183500-37-0Relevant articles and documents
Highly improved antiparasitic activity after introduction of an N -benzylimidazole moiety on protein farnesyltransferase inhibitors
Bosc, Damien,Mouray, Elisabeth,Cojean, Sandrine,Franco, Caio Haddad,Loiseau, Philippe M.,Freitas-Junior, Lucio H.,Moraes, Carolina Borsoi,Grellier, Philippe,Dubois, Jo?lle
supporting information, p. 173 - 186 (2016/01/25)
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.
Structurally simple inhibitors of lanosterol 14α-demethylase are efficacious in a rodent model of acute Chagas disease
Suryadevara, Praveen Kumar,Olepu, Srinivas,Lockman, Jeffrey W.,Ohkanda, Junko,Karimi, Mandana,Verlinde, Christophe L. M. J.,Kraus, James M.,Schoepe, Jan,Van Voorhis, Wesley C.,Hamilton, Andrew D.,Buckner, Frederick S.,Gelb, Michael H.
experimental part, p. 3703 - 3715 (2010/04/24)
We report structure-activity studies of a large number of dialkyl imidazoles as inhibitors of Trypanosoma cruzi lanosterol-14α-demethylase (L14DM). The compounds have a simple structure compared to posaconazole, another L14DM inhibitor that is an anti-Chagas drug candidate. Several compounds display potency for killing T. cruzi amastigotes in vitro with values of EC 50 in the 0.4-10 nM range. Two compounds were selected for efficacy studies in a mouse model of acute Chagas disease. At oral doses of 20-50 mg/kg given after establishment of parasite infection, the compounds reduced parasitemia in the blood to undetectable levels, and analysis of remaining parasites by PCR revealed a lack of parasites in the majority of animals. These dialkyl imidazoles are substantially less expensive to produce than posaconazole and are appropriate for further development toward an anti-Chagas disease clinical candidate.
Novel N-(4-piperidinyl)benzamide antimalarials with mammalian protein farnesyltransferase inhibitory activity
Ryckebusch, Adina,Gilleron, Pauline,Millet, Regis,Houssin, Raymond,Lemoine, Amelie,Pommery, Nicole,Grellier, Philippe,Sergheraert, Christian,Henichart, Jean-Pierre
, p. 1324 - 1326 (2007/10/03)
Protein farnesyltransferase of Plasmodium falciparum is a potential target in the treatment of malaria for which increased drug resistance is observed. The design, synthesis and evaluation of a series of N-(4-piperidinyl)benzamides is reported. The most potent compounds showed in vitro activity against the parasite at submicromolar concentrations.