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2025-01-01
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IDENTIFICATION OF PHENYLPYRAZOLONE DIMERS AS A NEW CLASS OF ANTI-TRYPANOSOMA CRUZI AGENTS
Sijm, Maarten et al. | Date Issued: 2019
Author
Sijm, Maarten
Araújo, Julianna Siciliano de
Ramos Llorca, Alba
Orrling, Kristina
Stiny, Lydia
Matheeussen, An
Maes, Louis
de Esch, Iwan J. P.
Soeiro, Maria de Nazaré C.
Sterk, Geert Jan
Leurs, Rob
Affilliation
Vrije Universiteit Amsterdam. Amsterdam Institute for Molecules, Medicines & Systems. Division of Medicinal Chemistry. Faculty of Science. Amsterdam, The Netherlands.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Vrije Universiteit Amsterdam. Amsterdam Institute for Molecules, Medicines & Systems. Division of Medicinal Chemistry. Faculty of Science. Amsterdam, The Netherlands.
Vrije Universiteit Amsterdam. Amsterdam Institute for Molecules, Medicines & Systems. Division of Medicinal Chemistry. Faculty of Science. Amsterdam, The Netherlands.
Vrije Universiteit Amsterdam. Amsterdam Institute for Molecules, Medicines & Systems. Division of Medicinal Chemistry. Faculty of Science. Amsterdam, The Netherlands.
Universiteit Antwerpen. Laboratory for Microbiology, Parasitology and Hygiene. Antwerp, Belgium.
Universiteit Antwerpen. Laboratory for Microbiology, Parasitology and Hygiene. Antwerp, Belgium.
Vrije Universiteit Amsterdam. Amsterdam Institute for Molecules, Medicines & Systems. Division of Medicinal Chemistry. Faculty of Science. Amsterdam, The Netherlands.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Vrije Universiteit Amsterdam. Amsterdam Institute for Molecules, Medicines & Systems. Division of Medicinal Chemistry. Faculty of Science. Amsterdam, The Netherlands.
Vrije Universiteit Amsterdam. Amsterdam Institute for Molecules, Medicines & Systems. Division of Medicinal Chemistry. Faculty of Science. Amsterdam, The Netherlands.
Abstract
Chagas disease is becoming a worldwide problem; it is currently estimated that over six million people are infected. The two drugs in current use, benznidazole and nifurtimox, require long treatment regimens, show limited efficacy in the chronic phase of infection, and are known to cause adverse effects. Phenotypic screening of an in-house library led to the identification of 2,2'-methylenebis(5-(4-bromophenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one), a phenyldihydropyrazolone dimer, which shows an in vitro pIC50 value of 5.4 against Trypanosoma cruzi. Initial optimization was done by varying substituents of the phenyl ring, after which attempts were made to replace the phenyl ring. Finally, the linker between the dimer units was varied, ultimately leading to 2,2'-methylenebis(5-(3-bromo-4-methoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (NPD-0228) as the most potent analogue. NPD-0228 has an in vitro pIC50 value of 6.4 against intracellular amastigotes of T. cruzi and no apparent toxicity against the human MRC-5 cell line and murine cardiac cells.
Keywords in Portuguese
Doença de Chagas
Trypanosoma cruzi
Dímeros de fenilpirazolona
Identificação
Agentes anti-Trypanosoma cruzi
 
Keywords
Phenylpyrazolone Dimers
Identification
Anti-Trypanosoma cruzi Agents
New Class
 
Publisher
Wiley
Citation
SJIM, Maarten et al. Identification of Phenylpyrazolone Dimers as a New Class of Anti-Trypanosoma cruzi Agents. ChemMedChem, v. 14, p. 1662-1668, 2019.
DOI
10.1002/cmdc.201900370
ISSN
1860-7179