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.
References
Dec 1, 1979·Antimicrobial Agents and Chemotherapy·R E DesjardinsJ D Chulay
Jul 13, 1990·Cell·Y ReissM S Brown
Jan 1, 1996·Annual Review of Biochemistry·F L Zhang, P J Casey
Dec 5, 1997·Acta Tropica·B RäzR Brun
Aug 27, 1998·Molecular and Biochemical Parasitology·K YokoyamaM H Gelb
Aug 22, 2000·European Journal of Biochemistry·J O'BrienF Pognan
Oct 13, 2001·The Journal of Biological Chemistry·P GrellierJ M Santana
Oct 19, 2001·The Journal of Peptide Research : Official Journal of the American Peptide Society·G HanV J Hruby
Jul 11, 2002·Molecular and Biochemical Parasitology·Frederick S BucknerKohei Yokoyama
Jan 9, 2004·Journal of Medicinal Chemistry·Junko OhkandaAndrew D Hamilton
Apr 2, 2004·Journal of Medicinal Chemistry·Jean GuillonChristian Jarry
Jan 1, 1994·Parasitology Today·H Hirumi, K Hirumi
Aug 19, 2005·Journal of Medicinal Chemistry·Oliver HuckeFrederick S Buckner
May 3, 2006·Chemical & Pharmaceutical Bulletin·Motoharu SonegawaTsuyoshi Tomiyama
Aug 9, 2008·Journal of Medicinal Chemistry·Steven FletcherAndrew D Hamilton
Jun 27, 2009·Journal of Enzyme Inhibition and Medicinal Chemistry·Laëtitia CoudrayJoëlle Dubois
Sep 24, 2009·Journal of Medicinal Chemistry·Sébastien LethuJoëlle Dubois
Mar 2, 2010·Microbes and Infection·Izabela M D BastosPhilippe Grellier
Jan 12, 2011·Antimicrobial Agents and Chemotherapy·Philippe M LoiseauDidier Desmaele
Jan 12, 2012·Journal of Enzyme Inhibition and Medicinal Chemistry·Sébastien LethuJoëlle Dubois
Jul 11, 2012·Antimicrobial Agents and Chemotherapy·Frederick S BucknerMichael H Gelb
Apr 17, 2014·Scientific Reports·Carolina B MoraesLucio H Freitas-Junior
Mar 1, 2013·MedChemComm·Joshua D Ochocki, Mark D Distefano
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