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Structure‐Activity Relationship of Phenylpyrazolones against Trypanosoma cruzi
Author(s) -
Sijm Maarten,
Sterk Geert Jan,
Caljon Guy,
Maes Louis,
Esch Iwan J. P.,
Leurs Rob
Publication year - 2020
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.202000136
Subject(s) - substituent , trypanosoma cruzi , oxazole , pyrazolone , chemistry , moiety , stereochemistry , structure–activity relationship , isopropyl , combinatorial chemistry , medicinal chemistry , biochemistry , in vitro , parasite hosting , world wide web , computer science
Chagas disease is a neglected parasitic disease caused by the parasitic protozoan Trypanosoma cruzi and currently affects around 8 million people. Previously, 2‐isopropyl‐5‐(4‐methoxy‐3‐(pyridin‐3‐yl)phenyl)‐4,4‐dimethyl‐2,4‐dihydro‐3 H ‐pyrazol‐3‐one (NPD‐0227) was discovered to be a sub‐micromolar inhibitor (pIC 50 =6.4) of T. cruzi . So far, SAR investigations of this scaffold have focused on the alkoxy substituent, the pyrazolone nitrogen substituent and the aromatic substituent of the core phenylpyrazolone. In this study, modifications of the phenyldihydropyrazolone scaffold are described. Variations were introduced by installing different substituents on the phenyl core, modifying the geminal dimethyl and installing various bio‐isosteres of the dihydropyrazolone group. The anti T. cruzi activity of NPD‐0227 could not be surpassed as the most potent compounds show pIC 50 values of around 6.3. However, valuable additional SAR data for this interesting scaffold was obtained, and the data suggest that a scaffold hop is feasible as the pyrazolone moiety can be replaced by a oxazole or oxadiazole with minimal loss of activity.