Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/35450
Title: Phenyldihydropyrazolones as Novel Lead Compounds Against Trypanosoma cruzi
Authors: Sijm, Maarten
Araújo, Julianna Siciliano de
Kunz, Stefan
Schroeder, Susane
Edink, Ewald
Orrling, Kristina M.
Matheeussen, An
van de Meer, Tiffany
Sadek, Payman
Custers, Hans
Cotillo, Ignacio
Martin, Julio J.
Siderius, Marco
Maes, Louis
Brown, David G.
Soeiro, Maria Nazaré C.
Sterk, GeertJan
Esch, Iwan J. P. de
Leurs, Rob
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.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
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.
University of Kent. School of Biosciences. Canteburry, U.K.
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.
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.
University of Antwerp. Laboratory for Microbiology, Parasitology and Hygiene. Antwerpen, Belgium.
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.
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.
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.
GlaxoSmithKline. Diseases of the Developing World. Tres Cantos, Madrid, Spain.
GlaxoSmithKline. Diseases of the Developing World. Tres Cantos, Madrid, Spain.
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.
University of Antwerp. Laboratory for Microbiology, Parasitology and Hygiene. Antwerpen, Belgium.
University of Kent. School of Biosciences. Canteburry, U.K.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
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.
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.
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.
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.
Keywords: Trypanosoma cruzi
Phenyldihydropyrazolones
Novel Lead Compounds
keywords: Trypanosoma cruzi
Fenildiidropirazolonas
Novos compostos de chumbo
Terapia
Issue Date: 2019
Publisher: American Chemical Society
Citation: SIJM, Maarten et al. Phenyldihydropyrazolones as Novel Lead Compounds Against Trypanosoma cruzi. ACS Omega, v. 4, p. 6585-6596, 2019.
DOI: 10.1021/acsomega.8b02847
ISSN: 2470-1343
Copyright: open access
Appears in Collections:IOC - Artigos de Periódicos

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