Efficacy of Novel Pyrazolone Phosphodiesterase Inhibitors in Experimental Mouse Models of Trypanosoma cruzi

Julianna Siciliano de Araújo, Cristiane França da Silva, Denise da Gama Jaén Batista, Aline Nefertiti, Ludmila Ferreira de Almeida Fiuza, Cristina Rosa Fonseca-Berzal, Patrícia Bernardino da Silva, Marcos Meuser Batista, Maarten Sijm, Titilola D. Kalejaiye, Harry P. de Koning, Louis Maes, Geert Jan Sterk, Rob Leurs, Maria de Nazaré Correia Soeiro

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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 μM 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.

Original languageEnglish
Article numbere00414-20
Pages (from-to)1-11
Number of pages11
JournalAntimicrobial agents and chemotherapy
Volume64
Issue number9
DOIs
Publication statusPublished - 20 Aug 2020

Funding

This work was supported by grants from Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Conselho Nacional de Desenvolvi-mento Científico e Tecnológico (CNPq), and Fundação Oswaldo Cruz. M.N.C.S. is a research fellow of CNPq and Cientista do Nosso Estado (CNE). The PDE4NPD project is supported by the European Union 7th Framework Program (FP7/2007-2013) under the grant agreement 602666. The funders had no role in the study design, data collection and interpretation, or the decision to submit the work for publication. We thank the Program for Technological Development in Tools for Health-PDTISFIOCRUZ for use of its facilities and David W. Boykin (Department of Chemistry, Georgia State University, Atlanta, Georgia) for the synthesis of positive controls (the amidine derivatives DB569 and DB745) used in this study. This work was supported by grants from Funda??o Carlos Chagas Filho de Amparo ? Pesquisa do Estado do Rio de Janeiro (FAPERJ), Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (CNPq), and Funda??o Oswaldo Cruz. M.N.C.S. is a research fellow of CNPq and Cientista do Nosso Estado (CNE). The PDE4NPD project is supported by the European Union 7th Framework Program (FP7/2007-2013) under the grant agreement 602666. The funders had no role in the study design, data collection and interpretation, or the decision to submit the work for publication.

FundersFunder number
Cientista do Nosso Estado
Conselho Nacional de Desenvolvi-mento Científico e Tecnológico
Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico
European Union 7th Framework Program
FP7/2007
Funda??
Seventh Framework Programme602666
Conselho Nacional de Desenvolvimento Científico e Tecnológico
Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro
Fundação Oswaldo Cruz
Universidade do Estado do Rio de Janeiro

    Keywords

    • Chagas disease
    • experimental chemotherapy
    • phosphodiesterase inhibitors
    • pyrazolone derivatives
    • Trypanosoma cruzi

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