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Experimental Therapeutics

Tetrahydrophthalazinone Inhibitor of Phosphodiesterase with In Vitro Activity against Intracellular Trypanosomatids

Julianna Siciliano de Araújo, Raiza Brandão Peres, Patrícia Bernardino da Silva, Marcos Meuser Batista, Geert Jan Sterk, Louis Maes, Guy Caljon, Rob Leurs, Harry P. de Koning, Titilola D. Kalejaiye, Maria de Nazaré Correia Soeiro
Julianna Siciliano de Araújo
aLaboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
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Raiza Brandão Peres
aLaboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
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Patrícia Bernardino da Silva
aLaboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
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Marcos Meuser Batista
aLaboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
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Geert Jan Sterk
bDivision of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Louis Maes
cLaboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Antwerp, Belgium
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Guy Caljon
cLaboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Antwerp, Belgium
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  • ORCID record for Guy Caljon
Rob Leurs
bDivision of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Harry P. de Koning
dInstitute of Infection, Immunity & Inflammation, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, United Kingdom
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Titilola D. Kalejaiye
dInstitute of Infection, Immunity & Inflammation, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, United Kingdom
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Maria de Nazaré Correia Soeiro
aLaboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
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  • ORCID record for Maria de Nazaré Correia Soeiro
DOI: 10.1128/AAC.00960-20
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ABSTRACT

The phosphodiesterase inhibitor tetrahydrophthalazinone NPD-008 was explored by phenotypic in vitro screening, target validation, and ultrastructural approaches against Trypanosoma cruzi. NPD-008 displayed activity against different forms and strains of T. cruzi (50% effective concentration [EC50], 6.6 to 39.5 μM). NPD-008 increased cAMP levels of T. cruzi and its combination with benznidazole gave synergistic interaction. It was also moderately active against intracellular amastigotes of Leishmania amazonensis and Leishmania infantum, confirming a potential activity profile as an antitrypanosomatid drug candidate.

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Tetrahydrophthalazinone Inhibitor of Phosphodiesterase with In Vitro Activity against Intracellular Trypanosomatids
Julianna Siciliano de Araújo, Raiza Brandão Peres, Patrícia Bernardino da Silva, Marcos Meuser Batista, Geert Jan Sterk, Louis Maes, Guy Caljon, Rob Leurs, Harry P. de Koning, Titilola D. Kalejaiye, Maria de Nazaré Correia Soeiro
Antimicrobial Agents and Chemotherapy Feb 2021, 65 (3) e00960-20; DOI: 10.1128/AAC.00960-20

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Tetrahydrophthalazinone Inhibitor of Phosphodiesterase with In Vitro Activity against Intracellular Trypanosomatids
Julianna Siciliano de Araújo, Raiza Brandão Peres, Patrícia Bernardino da Silva, Marcos Meuser Batista, Geert Jan Sterk, Louis Maes, Guy Caljon, Rob Leurs, Harry P. de Koning, Titilola D. Kalejaiye, Maria de Nazaré Correia Soeiro
Antimicrobial Agents and Chemotherapy Feb 2021, 65 (3) e00960-20; DOI: 10.1128/AAC.00960-20
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KEYWORDS

L. amazonensis
L. infantum
T. cruzi
cAMP
in vitro activity
phosphodiesterase inhibitor

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