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

European Journal of Medicinal Chemistry
Damien BoscJoëlle Dubois

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.

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Citations

Aug 23, 2016·Journal of Medicinal Chemistry·Stephanie RussellMatthew J Piggott
Sep 15, 2017·Organic & Biomolecular Chemistry·Germain HomerinAlina Ghinet
May 15, 2020·Cellular Microbiology·Sandrine CojeanVanessa Lievin-Le Moal
Jul 30, 2020·PLoS Neglected Tropical Diseases·Sandrine CojeanVanessa Lievin-Le Moal
May 22, 2019·Tropical Medicine and Infectious Disease·Caio Haddad FrancoCarolina Borsoi Moraes
May 22, 2020·ACS Medicinal Chemistry Letters·Dionissia A PepeConstantinos M Athanassopoulos

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