Methoxylated 2'-hydroxychalcones as antiparasitic hit compounds

  • Eur J Med Chem. 2017 Jan 27:126:1129-1135. doi: 10.1016/j.ejmech.2016.12.017.
Chiara Borsari  1 ,  Nuno Santarem  2 ,  Juan Torrado  3 ,  Ana Isabel Olías  4 ,  María Jesús Corral  4 ,  Catarina Baptista  2 ,  Sheraz Gul  5 ,  Markus Wolf  5 ,  Maria Kuzikov  5 ,  Bernhard Ellinger  5 ,  Gesa Witt  6 ,  Philip Gribbon  7 ,  Jeanette Reinshagen  5 ,  Pasquale Linciano  1 ,  Annalisa Tait  1 ,  Luca Costantino  1 ,  Lucio H Freitas-Junior  8 ,  Carolina B Moraes  8 ,  Pascoalino Bruno Dos Santos  8 ,  Laura Maria Alcântara  8 ,  Caio Haddad Franco  8 ,  Claudia Danielli Bertolacini  8 ,  Vanessa Fontana  8 ,  Paloma Tejera Nevado  9 ,  Joachim Clos  9 ,  José María Alunda  4 ,  Anabela Cordeiro-da-Silva  2 ,  Stefania Ferrari  1 ,  Maria Paola Costi  10
Affiliations
  • 1. University of Modena and Reggio Emilia, Via Campi 103, 41125, Modena, Italy.
  • 2. Institute for Molecular and Cell Biology, 4150-180 Porto, Portugal and Instituto de Investigação e Inovação em Saúde, Universidade do Porto and Institute for Molecular and Cell Biology, 4150-180, Porto, Portugal.
  • 3. Complutense University of Madrid, 28040, Madrid, Spain.
  • 4. Complutense University of Madrid, 28040, Madrid, Spain; Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain.
  • 5. Fraunhofer Institute for Molecular Biology and Applied Ecology Screening Port, Hamburg, Germany.
  • 6. Fraunhofer Institute for Molecular Biology and Applied Ecology Screening Port, Hamburg, Germany. Electronic address: [email protected].
  • 7. Fraunhofer Institute for Molecular Biology and Applied Ecology Screening Port, Hamburg, Germany. Electronic address: [email protected].
  • 8. Brazilian Centre for Research in Energy and Materials, Campinas, Brazil.
  • 9. Bernhard Nocht Institute for Tropical Medicine, D-20359, Hamburg, Germany.
  • 10. University of Modena and Reggio Emilia, Via Campi 103, 41125, Modena, Italy. Electronic address: [email protected].
PMID: 28064141 DOI: 10.1016/j.ejmech.2016.12.017
Abstract

Chalcones display a broad spectrum of pharmacological activities. Herein, a series of 2'-hydroxy methoxylated Chalcones was synthesized and evaluated towards Trypanosoma brucei, Trypanosoma cruzi and Leishmania infantum. Among the synthesized library, compounds 1, 3, 4, 7 and 8 were the most potent and selective anti-T. brucei compounds (EC50 = 1.3-4.2 μM, selectivity index >10-fold). Compound 4 showed the best early-tox and antiparasitic profile. The pharmacokinetic studies of compound 4 in BALB/c mice using hydroxypropil-β-cyclodextrins formulation showed a 7.5 times increase in oral bioavailability.

Keywords
Chalcones; Cyclodextrins formulation; Early toxicity studies; Leishmania infantum; Trypanosoma brucei; Trypanosoma cruzi.