2. Academic Validation
  3. Highly improved antiparasitic activity after introduction of an N-benzylimidazole moiety on protein farnesyltransferase inhibitors

Highly improved antiparasitic activity after introduction of an N-benzylimidazole moiety on protein farnesyltransferase inhibitors

  • Eur J Med Chem. 2016 Feb 15:109:173-86. doi: 10.1016/j.ejmech.2015.12.045.
Damien Bosc 1,  Elisabeth Mouray 2,  Sandrine Cojean 3,  Caio Haddad Franco 4,  Philippe M Loiseau 3,  Lucio H Freitas-Junior 4,  Carolina Borsoi Moraes 4,  Philippe Grellier 2,  Joëlle Dubois 5
Affiliations

Affiliations

  • 1 CNRS UPR2301, Institut de Chimie des Substances Naturelles, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France.
  • 2 Unité Molécules de Communication et Adaptation des Microorganismes (MCAM, UMR 7245), Muséum National d'Histoire Naturelle, Sorbonne Universités, CNRS, CP52, 57 Rue Cuvier, 75005 Paris, France.
  • 3 Univ Paris-Sud, CNRS, BioCIS-UMR 8076, Chimiothérapie Antiparasitaire, LabEx LERMIT, Faculté de Pharmacie, 5 Rue J.-B. Clément, Châtenay-Malabry, F-92296, France.
  • 4 Chemical Biology and Screening Platform, National Laboratory of Biosciences, National Center for Research on Energy and Materials, Rua Giuseppe Maximo Scolfaro, 10000, Campinas, SP 13083-100, Brazil.
  • 5 CNRS UPR2301, Institut de Chimie des Substances Naturelles, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France. Electronic address: joelle.dubois@cnrs.fr.
PMID: 26774924 DOI: 10.1016/j.ejmech.2015.12.045
Abstract

In our search for new protein farnesyltransferase inhibitors with improved antiparasitic activities, we modified our previously developed 3-arylthiophene series of inhibitors by replacing the thioisopropyl group by different substituted imidazolylmethanamino moieties. Twenty four new derivatives were synthesized and evaluated against human and Parasite farnesyltransferases, and their Anti-parasitic activity was determined against Plasmodium falciparum, Trypanosoma brucei, Trypanosoma cruzi, and Leishmania donovani. Introduction of a N-p-substituted-benzylimidazole led to significantly increase the inhibition of Parasite proliferation in the submicromolar range. The structure of the best inhibitors was Parasite dependent. Three compounds possess IC50 values at the same range as the reference miltefosine against L. donovani proliferation and Other new derivatives display high level of anti-trypanosomal activity against T. cruzi, higher or in the same order of magnitude as the reference compounds benznidazole and nifurtimox.

Keywords

Arylthiophene; Leishmania; Malaria; Protozoan parasites; Trypanosoma.

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