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Phenyldihydropyrazolones as Novel Lead Compounds Against Trypanosoma cruzi

Sijm, Maarten, Siciliano de Araújo, Julianna, Kunz, Stefan, Schroeder, Susanne, Edink, Ewald, Orrling, Kristina M., Matheeussen, An, van de Meer, Tiffany, Sadek, Payman, Custers, Hans, and others. (2019) Phenyldihydropyrazolones as Novel Lead Compounds Against Trypanosoma cruzi. ACS Omega, 4 (4). pp. 6585-6596. ISSN 2470-1343. (doi:10.1021/acsomega.8b02847) (KAR id:73804)


As over 6 million people are infected with Chagas disease and only limited therapeutic options are available, there is an urgent need for novel drugs. The involvement of cyclic nucleotide phosphodiesterases (PDE) in the lifecycle and biological fitness of a number of protozoan parasites has been described and several of these enzymes are thought to be viable drug targets. Within this context, a PDE-focused library was screened for its ability to affect the viability of Trypanosoma cruzi parasites. 5-(3-(Benzyloxy)-4-methoxyphenyl)-2-isopropyl-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (4), previously reported as a human PDE4 inhibitor, was identified as a hit. Upon optimization on three positions of the phenylpyrazolone scaffold, 2-isopropyl-5-(4-methoxy-3-(pyridin-3-yl)phenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (34) proved to be the most active compound against intracellular forms of T. cruzi (pIC50 = 6.4) with a 100-fold selectivity with respect to toxicity toward human MRC-5 cells. Evaluation on different life stages and clinically relevant T. cruzi strains revealed that the phenylpyrazolones are not active against the bloodstream form of the Y strain but show submicromolar activity against the intracellular form of the Y- and Tulahuen strains as well as against the nitro-drug-resistant Colombiana strain. In vitro screening of phenylpyrazolones against TcrPDEB1, TcrPDEC, and TcrCYP51 showed that there was a poor correlation between enzyme inhibition and the observed phenotypic effect. Among the most potent compounds, both TcrCYP51 and non-TcrCYP51 inhibitors are identified, which were both equally able to inhibit T. cruzi in vitro.

Item Type: Article
DOI/Identification number: 10.1021/acsomega.8b02847
Divisions: Divisions > Division of Natural Sciences > Biosciences
Depositing User: David Brown
Date Deposited: 08 May 2019 15:09 UTC
Last Modified: 04 Mar 2024 19:45 UTC
Resource URI: (The current URI for this page, for reference purposes)

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