| Author | Sijm, Maarten | |
| Author | Araújo, Julianna Siciliano de | |
| Author | Kunz, Stefan | |
| Author | Schroeder, Susane | |
| Author | Edink, Ewald | |
| Author | Orrling, Kristina M. | |
| Author | Matheeussen, An | |
| Author | van de Meer, Tiffany | |
| Author | Sadek, Payman | |
| Author | Custers, Hans | |
| Author | Cotillo, Ignacio | |
| Author | Martin, Julio J. | |
| Author | Siderius, Marco | |
| Author | Maes, Louis | |
| Author | Brown, David G. | |
| Author | Soeiro, Maria Nazaré C. | |
| Author | Sterk, GeertJan | |
| Author | Esch, Iwan J. P. de | |
| Author | Leurs, Rob | |
| Access date | 2019-09-10T15:04:50Z | |
| Available date | 2019-09-10T15:04:50Z | |
| Document date | 2019 | |
| Citation | SIJM, Maarten et al. Phenyldihydropyrazolones as Novel Lead Compounds Against Trypanosoma cruzi. ACS Omega, v. 4, p. 6585-6596, 2019. | pt_BR |
| ISSN | 2470-1343 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/35450 | |
| Language | eng | pt_BR |
| Publisher | American Chemical Society | pt_BR |
| Rights | open access | |
| Subject in Portuguese | Trypanosoma cruzi | pt_BR |
| Subject in Portuguese | Fenildiidropirazolonas | pt_BR |
| Subject in Portuguese | Novos compostos de chumbo | pt_BR |
| Subject in Portuguese | Terapia | pt_BR |
| Title | Phenyldihydropyrazolones as Novel Lead Compounds Against Trypanosoma cruzi | pt_BR |
| Type | Article | |
| DOI | 10.1021/acsomega.8b02847 | |
| Abstract | As over 6 million people are infected with Chagas disease and
only limited therapeutic options are available, there is an urgent need for
novel drugs. The involvement of cyclic nucleotide phosphodiesterases (PDE)
in the lifecycle and biological fitness of a number of protozoan parasites has
been described and several of these enzymes are thought to be viable drug
targets. Within this context, a PDE-focused library was screened for its ability
to affect the viability of Trypanosoma cruzi parasites. 5-(3-(Benzyloxy)-4-
methoxyphenyl)-2-isopropyl-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (4),
previously reported as a human PDE4 inhibitor, was identified as a hit. Upon
optimization on three positions of the phenylpyrazolone scaffold, 2-isopropyl-
5-(4-methoxy-3-(pyridin-3-yl)phenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-
3-one (34) proved to be the most active compound against intracellular forms
of T. cruzi (pIC50 = 6.4) with a 100-fold selectivity with respect to toxicity
toward human MRC-5 cells. Evaluation on different life stages and clinically relevant T. cruzi strains revealed that the
phenylpyrazolones are not active against the bloodstream form of the Y strain but show submicromolar activity against the
intracellular form of the Y- and Tulahuen strains as well as against the nitro-drug-resistant Colombiana strain. In vitro screening
of phenylpyrazolones against TcrPDEB1, TcrPDEC, and TcrCYP51 showed that there was a poor correlation between enzyme
inhibition and the observed phenotypic effect. Among the most potent compounds, both TcrCYP51 and non-TcrCYP51
inhibitors are identified, which were both equally able to inhibit T. cruzi in vitro. | pt_BR |
| Affilliation | Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules. Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil. | pt_BR |
| Affilliation | Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules. Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands. | pt_BR |
| Affilliation | University of Kent. School of Biosciences. Canteburry, U.K. | pt_BR |
| Affilliation | Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules. Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands. | pt_BR |
| Affilliation | Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules. Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands. | pt_BR |
| Affilliation | University of Antwerp. Laboratory for Microbiology, Parasitology and Hygiene. Antwerpen, Belgium. | pt_BR |
| Affilliation | Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules. Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands. | pt_BR |
| Affilliation | Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules. Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands. | pt_BR |
| Affilliation | Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules. Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands. | pt_BR |
| Affilliation | GlaxoSmithKline. Diseases of the Developing World. Tres Cantos, Madrid, Spain. | pt_BR |
| Affilliation | GlaxoSmithKline. Diseases of the Developing World. Tres Cantos, Madrid, Spain. | pt_BR |
| Affilliation | Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules. Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands. | pt_BR |
| Affilliation | University of Antwerp. Laboratory for Microbiology, Parasitology and Hygiene. Antwerpen, Belgium. | pt_BR |
| Affilliation | University of Kent. School of Biosciences. Canteburry, U.K. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil. | pt_BR |
| Affilliation | Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules. Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands. | pt_BR |
| Affilliation | Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules. Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands. | pt_BR |
| Affilliation | Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules. Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands. | pt_BR |
| Subject | Trypanosoma cruzi | pt_BR |
| Subject | Phenyldihydropyrazolones | pt_BR |
| Subject | Novel Lead Compounds | pt_BR |
