| Author | Araújo, Julianna Siciliano de | |
| Author | Silva, Cristiane França da | |
| Author | Batista, Denise da Gama Jaén | |
| Author | Nefertiti, Aline | |
| Author | Fiuza, Ludmila Ferreira de Almeida | |
| Author | Fonseca-Berzal, Cristina Rosa | |
| Author | Silva, Patrícia Bernardino da | |
| Author | Batista, Marcos Meuser | |
| Author | Sijm, Maarten | |
| Author | Kalejaiye, Titilola D. | |
| Author | Koning, Harry P. de | |
| Author | Maes, Louis | |
| Author | Sterk, Geert Jan | |
| Author | Leurs, Rob | |
| Author | Soeiro, Maria de Nazaré Correia | |
| Access date | 2021-01-25T20:10:37Z | |
| Available date | 2021-01-25T20:10:37Z | |
| Document date | 2020 | |
| Citation | ARAÚJO, Juliana Siciliano de et al. Efficacy of Novel Pyrazolone Phosphodiesterase Inhibitors in Experimental Mouse Models of Trypanosoma cruzi, Antimicrobial Agents and Chemotherapy, v. 64, n. 9, p. 1-11, Sept. 2020. | pt_BR |
| ISSN | 0066-4804 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/45810 | |
| Language | eng | pt_BR |
| Publisher | American Society for Microbiology | pt_BR |
| Rights | restricted access | |
| Subject in Portuguese | Doença de Chagas | pt_BR |
| Subject in Portuguese | Trypanosoma cruzi | pt_BR |
| Subject in Portuguese | Quimioterapia experimental | pt_BR |
| Subject in Portuguese | Inibidores de fosfodiesterase | pt_BR |
| Subject in Portuguese | Derivados de pirazolona | pt_BR |
| Title | Efficacy of Novel Pyrazolone Phosphodiesterase Inhibitors in Experimental Mouse Models of Trypanosoma cruzi | pt_BR |
| Type | Article | |
| DOI | 10.1128/AAC.00414-20 | |
| Abstract | Pyrazolones are heterocyclic compounds with interesting biological properties. Some derivatives inhibit phosphodiesterases (PDEs) and thereby increase the cellular concentration of cyclic AMP (cAMP), which plays a vital role in the control of metabolism in eukaryotic cells, including the protozoan Trypanosoma cruzi, the etiological agent of Chagas disease (CD), a major neglected tropical disease. In vitro phenotypic screening identified a 4-bromophenyl-dihydropyrazole dimer as an anti-T. cruzi hit and 17 novel pyrazolone analogues with variations on the phenyl ring were investigated in a panel of phenotypic laboratory models. Potent activity against the intracellular forms (Tulahuen and Y strains) was obtained with 50% effective concentration (EC50) values within the 0.17 to 3.3 M range. Although most were not active against bloodstream trypomastigotes, an altered morphology and loss of infectivity were observed. Pretreatment of the mammalian host cells with pyrazolones did not interfere with infection and proliferation, showing that the drug activity was not the result of changes to host cell metabolism. The pyrazolone NPD- 227 increased the intracellular cAMP levels and was able to sterilize T. cruzi-infected cell cultures. Thus, due to its high potency and selectivity in vitro, and its additive interaction with benznidazole (Bz), NPD-227 was next assessed in the acute mouse model. Oral dosing for 5 days of NPD-227 at 10 mg/kg Bz at 10 mg/kg not only reduced parasitemia ( 87%) but also protected against mortality ( 83% survival), hence demonstrating superiority to the monotherapy schemes. These data support these pyrazolone molecules as potential novel therapeutic alternatives for Chagas disease. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil / Universidad Complutense de Madrid. Facultad de Farmacia. Departamento de Parasitología,. Madrid, Spain. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | 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, VU University Amsterdam. Amsterdam, The Netherlands. | pt_BR |
| Affilliation | Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow. Glasgow, United Kingdom. | pt_BR |
| Affilliation | Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow. Glasgow, United Kingdom. | pt_BR |
| Affilliation | Laboratory for Microbiology, Parasitology and Hygiene, University of Antwerp. Antwerp, Belgium. | pt_BR |
| Affilliation | Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems, VU University Amsterdam. Amsterdam, The Netherlands. | pt_BR |
| Affilliation | Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems, VU University Amsterdam. Amsterdam, The Netherlands. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Subject | Chagas disease | pt_BR |
| Subject | Trypanosoma cruzi | pt_BR |
| Subject | Experimental chemotherapy | pt_BR |
| Subject | Phosphodiesterase inhibitors | pt_BR |
| Subject | Pyrazolone derivatives | pt_BR |
| e-ISSN | 1098-6596 | |
| xmlui.metadata.dc.subject.ods | 03 Saúde e Bem-Estar | |
