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.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
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
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
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
Barrett MP, Mottram JC, Coombs GH (1999) Recent advances in identifying and validating drug targets in trypanosomes and leishmanias. Trends Microbiol 7:82–88
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
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
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
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
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
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
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
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
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
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
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
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
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
Schmid W (1975) The micronucleus test. Mutat Res Mutagen Relat Subj 31:9–15. https://doi.org/10.1016/0165-1161(75)90058-8
Mortelmans K, Zeiger E (2000) The Ames Salmonella/microsome mutagenicity assay. Mutat Res 455:29–60
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
Acknowledgments
This work was supported by CSIC I+D 2016 grant #435.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Álvarez Touron, G.I. (2018). Bioguided Design of Trypanosomicidal Compounds: A Successful Strategy in Drug Discovery. In: Mavromoustakos, T., Kellici, T. (eds) Rational Drug Design. Methods in Molecular Biology, vol 1824. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8630-9_8
Download citation
DOI: https://doi.org/10.1007/978-1-4939-8630-9_8
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-8629-3
Online ISBN: 978-1-4939-8630-9
eBook Packages: Springer Protocols