Advertisement

Bioguided Design of Trypanosomicidal Compounds: A Successful Strategy in Drug Discovery

  • Guzmán Ignacio Álvarez Touron
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1824)

Abstract

Drug development is a long and expensive process that takes about 15 years and is mostly carried out by the pharmaceutical industry. In the case of the diseases produced by trypanosomatids, this development is poorly performed by the pharmaceutical industry. As a result the academia is the one that take a leading role with the drug development process. More effective and economic methodologies to obtain safe compounds and with strong trypanosomicidal activity are urgently needed. In this work, a series of methods are described to obtain bioactive molecules with antiparasitic activity and good pharmacological profiles.

Key words

Targeted and phenotypic screening Toxicology Oral formulations Preclinical studies Trypanosomiasis Bioguided design 

Notes

Acknowledgments

This work was supported by CSIC I+D 2016 grant #435.

References

  1. 1.
    Cavalli A, Bolognesi ML (2009) Neglected tropical diseases: multi-target-directed ligands in the search for novel lead candidates against Trypanosoma and Leishmania. J Med Chem 52:7339–7359. https://doi.org/10.1021/jm9004835 CrossRefPubMedGoogle Scholar
  2. 2.
    Renslo AR, McKerrow JH (2006) Drug discovery and development for neglected parasitic diseases. Nat Chem Biol 2:701–710. https://doi.org/10.1038/nchembio837 CrossRefPubMedGoogle Scholar
  3. 3.
    Papadopoulou MV, Bloomer WD, Rosenzweig HS et al (2016) Nitrotriazole-based acetamides and propanamides with broad spectrum antitrypanosomal activity. Eur J Med Chem 123:895–904. https://doi.org/10.1016/j.ejmech.2016.08.002 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Barrett MP, Mottram JC, Coombs GH (1999) Recent advances in identifying and validating drug targets in trypanosomes and leishmanias. Trends Microbiol 7:82–88CrossRefPubMedGoogle Scholar
  5. 5.
    Bettiol E, Samanovic M, Murkin AS et al (2009) Identification of three classes of heteroaromatic compounds with activity against intracellular Trypanosoma cruzi by chemical library screening. PLoS Negl Trop Dis 3:e384. https://doi.org/10.1371/journal.pntd.0000384 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    McKim JM (2010) Building a tiered approach to in vitro predictive toxicity screening: a focus on assays with in vivo relevance. Comb Chem High Throughput Screen 13:188–206. https://doi.org/10.2174/138620710790596736 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Alvarez G, Aguirre-López B, Varela J et al (2010) Massive screening yields novel and selective Trypanosoma cruzi triosephosphate isomerase dimer-interface-irreversible inhibitors with anti-trypanosomal activity. Eur J Med Chem 45:5767–5772. https://doi.org/10.1016/j.ejmech.2010.09.034 CrossRefPubMedGoogle Scholar
  8. 8.
    Olivares-Illana V, Pérez-Montfort R, López-Calahorra F et al (2006) Structural differences in triosephosphate isomerase from different species and discovery of a multitrypanosomatid inhibitor. Biochemistry 45:2556–2560. https://doi.org/10.1021/bi0522293 CrossRefPubMedGoogle Scholar
  9. 9.
    Ferreira ME, Rojas de Arias A, Yaluff G et al (2010) Antileishmanial activity of furoquinolines and coumarins from Helietta apiculata. Phytomedicine 17:375–378. https://doi.org/10.1016/j.phymed.2009.09.009 CrossRefPubMedGoogle Scholar
  10. 10.
    Aguilera E, Varela J, Birriel E et al (2016) Potent and selective inhibitors of trypanosoma cruzi triosephosphate isomerase with concomitant inhibition of cruzipain: inhibition of parasite growth through multitarget activity. ChemMedChem 11:1328–1338. https://doi.org/10.1002/cmdc.201500385 CrossRefPubMedGoogle Scholar
  11. 11.
    Álvarez G, Varela J, Márquez P et al (2014) Optimization of antitrypanosomatid agents: identification of nonmutagenic drug candidates with in vivo activity. J Med Chem 57:3984–3999. https://doi.org/10.1021/jm500018m CrossRefPubMedGoogle Scholar
  12. 12.
    Liao TT, Jia RW, Shi YL et al (2011) Propidium iodide staining method for testing the cytotoxicity of 2,4,6-trichlorophenol and perfluorooctane sulfonate at low concentrations with Vero cells. J Environ Sci Health A Tox Hazard Subst Environ Eng 46:1769–1775. https://doi.org/10.1080/10934529.2011.624016 CrossRefPubMedGoogle Scholar
  13. 13.
    Álvarez G, Perdomo C, Coronel C et al (2017) Multi-anti-parasitic activity of arylidene ketones and thiazolidene hydrazines against Trypanosoma cruzi and Leishmania spp. Molecules 22(5):pii: E709. https://doi.org/10.3390/molecules22050709 CrossRefGoogle Scholar
  14. 14.
    Gerpe A, Alvarez G, Benítez D et al (2009) 5-Nitrofuranes and 5-nitrothiophenes with anti-Trypanosoma cruzi activity and ability to accumulate squalene. Bioorg Med Chem 17:7500–7509. https://doi.org/10.1016/j.bmc.2009.09.013 CrossRefPubMedGoogle Scholar
  15. 15.
    Ferraro F, Merlino A, dell’Oca N et al (2016) Identification of chalcones as fasciola hepatica cathepsin L inhibitors using a comprehensive experimental and computational approach. PLoS Negl Trop Dis 10:e0004834. https://doi.org/10.1371/journal.pntd.0004834 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Álvarez G, Varela J, Cruces E et al (2015) Identification of a new amide-containing thiazole as a drug candidate for treatment of chagas’ disease. Antimicrob Agents Chemother 59(3):1398–1404. https://doi.org/10.1128/AAC.03814-14 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    OECD (2001) OECD Guidelines for the Testing of Chemicals, Section 4, Test No. 425: Acute Oral Toxicity—Up-and-Down Procedure. Guidel Test Chem 26. https://doi.org/10.1787/9789264071049-en
  18. 18.
    Schmid W (1975) The micronucleus test. Mutat Res Mutagen Relat Subj 31:9–15. https://doi.org/10.1016/0165-1161(75)90058-8 CrossRefGoogle Scholar
  19. 19.
    Mortelmans K, Zeiger E (2000) The Ames Salmonella/microsome mutagenicity assay. Mutat Res 455:29–60CrossRefPubMedGoogle Scholar
  20. 20.
    Cabrera M, Lavaggi ML, Hernández P et al (2009) Cytotoxic, mutagenic and genotoxic effects of new anti-T. cruzi 5-phenylethenylbenzofuroxans. Contribution of phase I metabolites on the mutagenicity induction. Toxicol Lett 190:140–149. https://doi.org/10.1016/j.toxlet.2009.07.006 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Guzmán Ignacio Álvarez Touron
    • 1
  1. 1.Laboratorio de Moléculas Bioactivas, CENUR Litoral NorteUniversidad de la RepúblicaPaysandúUruguay

Personalised recommendations