Bioguided Design of Trypanosomicidal Compounds: A Successful Strategy in Drug Discovery
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 wordsTargeted and phenotypic screening Toxicology Oral formulations Preclinical studies Trypanosomiasis Bioguided design
This work was supported by CSIC I+D 2016 grant #435.
- 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
- 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
- 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
- 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
- 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
- 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