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 language | English |
---|---|
Article number | e00414-20 |
Pages (from-to) | 1-11 |
Number of pages | 11 |
Journal | Antimicrobial agents and chemotherapy |
Volume | 64 |
Issue number | 9 |
DOIs | |
Publication status | Published - 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.
Funders | Funder 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 Programme | 602666 |
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