Journal of Computer-Aided Molecular Design

, Volume 30, Issue 4, pp 305–321 | Cite as

Discovery of novel polyamine analogs with anti-protozoal activity by computer guided drug repositioning

  • Lucas N. Alberca
  • María L. Sbaraglini
  • Darío Balcazar
  • Laura Fraccaroli
  • Carolina Carrillo
  • Andrea Medeiros
  • Diego Benitez
  • Marcelo Comini
  • Alan Talevi


Chagas disease is a parasitic infection caused by the protozoa Trypanosoma cruzi that affects about 6 million people in Latin America. Despite its sanitary importance, there are currently only two drugs available for treatment: benznidazole and nifurtimox, both exhibiting serious adverse effects and limited efficacy in the chronic stage of the disease. Polyamines are ubiquitous to all living organisms where they participate in multiple basic functions such as biosynthesis of nucleic acids and proteins, proliferation and cell differentiation. T. cruzi is auxotroph for polyamines, which are taken up from the extracellular medium by efficient transporters and, to a large extent, incorporated into trypanothione (bis-glutathionylspermidine), the major redox cosubstrate of trypanosomatids. From a 268-compound database containing polyamine analogs with and without inhibitory effect on T. cruzi we have inferred classificatory models that were later applied in a virtual screening campaign to identify anti-trypanosomal compounds among drugs already used for other therapeutic indications (i.e. computer-guided drug repositioning) compiled in the DrugBank and Sweetlead databases. Five of the candidates identified with this strategy were evaluated in cellular models from different pathogenic trypanosomatids (T. cruzi wt, T. cruzi PAT12, T. brucei and Leishmania infantum), and in vitro models of aminoacid/polyamine transport assays and trypanothione synthetase inhibition assay. Triclabendazole, sertaconazole and paroxetine displayed inhibitory effects on the proliferation of T. cruzi (epimastigotes) and the uptake of putrescine by the parasite. They also interfered with the uptake of others aminoacids and the proliferation of infective T. brucei and L. infantum (promastigotes). Trypanothione synthetase was ruled out as molecular target for the anti-parasitic activity of these compounds.


Chagas disease Drug repositioning Polyamines Trypanosomatids virtual screening Paroxetine Triclabendazole 



The authors would like to thank the following public and non-profit organizations: National University of La Plata and Exact Sciences Faculty PIRPS. National University of La Plata Travel Grants and Incentivos X-730, Argentinean National Agency of Scientific and Technical Research(ANPCyT), PICT 2013-0520, CONICET. DB and MAC acknowledge the support of ANII for postgraduate fellowship (POS_NAC_2013_1_114477) and FOCEM (MERCOSUR Structural Convergence Fund, COF 03/11), respectively.

Supplementary material

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Supplementary material 1 (PDF 4013 kb)
10822_2016_9903_MOESM2_ESM.pdf (43 kb)
Supplementary material 2 (PDF 43 kb)


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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Lucas N. Alberca
    • 1
  • María L. Sbaraglini
    • 1
  • Darío Balcazar
    • 2
  • Laura Fraccaroli
    • 2
  • Carolina Carrillo
    • 2
  • Andrea Medeiros
    • 3
  • Diego Benitez
    • 3
  • Marcelo Comini
    • 3
  • Alan Talevi
    • 1
  1. 1.Laboratory of Bioactive Compounds Research and Development (LIDeB), Medicinal Chemistry, Department of Biological Science, Exact Sciences CollegeNational University of La Plata (UNLP), ArgentinaLa PlataArgentina
  2. 2.Instituto de Ciencias y Tecnología Dr. César Milstein (ICT Milstein)Argentinean National Council of Scientific and Technical Research (CONICET)Buenos AiresArgentina
  3. 3.Laboratory Redox Biology of TrypanosomesInstitut Pasteur de MontevideoMontevideoUruguay

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