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EVALUATION OF PHTHALAZINONE PHOSPHODIESTERASE INHIBITORS WITH IMPROVED ACTIVITY AND SELECTIVITY AGAINST TRYPANOSOMA CRUZI
Araújo, Julianna Siciliano de et al. | Date Issued: 2020
Author
Araújo, Julianna Siciliano de
Silva, Patrícia Bernardino da
Batista, Marcos Meuser
Peres, Raiza Brandão
Cardoso-Santos, Camila
Kalejaiye, Titilola D.
Munday, Jane C.
De Heuvel, Erik
Sterk, Geert Jan
Augustyns, Koen
Salado, Irene G.
Matheeussen, An
De Esch, Iwan
De Koning, Harry P.
Leurs, Rob
Maes, Louis
Soeiro, Maria de Nazaré Correia
Affilliation
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
University of Glasgow. College of Medical, Veterinary & Life Sciences. Institute of Infection, Immunity & Inflammation. Glasgow, UK.
University of Glasgow. College of Medical, Veterinary & Life Sciences. Institute of Infection, Immunity & Inflammation. Glasgow, UK.
Vrije Universiteit Amsterdam. Amsterdam Institute for Molecules, Medicines & Systems. Medicinal Chemistry. Amsterdam, The Netherlands.
Vrije Universiteit Amsterdam. Amsterdam Institute for Molecules, Medicines & Systems. Medicinal Chemistry. Amsterdam, The Netherlands.
University of Antwerp. Laboratory of Medicinal Chemistry. Antwerp, Belgium.
University of Antwerp. Laboratory of Medicinal Chemistry. Antwerp, Belgium.
University of Antwerp. Laboratory for Microbiology, Parasitology and Hygiene. Antwerp, Belgium.
Vrije Universiteit Amsterdam. Amsterdam Institute for Molecules, Medicines & Systems. Medicinal Chemistry. Amsterdam, The Netherlands.
University of Glasgow. College of Medical, Veterinary & Life Sciences. Institute of Infection, Immunity & Inflammation. Glasgow, UK.
Vrije Universiteit Amsterdam. Amsterdam Institute for Molecules, Medicines & Systems. Medicinal Chemistry. Amsterdam, The Netherlands.
University of Antwerp. Laboratory for Microbiology, Parasitology and Hygiene. Antwerp, Belgium.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Abstract
Background: Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, needs urgent alternative therapeutic options as the treatments currently available display severe limitations, mainly related to efficacy and toxicity. Objectives: As phosphodiesterases (PDEs) have been claimed as novel targets against T. cruzi, our aim was to evaluate the biological aspects of 12 new phthalazinone PDE inhibitors against different T. cruzi strains and parasite forms relevant for human infection. Methods: In vitro trypanocidal activity of the inhibitors was assessed alone and in combination with benznidazole. Their effects on parasite ultrastructural and cAMP levels were determined. PDE mRNA levels from the different T. cruzi forms were measured by quantitative reverse transcription PCR. Results: Five TcrPDEs were found to be expressed in all parasite stages. Four compounds displayed strong effects against intracellular amastigotes. Against bloodstream trypomastigotes (BTs), three were at least as potent as benznidazole. In vitro combination therapy with one of the most active inhibitors on both parasite forms (NPD-040) plus benznidazole demonstrated a quite synergistic profile (xΣ FICI = 0.58) against intracellular amastigotes but no interaction (xΣ FICI = 1.27) when BTs were assayed. BTs treated with NPD-040 presented disrupted Golgi apparatus, a swollen flagellar pocket and signs of autophagy. cAMP measurements of untreated parasites showed that amastigotes have higher ability to efflux this second messenger than BTs. NPD-001 and NPD-040 increase the intracellular cAMP content in both BTs and amastigotes, which is also released into the extracellular milieu. Conclusions: The findings demonstrate the potential of PDE inhibitors as anti-T. cruzi drug candidates.
Keywords
Chagas disease
Polymerase chain reaction
Phosphodiesterase inhibitors
Blalock-taussig shunt
Benznidazole
Combined modality therapy
Golgi apparatus
Parasites
Trypanosoma cruzi
Infections
Cyclic ampcyclic amp measurement
Diethylstilbestrol monophosphate
Toxic effect
Trypomastigote form of protozoa
 
Publisher
Oxford
Citation
ARAÚJO, Julianna Siciliano de et al. Evaluation of phthalazinone phosphodiesterase inhibitors with improved activity and selectivity against Trypanosoma cruzi. Journal of Antimicrobial Chemotherapy, v. 75, n. 4, p. 958-967, Apr. 2020.
DOI
10.1093/jac/dkz516
ISSN
0305-7453
Notes
Produção científica do Laboratório de Biologia Celular.