Identification of Phenylpyrazolone Dimers as a New Class of Anti-Trypanosoma cruzi Agents

Maarten Sijm, Julianna Siciliano de Araújo, Alba Ramos Llorca, Kristina Orrling, Lydia Stiny, An Matheeussen, Louis Maes, Iwan J.P. de Esch, Maria de Nazaré Correia Soeiro, Geert Jan Sterk, Rob Leurs*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)1662-1668
Number of pages7
JournalChemMedChem
Volume14
Issue number18
DOIs
Publication statusPublished - 1 Jan 2019

Keywords

  • benznidazole
  • Chagas disease
  • nifurtimox
  • phenotypic screening
  • Trypanosoma cruzi

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    Sijm, M., Siciliano de Araújo, J., Ramos Llorca, A., Orrling, K., Stiny, L., Matheeussen, A., ... Leurs, R. (2019). Identification of Phenylpyrazolone Dimers as a New Class of Anti-Trypanosoma cruzi Agents. ChemMedChem, 14(18), 1662-1668. https://doi.org/10.1002/cmdc.201900370