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Identification of Phenylpyrazolone Dimers as a New Class of Anti‐ Trypanosoma cruzi Agents
Author(s) -
Sijm Maarten,
Siciliano de Araújo Julianna,
Ramos Llorca Alba,
Orrling Kristina,
Stiny Lydia,
Matheeussen An,
Maes Louis,
Esch Iwan J. P.,
Nazaré Correia Soeiro Maria,
Sterk Geert Jan,
Leurs Rob
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900370
Subject(s) - benznidazole , trypanosoma cruzi , nifurtimox , amastigote , chagas disease , dimer , intracellular , in vitro , pharmacology , chemistry , biology , stereochemistry , virology , biochemistry , parasite hosting , world wide web , computer science , leishmania , organic chemistry
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‐3 H ‐pyrazol‐3‐one), a phenyldihydropyrazolone dimer, which shows an in vitro pIC 50 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‐3 H ‐pyrazol‐3‐one (NPD‐0228) as the most potent analogue. NPD‐0228 has an in vitro pIC 50 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.