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Parasitology Research

, Volume 115, Issue 5, pp 2081–2096 | Cite as

A new type of quinoxalinone derivatives affects viability, invasion, and intracellular growth of Toxoplasma gondii tachyzoites in vitro

  • Norma Rivera Fernández
  • Mónica Mondragón Castelán
  • Sirenia González Pozos
  • Carlos J. Ramírez Flores
  • Ricardo Mondragón González
  • Carmen T. Gómez de León
  • Kitzia N. Castro Elizalde
  • Yovani Marrero Ponce
  • Vicente J. Arán
  • Miriam A. Martins Alho
  • Ricardo Mondragón Flores
Original Paper

Abstract

Quinoxalinone derivatives, identified as VAM2 compounds (7-nitroquinoxalin-2-ones), were evaluated against Toxoplasma gondii tachyzoites of the RH strain. The VAM2 compounds were previously synthesized based on the design obtained from an in silico prediction with the software TOMOCOMD-CARDD. From the ten VAM2 drugs tested, several showed a deleterious effect on tachyzoites. However, VAM2-2 showed the highest toxoplasmicidal activity generating a remarkable decrease in tachyzoite viability (in about 91 %) and a minimal alteration in the host cell. An evident inhibition of host cell invasion by tachyzoites previously treated with VAM2-2 was observed in a dose-dependent manner. In addition, remarkable alterations were observed in the pellicle parasite, such as swelling, roughness, and blebbing. Toxoplasma motility was inhibited, and subpellicular cytoskeleton integrity was altered, inducing a release of its components to the soluble fraction. VAM2-2 showed a clear and specific deleterious effect on tachyzoites viability, structural integrity, and invasive capabilities with limited effects in host cells morphology and viability. VAM2-2 minimum inhibitory concentration (MIC50) was determined as 3.3 μM ± 1.8. Effects of quinoxalinone derivatives on T. gondii provide the basis for a future therapeutical alternative in the treatment of toxoplasmosis.

Keywords

Apicomplexan Toxoplasma gondii Pellicle Quinoxalinone derivatives In silico drug design TOMOCOMD-CARDD 

Notes

Acknowledgments

Electron micrographs were obtained at the Electron Microscopy Unit (LANSE-CINVESTAV), México. The authors acknowledge Corinne Mercier (Université Joseph Fourier, Grenoble, France) for sharing antibodies. Animals were provided by the Animal Facility (UPEAL-LaNSE) at CINVESTAV, Mexico.

Compliance with ethical standards

Funding

Research was supported by a grant from the Consejo Nacional de Ciencia y Tecnología (CONACyT, Grant # 155459 to RMF). CRF, RMG, CGL, and KCE were supported by doctoral fellowships, number # 424851, # 394378, # 324983, and # 369769 from CONACyT-México, respectively.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Carruthers VB, Giddings OK, Sibley LD (1999) Secretion of micronemal proteins is associated with Toxoplasma invasion of host cells. Cell Microbiol 1(3):225–235CrossRefPubMedGoogle Scholar
  2. Castillo-Romero A, León-Avila G, Pérez-Rangel A, Cortés-Zarate R, García-Tovar C, Hernández JM (2009) Participation of actin on Giardia lamblia growth and encystation. PLoS One 4(9):e7156CrossRefPubMedPubMedCentralGoogle Scholar
  3. Charras GT (2008) A short history of blebbing. J Microsc 231(3):466–478CrossRefPubMedGoogle Scholar
  4. Correa G, Benchimol M (2006) Giardia lamblia behavior under cytochalasins treatment. Parasitol Res 98(3):250–256CrossRefPubMedGoogle Scholar
  5. Dannemann B, McCutchan JA, Israelski D, Antoniskis D, Leport C, Luft B, Nussbaum J, Clumeck N, Morlat P, Chiu J, Vilde JL, Orellana M, Feigal D, Bartok A, Heseltine P, Leedom J, Remington J (1992) Treatment of toxoplasmic encephalitis in patients with AIDS. A randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. The California Collaborative Treatment Group. Ann Intern Med 116(1):33–43CrossRefPubMedGoogle Scholar
  6. Delbac F, Sanger A, Neuhaus EM, Stratmann R, Ajioka JW, Toursel C, Herm-Gotz A, Tomavo S, Soldati T, Soldati D (2001) Toxoplasma gondii myosins B/C: one gene, two tails, two localizations, and a role in parasite division. J Cell Biol 155(4):613–623CrossRefPubMedPubMedCentralGoogle Scholar
  7. Dobrowolski JM, Sibley LD (1996) Toxoplasma invasion of mammalian cells is powered by the actin cytoskeleton of the parasite. Cell 84(6):933–939CrossRefPubMedGoogle Scholar
  8. Dubremetz JF, Torpier G (1978) Freeze fracture study of the pellicle of an eimerian sporozoite (Protozoa, Coccidia). J Ultrastruct Res 62(2):94–109CrossRefPubMedGoogle Scholar
  9. Fackler OT, Grosse R (2008) Cell motility through plasma membrane blebbing. J Cell Biol 181(6):879–884CrossRefPubMedPubMedCentralGoogle Scholar
  10. González-del Carmen M, Mondragón M, González S, Mondragón R (2009) Induction and regulation of conoid extrusion in Toxoplasma gondii. Cell Microbiol 11(6):967–982CrossRefPubMedGoogle Scholar
  11. Hagmann J, Burger MM, Dagan D (1999) Regulation of plasma membrane blebbing by the cytoskeleton. J Cell Biochem 73(4):488–499CrossRefPubMedGoogle Scholar
  12. Madeiro da Costa RF, Benchimol M (2004) The effect of drugs on cell structure of Tritrichomonas foetus. Parasitol Res 92(2):159–170CrossRefPubMedGoogle Scholar
  13. Magno RC, Lemgruber L, Vommaro RC, De Souza W, Attias M (2005) Intravacuolar network may act as a mechanical support for Toxoplasma gondii inside the parasitophorous vacuole. Microsc Res Tech 67(1):45–52CrossRefPubMedGoogle Scholar
  14. Martins-Alho MA, Marrero-Ponce Y, Barigye SJ, Meneses-Marcel A, Machado-Tugores Y, Montero-Torres A, Gómez-Barrio A, Nogal JJ, García-Sanchez RN, Vega MC, Rolon M, Martínez-Fernandez AR, Escario JA, Pérez-Gimenez F, García-Domenech R, Rivera N, Mondragón R, Mondragón M, Ibarra-Velarde F, López-Arencibia A, Martin-Navarro C, Lorenzo-Morales J, Cabrera-Serra MG, Pinero J, Tytgat J, Chicharro R, Aran VJ (2014) Antiprotozoan lead discovery by aligning dry and wet screening: prediction, synthesis, and biological assay of novel quinoxalinones. Bioorg Med Chem 22(5):1568–1585CrossRefPubMedGoogle Scholar
  15. McCabe RE (2001) Toxoplasmosis: a comprenhensive clinical guide. Cambridge Univ Press, LondonGoogle Scholar
  16. Menna-Barreto RF, Salomao K, Dantas AP, Santa-Rita RM, Soares MJ, Barbosa HS, de Castro SL (2009) Different cell death pathways induced by drugs in Trypanosoma cruzi: an ultrastructural study. Micron 40(2):157–168CrossRefPubMedGoogle Scholar
  17. Mineo JR, Kasper LH (1994) Attachment of Toxoplasma gondii to host cells involves major surface protein, SAG-1 (P30). Exp Parasitol 79(1):11–20CrossRefPubMedGoogle Scholar
  18. Mondragón R, Frixione E (1996) Ca(2+)-dependence of conoid extrusion in Toxoplasma gondii tachyzoites. J Eukaryot Microbiol 43(2):120–127CrossRefPubMedGoogle Scholar
  19. Montoya JG, Liesenfeld O (2004) Toxoplasmosis. Lancet 363(9425):1965–1976CrossRefPubMedGoogle Scholar
  20. Morrissette NS, Sibley LD (2002) Cytoskeleton of apicomplexan parasites. Microbiol Mol Biol Rev 66(1):21–38CrossRefPubMedPubMedCentralGoogle Scholar
  21. Muñiz-Hernández S, González-del Carmen M, Mondragón M, Mercier C, Cesbron MF, Mondragón-Gonzalez SL, González S, Mondragón R (2011) Contribution of the residual body in the spatial organization of Toxoplasma gondii tachyzoites within the parasitophorous vacuole. J Biomed Biotechnol 2011:473983CrossRefPubMedPubMedCentralGoogle Scholar
  22. Patrón SA, Mondragón M, González S, Ambrosio JR, Guerrero BA, Mondragón R (2005) Identification and purification of actin from the subpellicular network of Toxoplasma gondii tachyzoites. Int J Parasitol 35(8):883–894CrossRefGoogle Scholar
  23. Poupel O, Tardieux I (1999) Toxoplasma gondii motility and host cell invasiveness are drastically impaired by jasplakinolide, a cyclic peptide stabilizing F-actin. Microbes Infect 1(9):653–662CrossRefPubMedGoogle Scholar
  24. Rivera N, Ponce YM, Aran VJ, Martínez C, Malagon F (2013) Biological assay of a novel quinoxalinone with antimalarial efficacy on Plasmodium yoelii yoelii. Parasitol Res 112(4):1523–1527CrossRefPubMedGoogle Scholar
  25. Rivera-Borroto OM, Marrero-Ponce Y, Meneses-Marcel A, Escario JA, Gómez-Barrio A, Arán V, Martins-Alho MA, Montero-Pereira D, Nogal JJ, Torrens F, Ibarra-Velarde F, Vera-Montenegro Y, Huesca-Guillén A, Rivera N, Vogel C (2009) Discovery of novel trichomonacidals using LDA-driven QSAR models and bond-based bilinear indices as molecular descriptors. QSAR Comb Sci 28(1):9–26CrossRefGoogle Scholar
  26. Sarciron ME, Nebois P, Pautet F, Petavy AF, Fillion H, Walchshofer N (2002) Quinonic derivatives active against Toxoplasma gondii. Parasitol Res 88(11):969–971CrossRefPubMedGoogle Scholar
  27. Shaw MK, Compton HL, Roos DS, Tilney LG (2000) Microtubules, but not actin filaments, drive daughter cell budding and cell division in Toxoplasma gondii. J Cell Sci 113(Pt 7):1241–1254PubMedGoogle Scholar
  28. Stehn JR, Schevzov G, O’Neill GM, Gunning PW (2006) Specialisation of the tropomyosin composition of actin filaments provides new potential targets for chemotherapy. Curr Cancer Drug Targets 6(3):245–256CrossRefPubMedGoogle Scholar
  29. Tempone AG, Taniwaki NN, Reimao JQ (2009) Antileishmanial activity and ultrastructural alterations of Leishmania (L.) chagasi treated with the calcium channel blocker nimodipine. Parasitol Res 105(2):499–505CrossRefPubMedGoogle Scholar
  30. Tiwari P, Singh D, Singh MM (2008) Anti-Trichomonas activity of Sapindus saponins, a candidate for development as microbicidal contraceptive. J Antimicrob Chemother 62(3):526–534CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Norma Rivera Fernández
    • 1
    • 2
  • Mónica Mondragón Castelán
    • 2
  • Sirenia González Pozos
    • 3
  • Carlos J. Ramírez Flores
    • 2
  • Ricardo Mondragón González
    • 4
  • Carmen T. Gómez de León
    • 2
  • Kitzia N. Castro Elizalde
    • 2
  • Yovani Marrero Ponce
    • 5
  • Vicente J. Arán
    • 6
  • Miriam A. Martins Alho
    • 6
    • 7
  • Ricardo Mondragón Flores
    • 2
  1. 1.Departamento de Microbiología y ParasitologíaFacultad de Medicina, Universidad Nacional Autónoma de MéxicoDFMéxico
  2. 2.Departamento de BioquímicaCentro de Investigación y de Estudios Avanzados del IPN (CINVESTAV)DFMéxico
  3. 3.Unidad de Microscopía Electrónica (LANSE), CINVESTAVDFMexico
  4. 4.Departamento de Genética y Biología Molecular, CINVESTAVDFMexico
  5. 5.Edificio de Especialidades Médicas, Hospital de los VallesColegio de Ciencias de la Salud, Universidad de San Francisco de QuitoQuitoEcuador
  6. 6.Instituto de Química Médica, CSICMadridEspaña
  7. 7.Centro de Investigaciones en Hidratos de Carbono (CIHIDECAR-CONICET), Departamento de Química Orgánica, FCEN y LabMOr – INTECIN, FI, UBABuenos AiresArgentina

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