Efficacy of novel pyrazolone phosphodiesterase inhibitors in experimental mouse models of Trypanosoma cruzi

de Araújo, J. S. et al. (2020) Efficacy of novel pyrazolone phosphodiesterase inhibitors in experimental mouse models of Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy, 64(9), e00414-20. (doi: 10.1128/AAC.00414-20) (PMID:32601163) (PMCID:PMC7449165)

Full text not currently available from Enlighten.


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.

Item Type:Articles
Additional Information: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 Desenvolvimento 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.
Glasgow Author(s) Enlighten ID:Kalejaiye, Miss Titilola and De Koning, Professor Harry
Authors: de Araújo, J. S., da Silva, C. F., Batista, D. d. G. J., Nefertiti, A., Fiuza, L. F. d. A., Fonseca-Berzal, C. R., da Silva, P. B., Batista, M. M., Sijm, M., Kalejaiye, T. D., De Koning, H. P., Maes, L., Sterk, G. J., Leurs, R., and Soeiro, M. d. N. C.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Antimicrobial Agents and Chemotherapy
Publisher:American Society for Microbiology
ISSN (Online):1098-6596
Published Online:29 June 2020

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
169936PDE4NTD: Phosphodieasease inhibitors for the treatment of Neglected Parasitic Diseases.Harry De KoningEuropean Commission (EC)602666III - Parasitology