In vitro Immunobiological Studies of Novel 5-(5-nitrofuran-2-yl)-1, 3, 4- Thiadiazoles with Piperazinyl-Linked Benzamidine Substituents against Leishmania Major
Abstract
It was recently demonstrated that 5-(5-nitrofuran-2-yl)-1, 3, 4-thiadiazoles with piperazinyl-linked benzamidine substituents are effective in vitro against Leishmania major.
Following on this evidence, we used colorimetric assay of acid phosphatase activity in the promastigotes as an indicator for cell viability. Also we studied the effect of these compounds on induction of nitric oxide (NO) in macrophage and production of reactive oxygen species (ROS) in lymphocyte that have important role in activation of immune response against Leishmania and elimination of parasite.
Results showed that these compounds decrease the viability of the parasite and increase ROS and NO production in lymphocyte and macrophage respectively.
These compounds can induce parasite killing, directly by decreasing the parasite viability and indirectly by exhibiting a significant increase on immune system.
1. Pearson RD, Wheeler DA, Harrison LH, Kay HD. The immunobiology of leishmaniasis. Rev Infect Dis 1983;5(5):907-27.
2. Taylor VM, Cedeno DL, Munoz DL, Jones MA, Lash TD, Young AM, et al. In vitro and in vivo studies of the utility of dimethyl and diethyl carbaporphyrin ketals in treatment of cutaneous leishmaniasis. Antimicrob Agents Chemother 2011; 55(10):4755-64.
3. Bringaud F, Riviere L, Coustou V. Energy metabolism of trypanosomatids: adaptation to available carbon sources. Mol Biochem Parasitol 2006; 149(1):1-9.
4. Croft SL, Sundar S, Fairlamb AH. Drug resistance in leishmaniasis. Clin Microbiol Rev 2006; 19(1):111-26.
5. Guillon J, Forfar I, Mamani-Matsuda M, Desplat V, Saliege M, Thiolat D, et al. Synthesis, analytical behaviour and biological evaluation of new 4-substituted pyrrolo[1,2-a]quinoxalines as antileishmanial agents. Bioorg Med Chem 2007; 15(1):194-210.
6. Tahghighi A, Marznaki FR, Kobarfard F, Dastmalchi S, Mojarrad JS, Razmi S, et al. Synthesis and antileishmanial activity of novel 5-(5-nitrofuran-2-yl)-1,3,4-thiadiazoles with piperazinyl-linked benzamidine substituents. Eur J Med Chem 2011; 46(6):2602-8.
7. Sacks DL. Leishmania-sand fly interactions controlling species-specific vector competence. Cell Microbiol 2001;3(4):189-96.
8. Doyle PS, Dwyer DM. Leishmania: immunochemical comparison of the secretory (extracellular) acid phosphatases from various species. Exp Parasitol 1993;77(4):435-44.
9. Shakarian AM, Dwyer DM. Structurally conserved soluble acid phosphatases are synthesized and released by Leishmania major promastigotes. Exp Parasitol 2000;95(2):79-84.
10. Shakarian AM, Joshi MB, Yamage M, Ellis SL, Debrabant A, Dwyer DM. Members of a unique histidine acid phosphatase family are conserved amongst a group of primitive eukaryotic human pathogens. Mol Cell Biochem 2003; 245(1-2):31-41.
11. Bates PA, Dwyer DM. Biosynthesis and secretion of acid phosphatase by Leishmania donovani promastigotes. Mol Biochem Parasitol 1987; 26(3):289-96.
12. Liew FY, Xu D, Chan WL. Immune effector mechanism in parasitic infections. Immunol Lett 1999; 65(1-2):101-4.
13. Mauel J, Ransijn A, Buchmuller-Rouiller Y. Killing of Leishmania parasites in activated murine macrophages is based on an L-arginine-dependent process that produces nitrogen derivatives. J Leukoc Biol 1991; 49(1):73-82.
14. Szabo SJ, Sullivan BM, Peng SL, Glimcher LH.Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol 2003; 21:713-58.
15. Koch N, Jung M, Sabat R, Kratzschmar J, Docke WD, Asadullah K, et al. IL-10 protects monocytes and macrophages from complement-mediated lysis. J Leukoc Biol 2009; 86(1):155-66.
16. Nishimura M. Cytokine release from phytohemagglutinin-blast triggered by normal human serum. Transfusion 2009; 49(3):602.
17. Schoene NW, Kamara KS. Population doubling time, phosphatase activity, and hydrogen peroxide generation in Jurkat cells. Free Radic Biol Med 1999; 27(3-4):364-9.
18. Behrouzi-Fardmoghadam M, Poorrajab F, Ardestani SK, Emami S, Shafiee A, Foroumadi A. Synthesis and in vitro anti-leishmanial activity of 1-[5-(5-nitrofuran-2-yl)-1,3,4- thiadiazol-2-yl]- and 1-[5-(5-nitrothiophen-2-yl)-1,3,4- thiadiazol-2-yl]-4-aroylpiperazines. Bioorg Med Chem 2008; 16(8):4509-15.
19. Katakura K, Kobayashi A. Acid phosphatase activity of virulent and avirulent clones of Leishmania donovani promastigotes. Infect Immun 1988; 56(11):2856-60.
20. Olivier M, Gregory DJ, Forget G. Subversion mechanisms by which Leishmania parasites can escape the host immune response: a signaling point of view. Clin Microbiol Rev 2005; 18(2):293-305.
21. Aragon V, Kurtz S, Cianciotto NP. Legionella pneumophila major acid phosphatase and its role in intracellular infection. Infect Immun 2001; 69(1):177-85.
22. Lee N, Gannavaram S, Selvapandiyan A, Debrabant A.Characterization of metacaspases with trypsin-like activity and their putative role in programmed cell death in the protozoan parasite Leishmania. Eukaryot Cell 2007; 6(10):1745-57.
23. Miranda KM, Espey MG, Wink DA. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide 2001; 5(1):62-71.
24. Kirsch JD, Yi AK, Spitz DR, Krieg AM. Accumulation of glutathione disulfide mediates NF-kappaB activation during immune stimulation with CpG DNA. Antisense Nucleic Acid Drug Dev 2002; 12(5):327-40.
25. Croft SL, Yardley V. Chemotherapy of leishmaniasis. Curr Pharm Des 2002; 8(4):319-42.
26. Vannier-Santos MA, Martiny A, de Souza W. Cell biology of Leishmania spp.: invading and evading. Curr Pharm Des 2002; 8(4):297-318.
27. Werbovetz KA. Target-based drug discovery for malaria, leishmaniasis, and trypanosomiasis. Curr Med Chem 2000 Aug; 7(8):835-60.
28. Ardestani SK, Poorrajab F, Razmi S, Foroumadi A, Ajdary S, Gharegozlou B, et al. Cell death features induced in Leishmania major by 1,3,4-thiadiazole derivatives. Exp Parasitol 2012; 132(2):116-22.
29. Laskay T, van Zandbergen G, Solbach W. Neutrophil granulocytes as host cells and transport vehicles for intracellular pathogens: apoptosis as infection-promoting factor. Immunobiology 2008; 213(3-4):183-91.
30. van Zandbergen G, Bollinger A, Wenzel A, Kamhawi S, Voll R, Klinger M, et al. Leishmania disease development depends on the presence of apoptotic promastigotes in the virulent inoculum. Proc Natl Acad Sci U S A 2006;103(37):13837-42.
31. Wanderley JL, Moreira ME, Benjamin A, Bonomo AC, Barcinski MA. Mimicry of apoptotic cells by exposing phosphatidylserine participates in the establishment of amastigotes of Leishmania (L) amazonensis in mammalian hosts. J Immunol 2006; 176(3):1834-9.
32. Liew FY, Wei XQ, Proudfoot L. Cytokines and nitric oxide as effector molecules against parasitic infections. Philos Trans R Soc Lond B Biol Sci 1997;352(1359):1311-5.
33. Ropert C, Gazzinelli RT. Signaling of immune system cells by glycosylphosphatidylinositol (GPI) anchor and related structures derived from parasitic protozoa. Curr Opin Microbiol 2000; 3(4):395-403.
34. Balaraman S, Tewary P, Singh VK, Madhubala R.Leishmania donovani induces interferon regulatory factor in murine macrophages: a host defense response. Biochem Biophys Res Commun 2004; 317(2):639-47.
35. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature 2000; 408(6809):239-47.
36. Adler V, Yin Z, Tew KD, Ronai Z. Role of redox potential and reactive oxygen species in stress signaling. Oncogene 1999; 18(45):6104-11.
37. Buttke TM, Sandstrom PA. Redox regulation of programmed cell death in lymphocytes. Free Radic Res 1995; 22(5):389-97.
38. Roth S, Droge W. Regulation of T-cell activation and T- cell growth factor (TCGF) production by hydrogen peroxide. Cell Immunol 1987; 108(2):417-24.
39. Staal FJ, Anderson MT, Staal GE, Herzenberg LA, Gitler C, Herzenberg LA. Redox regulation of signal transduction: tyrosine phosphorylation and calcium influx. Proc Natl Acad Sci U S A 1994; 91(9):3619-22.
40. Bromley SK, Burack WR, Johnson KG, Somersalo K, Sims TN, Sumen C, et al. The immunological synapse. Annu Rev Immunol 2001; 19:375-96.
41. Batista FD, Iber D, Neuberger MS. B cells acquire antigen from target cells after synapse formation. Nature 2001; 411(6836):489-94.
42. Rutault K, Alderman C, Chain BM, Katz DR. Reactive oxygen species activate human peripheral blood dendritic cells. Free Radic Biol Med 1999; 26(1-2):232-8.
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Issue | Vol 12, No 4 (2013) | |
Section | Articles | |
Keywords | ||
5-(5-nitrofuran-2-yl)-1 3 4- thiadiazoles piperazinyl-linked benzamidine substituents Acid phosphatase Leishmaniasis Nitric Oxide Reactive oxygen species |
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