title: Highly improved antiparasitic activity after introduction of an N-benzylimidazole moiety on protein farnesyltransferase inhibitors.
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.
authors.affiliation: CNRS UPR2301, Institut de Chimie des Substances Naturelles, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Bosc
authors.affiliation: 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.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mouray
authors.affiliation: Univ Paris-Sud, CNRS, BioCIS-UMR 8076, Chimiothérapie Antiparasitaire, LabEx LERMIT, Faculté de Pharmacie, 5 Rue J.-B. Clément, Châtenay-Malabry, F-92296, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Cojean
authors.affiliation: 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.
authors.forename: Caio Haddad
authors.initials: CH
authors.lastname: Franco
authors.affiliation: Univ Paris-Sud, CNRS, BioCIS-UMR 8076, Chimiothérapie Antiparasitaire, LabEx LERMIT, Faculté de Pharmacie, 5 Rue J.-B. Clément, Châtenay-Malabry, F-92296, France.
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Loiseau
authors.affiliation: 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.
authors.forename: Lucio H
authors.initials: LH
authors.lastname: Freitas-Junior
authors.affiliation: 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.
authors.forename: Carolina Borsoi
authors.initials: CB
authors.lastname: Moraes
authors.affiliation: 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.
authors.forename: Philippe
authors.initials: P
authors.lastname: Grellier
authors.affiliation: CNRS UPR2301, Institut de Chimie des Substances Naturelles, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France. Electronic address: joelle.dubois@cnrs.fr.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Dubois
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007893:Leishmania donovani / Q000187:drug effects / Q000201:enzymology*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy; D016778:Malaria, Falciparum / Q000188:drug therapy; D051379:Mice; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D014345:Trypanosoma / Q000187:drug effects / Q000201:enzymology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology; D014352:Trypanosomiasis / Q000188:drug therapy
chemical_list: D000977:Antiparasitic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; C017062:1-benzylimidazole; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase
keywords: Arylthiophene; Leishmania; Malaria; Protozoan parasites; Trypanosoma