS, Marques MJ, Freitas RP (2015) Leishmanicidal, antiproteolytic, and mutagenic evaluation of alkyltriazoles and alkylphosphocholines. Eur J Med Chem 101:24–33CrossRefGoogle Scholar
  12. 12.
    Castro RAO, Silva-Barcellos NM, Licio CSA, Souza JB, Souza-Testasicca MC, Ferreira FM, Batista MA, Silveira-Lemos D, Moura SL, Frezard F, Rezende SA (2014) Association of liposome-encapsulated trivalent antimonial with ascorbic acid: an effective and safe strategy in the treatment of experimental visceral Leishmaniasis. PLoS One 9(8):104055CrossRefGoogle Scholar
  13. 13.
    Shahverdi AR, Fakhimi A, Shahverdi HR, Minaian S (2007) Synthesis and effect of silver nanoparticles on the antibacterial activity of different antibiotics against Staphylococcus aureus and Escherichia coli. Nanomedicine. 3(2):168–171CrossRefGoogle Scholar
  14. 14.
    Sarkar B, Kumar M, Verma S, Rathore RM (2015) Effect of dietary nanosilver on gut proteases and general performance in Zebrafish (Danio rerio). Int J Aquat Biol 3(2):60–67Google Scholar
  15. 15.
    Beck I, Hotowy A, Sawosz E, Grodzik M, Wierzbicki M, Kutwin M, Jaworski S, Chwalibog A (2015) Effect of silver nanoparticles and hydroxyproline, administered in ovo, on the development of blood vessels and cartilage collagen structure in chicken embryos. Arch Anim Nutr 69:57–68CrossRefGoogle Scholar
  16. 16.
    Samuel U, Guggenbichler JP (2004) Prevention of catheter-rel the potential of a new nano silver impregnated catheter. Int J Antimicrob Agents 23S1:S75–S78CrossRefGoogle Scholar
  17. 17.
    Asharani P, Sethu S, Lim HK, Balaji G, Valiyaveettil S, Hande MP (2012) Differential regulation of intracellular factors mediating cell cycle, DNA repair and inflammation following exposure to silver nanoparticles in human cells. Genome Integr 3(1):2–14CrossRefGoogle Scholar
  18. 18.
    Yang EJ, Kim S, Kim JS, Choi IH (2018) Inflammasome formation and IL-1β release by human blood monocytes in response to silver nanoparticles. Biomaterials 33(28):6858–6867CrossRefGoogle Scholar
  19. 19.
    Kumar N, Krishnani KK, Gupta SK, Singh NP (2018) Effects of silver nanoparticles on stress biomarkers of Channa striatus: immuno-protective or toxic? Environ Sci Pollut Res Int 25(15):14813–14826CrossRefGoogle Scholar
  20. 20.
    Medici S, Peana M, Crisponi G, Nurchi VM, Lachowicz JI, Remelli M et al (2016) Silver coordination compounds: a new horizon in medicine. Coord Chem Rev 327–328:349–359CrossRefGoogle Scholar
  21. 21.
    Mccann M, Geraghty M, Devereux M, O’shea D, Mason J, O’sullivan L (2000) Insights into the mode of action of the anti-candida activity of 1,10-phenanthroline and its metal chelates. Metal Based Drugs 7(4):185–193CrossRefGoogle Scholar
  22. 22.
    Navarro M, Cisneros-Fajardo EJ, Marchan C (2006) New silver polypyridyl complexes: synthesis, characterization and biologic activity on Leishmania mexicana. Arzneimittelforschung 56:600–604Google Scholar
  23. 23.
    Segura DF, Netto AVG, Frem RCG, Mauro AE, Da Silva PB, Fernandes JA, Almeida Paz FA, Dias ALT, Silva NC, De Almeida ET, Marques MJ, De Almeida L, Alves KF, Pavan FR, De Souza PC, De Barros HB, Leite CQF (2014) Synthesis and biological evaluation of ternary silver compounds bearingN,N-chelating ligands and thiourea: X-ray structure of [{Ag(bpy)(μ-tu)}2](NO3)2 (bpy=2,2′-bipyridine; tu=thiourea). Polyhedron 79:197–206CrossRefGoogle Scholar
  24. 24.
    Cesarini S, Spallarossa A, Ranise A, Schenone S, Rosano C, la Colla P, Sanna G, Busonera B, Loddo R (2009) N-Acylated and N, N′-diacylated imidazolidine-2-thione derivatives and N, N′-diacylated tetrahydropyrimidine-2(1H)-thione analogues: synthesis and antiproliferative activity. Eur J Med Chem 44:1106–1118CrossRefGoogle Scholar
  25. 25.
    Bowmaker GA, Chaichit N, Pakawatchai C, Skelton BW, AH A (2009) White, Structural and spectroscopic studies of some adducts of silver(I) salts with ethylenethiourea. Can J Chem 87:161–170CrossRefGoogle Scholar
  26. 26.
    Peloso EF, Gonçalves CC, Silva TM, Ribeiro LH, Piñeyro MD, Robello C, Gadelha FR (2012) Tryparedoxin peroxidases and superoxide dismutases expression as well as ROS release are related to Trypanosoma cruzi epimastigotes growth phases. Arch Biochem Biophys 15(520–2):117–122CrossRefGoogle Scholar
  27. 27.
    Arrais-Silva WW, Colhone MC, Ayres DC, Souto PCS, Giorgio S (2005) Effects of hyperbaric oxygen on Leishmania amazonensis promastigotes and amastigotes. Parasitol Int 54(1):1–7CrossRefGoogle Scholar
  28. 28.
    Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxic assays. J Immunol Methods 65:55–63CrossRefGoogle Scholar
  29. 29.
    Colombo FA, Reis RA, Nunes JB, Dias DF, Dos Santos MH et al (2017) In vivo evaluation of leishmanicidal activity of benzophenone derivatives by qPCR. Med Chem (Los Angeles) 7:890–893CrossRefGoogle Scholar
  30. 30.
    Colombo FA, Pereira-Chioccola VL, Da Silva Meira C, Motoie G, Gava R et al (2015) Performance of a real time PCR for leishmaniasis diagnosis using a L. (L.) infantum hypothetical protein as target in canine samples. Exp Parasitol 157:156–162CrossRefGoogle Scholar
  31. 31.
    Colombo FA et al (2011) Detection of Leishmania (Leishmania) infantum RNA in fleas and ticks collected from naturally infected dogs. Parasitol Res 109(2):267–274CrossRefGoogle Scholar
  32. 32.
    Gutiérrez-Rebolledo GA, Siordia-Reyes AG, Meckes-Fischer M, Jiménez-Arellanes A (2016) Hepatoprotective properties of oleanolic and ursolic acids in antitubercular drug-induced liver damage. Asian Pac J Trop Med 9(7):644–651CrossRefGoogle Scholar
  33. 33.
    Geary WJ (1970) The use of conductivity measurements in organic solvents for the characterisation of coordination compounds. Coord Chem Rev 7:81–122CrossRefGoogle Scholar
  34. 34.
    De Moura TR, Cavalcanti SL, Godoy PRDV, Hojo ETS, Rocha FV, De Almeida ET, Deflon VM, Mauro AE, Netto AVG (2017) Synthesis, characterization and antitumor activity of palladium(II) complexes of imidazolidine-2-thione. Transit Met Chem 42:565–574CrossRefGoogle Scholar
  35. 35.
    Bezerra LJ et al (2006) Avaliação da atividade leishmanicida in vitro de plantas medicinais. Revista Brasileira de Farmacognosia 16:631–637CrossRefGoogle Scholar
  36. 36.
    Escobar P et al (2002) Sensitivities of Leishmania species to hexadecylphosphocholine (miltefosine), ET-18-OCH3 (edelfosine) and amphotericin B. Acta Trop 81:151–157CrossRefGoogle Scholar
  37. 37.
    Morais-Teixeira E, Carvalho AS, Costa JCS, Duarte SL, Mendonça JS, Boechat N, Rabello A (2008) In vitro and in vivo activity of meglumine antimoniate produced at Farmanguinhos-Fiocruz, Brazil, against Leishmania (Leishmania) amazonensis, L (L.) chagasi and L (Viannia) braziliensis. Mem Inst Oswaldo Cruz 103:358–362CrossRefGoogle Scholar
  38. 38.
    De Carvalho GSG, Machado PA, De Paula DTS, Coimbra ES, Da Silva AD (2010) Synthesis, cytotoxicity, and antileishmanial activity of N, N′-disubstituted ethylenediamine and imidazolidine derivatives. Sci World J 10:1723–1730.  https://doi.org/10.1100/tsw.2010.176 CrossRefGoogle Scholar
  39. 39.
    Barak E, Amin-Spector S, Gerliak E, Goyard S, Holland N, Zilberstein D (2005) Differentiation of Leishmania donovani in host-free system: analysis of signal perception and response. Mol Biochem Parasitol 141:99–108CrossRefGoogle Scholar
  40. 40.
    Mottram JC, Coombs GH (1985) Leishmania mexicana: enzyme activities of amastigotes and promastigotes and their inhibition by antimonials and arsenicals. Exp Parasitol 59:151–160CrossRefGoogle Scholar
  41. 41.
    Mondal S, Roy JJ, Berat T (2014) Characterization of mitochondrial bioenergetic functions between two forms of Leishmania donovani—a comparative analysis. J Bioenerg Biomembr 46(5):395–402CrossRefGoogle Scholar
  42. 42.
    Lahav T, Sivam D, Volpin H, Ronen M, Tsigankov P, Green A, Holland N, Kuzyk M, Borchers C, Zilberstein D, Myler PJ (2011) Multiple levels of gene regulation mediate differentiation of the intracellular pathogen Leishmania. FASEB J 25:515–525CrossRefGoogle Scholar
  43. 43.
    Kima PE (2007) The amastigote forms of Leishmania are experts at exploiting host cell processes to establish infection and persist. Int J Parasitol 37(10):1087–1096CrossRefGoogle Scholar
  44. 44.
    Robledo S, Osorio E, Munõz D, Jaramillo LM, Restrepo A, Arango G, Vélez I (2005) In vitro and in vivo cytotoxicities and antileishmanial activities of thymol and hemisynthetic derivatives. Antimicrob Agents Chemother 49(4):1652–1655CrossRefGoogle Scholar
  45. 45.
    Pires CM, Rodrigues SD, Bristot D, Gaeta HH, Toyama DO, Farias WRL, Toyama MH (2013) Evaluation of macroalgae sulfated polysaccharides on the Leishmania (L.) amazonensis promastigote. Mar Drugs 11:934–943CrossRefGoogle Scholar
  46. 46.
    Gelvez APC, Farias LH, Pereira VS et al (2018) Biosynthesis, characterization and leishmanicidal activity of a biocomposite containing AgNPs-PVP-glucantime. Nanomedicine (Lond) 13(4):373–390CrossRefGoogle Scholar
  47. 47.
    Ovais M, Khalil T, Raza A et al (2016) Green synthesis of silver nanoparticles via plant extracts: beginning a new era in cancer theranostics. Nanomedicine 11(23):3157–3177CrossRefGoogle Scholar
  48. 48.
    Mendonça DVC et al (2018) Comparing the therapeutic efficacy of different amphotericin B-carrying delivery systems against visceral leishmaniasis. Exp Parasitol 186:24–35CrossRefGoogle Scholar
  49. 49.
    Andrade JM et al (2016) Silver and nitrate oppositely modulate antimony susceptibility through aquaglyceroporin in Leishmania (Viannia) species. Antimicrob Agents Chemother 60:4482–4489CrossRefGoogle Scholar
  50. 50.
    Franco LP, Cicillini SA, Biazzotto JC, Schiavon A, Mikhailovsky A, Burks P, Garcia J, Ford PC, Da Silva RS (2014) Photoreactivity of a quantum dot-ruthenium nitrosyl conjugate. J Phys Chem A 118:12184–12191CrossRefGoogle Scholar
  51. 51.
    Ning ZH, Long S, Zhou YY, Peng ZY, Sun YN et al (2015) Effect of exposure routes on the relationships of lethal toxicity to rats from oral, intravenous, intraperitoneal and intramuscular routes. Regul Toxicol Pharmacol 73:613–619CrossRefGoogle Scholar
  52. 52.
    Berczyński P, Duchnik E, Kruk I, Piechowska T, Aboul-Enein HY, Bozdağ-Dündar O, Ceylan-Unlusoy M (2014) 6-Methyl 3-chromonyl 2,4-thiazolidinedione/2,4-imidazolidinedione/2-thioxo-imidazolidine-4-one compounds: novel scavengers of reactive oxygen species. Luminescence 29(4):367–373CrossRefGoogle Scholar
  53. 53.
    Weng Z, Shao X, Graf D, Wang C, Klein C, Wang J, Zhou G-C (2016) Identification of the fused bicyclic derivatives of pyrrolidine and imidazolidinone as dengue virus-2 NS2B-NS3 protease inhibitors. Eur J Med Chem 125:751–759.  https://doi.org/10.1016/j.ejmech.2016.09.063 CrossRefGoogle Scholar
  54. 54.
    Coombs GH, Mottram JC (1997) Parasite proteinases and amino acid metabolism: possibilities for chemotherapeutic exploitation. Parasitology 114(Suppl):S61–S80Google Scholar
  55. 55.
    Aparicio IM, Scharfstein J, Lima AP (2004) A new cruzipain-mediated pathway of human cell invasion by Trypanosoma cruzi requires trypomastigote membranes. Infect Immun 72:5892–5902CrossRefGoogle Scholar
  56. 56.
    Duchen MR (2000) Mitochondria and calcium: from cell signaling to cell death. J Physiolol 529:57–68CrossRefGoogle Scholar
  57. 57.
    Vercesi AE, Kowaltowski AJ, Oliveira HC, Castilho RF (2006) Mitochondrial Ca2+ transport, permeability transition and oxidative stress in cell death: implications in cardiotoxicity, neurodegeneration and dyslipidemias. Front Biosci 11:2554–2564CrossRefGoogle Scholar
  58. 58.
    Machado N, Gomes D, Vieira L, Nascimento M, Mittra B, Andrews N (2018) A new source of reactive oxygen species in Leishmania amazonensis: characterization of a heme-activated NADPH oxidase-like. Free Radic Biol Med 128(Supplement 1):S55CrossRefGoogle Scholar
  59. 59.
    Wilkinson SR, Temperton NJ, Mondragon A, Kelly JM (2000) Distinct mitochondrial and cytosolic enzymes mediate trypanothione-dependent peroxide metabolism in Trypanosoma cruzi. J Biol Chem 275(11):8220–8225CrossRefGoogle Scholar
  60. 60.
    Piacenza L, Peluffo G, Alvarez MN, Kelly JM, Wilkinson SR, Radi R (2008) Peroxiredoxins play a major role in protecting Trypanosoma cruzi against macrophage- and endogenously-derived peroxynitrite. Biochem J 410(2):359–368CrossRefGoogle Scholar
  61. 61.
    Piacenza L, Zago MP, Peluffo G, Alvarez MN, Basombrio MA, Radi R (2009) Enzymes of the antioxidant network as novel determiners of Trypanosoma cruzi virulence. Int J Parasitol 39(13):1455–1464CrossRefGoogle Scholar
  62. 62.
    Finzi JK, Chiavegatto CW, Corat KF, Lopez JA, Cabrera OG, Mielniczki-Pereira AA, Colli W, Alves MJ, Gadelha FR (2004) Trypanosoma cruzi response to the oxidative stress generated by hydrogen peroxide. Mol Biochem Parasitol 133(1):37–43CrossRefGoogle Scholar
  63. 63.
    Wiese AG, Pacifici RE, Davies KJ (1995) Transient adaptation of oxidative stress in mammalian cells. Ach Biochem Biophys 318:231–240Google Scholar
  64. 64.
    Davies JMS, Lowry CV, Davies KJA (1995) Transient adaptation to oxidative stress in yeast. Arch Biochem Biophys 317:1–6CrossRefGoogle Scholar
  65. 65.
    Sena LA, Chandel NS (2012) Physiological roles of mitochondrial reactive oxygen species. Mol Cell 48:158–167CrossRefGoogle Scholar
  66. 66.
    Reczek CR, Chandel NS (2015) ROS-dependent signal transduction. Curr Opin Cell Biol 33:8–13CrossRefGoogle Scholar
  67. 67.
    Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress. Curr Biol 24:R453–R462CrossRefGoogle Scholar
  68. 68.
    Lennicke C, Rahn J, Lichtenfels R, Wessjohann LA, Seliger B (2015) Hydrogen peroxide–production, fate and role in redox signaling of tumor cells. Cell Commun Signal 13:39CrossRefGoogle Scholar
  69. 69.
    Lee S, Tak E, Lee J, Rashid MA, Murphy MP, Ha J, Kim SS (2011) Mitochondrial H2O2 generated from electron transport chain complex I stimulates muscle differentiation. Cell Res 21:817–834CrossRefGoogle Scholar

Copyright information

© Society for Biological Inorganic Chemistry (SBIC) 2019

Authors and Affiliations

  • Patrícia Ferreira Espuri
    • 1
    • 5
    Email author
  • Larissa Luiza dos Reis
    • 1
  • Eduardo de Figueiredo Peloso
    • 2
  • Vanessa Silva Gontijo
    • 3
  • Fábio Antônio Colombo
    • 1
  • Juliana Barbosa Nunes
    • 1
  • Carine Ervolino de Oliveira
    • 1
  • Eduardo T. De Almeida
    • 3
  • Débora E. S. Silva
    • 4
  • Jessica Bortoletto
    • 4
  • Daniel Fonseca Segura
    • 4
  • Adelino V. G. Netto
    • 4
  • Marcos José Marques
    • 1
    • 5
    Email author
  1. 1.Laboratory of Parasitology, Department of Pathology and Parasitology, Institute of Biomedical SciencesUniversidade Federal de AlfenasAlfenasBrazil
  2. 2.Department of Biochemistry, Institute of Biomedical SciencesUniversidade Federal de AlfenasAlfenasBrazil
  3. 3.Laboratory of Researche on Medicinal Chemistry, Institute of ChemistryUniversidade Federal de AlfenasAlfenasBrazil
  4. 4.Institute of ChemistryUNESP-Univ. Estadual PaulistaAraraquaraBrazil
  5. 5.Institute of Biomedical SciencesFederal University of AlfenasAlfenasBrazil

Personalised recommendations