Phenyldihydropyrazolones as Novel Lead Compounds Against Trypanosoma cruzi

Maarten Sijm, Julianna Siciliano De Araújo, Stefan Kunz, Susanne Schroeder, Ewald Edink, Kristina M. Orrling, An Matheeussen, Tiffany Van De Meer, Payman Sadek, Hans Custers, Ignacio Cotillo, Julio J. Martin, Marco Siderius, Louis Maes, David G. Brown, Maria De Nazaré Correia Soeiro, Geert Jan Sterk, Iwan J.P. De Esch, Rob Leurs

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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 (pIC 50 = 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.

Original languageEnglish
Pages (from-to)6585-6596
Number of pages12
JournalACS Omega
Volume4
Issue number4
DOIs
Publication statusPublished - 10 Apr 2019

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Lead compounds
Phosphoric Diester Hydrolases
Pharmaceutical Preparations
Phosphodiesterase 4 Inhibitors
Enzyme inhibition
Cyclic Nucleotides
Scaffolds
Toxicity
Screening
Enzymes
Parasites

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Sijm, M., Siciliano De Araújo, J., Kunz, S., Schroeder, S., Edink, E., Orrling, K. M., ... Leurs, R. (2019). Phenyldihydropyrazolones as Novel Lead Compounds Against Trypanosoma cruzi. ACS Omega, 4(4), 6585-6596. https://doi.org/10.1021/acsomega.8b02847
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 ; Cotillo, Ignacio ; Martin, Julio J. ; Siderius, Marco ; Maes, Louis ; Brown, David G. ; De Nazaré Correia Soeiro, Maria ; Sterk, Geert Jan ; De Esch, Iwan J.P. ; Leurs, Rob. / Phenyldihydropyrazolones as Novel Lead Compounds Against Trypanosoma cruzi. In: ACS Omega. 2019 ; Vol. 4, No. 4. pp. 6585-6596.
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abstract = "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 (pIC 50 = 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.",
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Sijm, M, Siciliano De Araújo, J, Kunz, S, Schroeder, S, Edink, E, Orrling, KM, Matheeussen, A, Van De Meer, T, Sadek, P, Custers, H, Cotillo, I, Martin, JJ, Siderius, M, Maes, L, Brown, DG, De Nazaré Correia Soeiro, M, Sterk, GJ, De Esch, IJP & Leurs, R 2019, 'Phenyldihydropyrazolones as Novel Lead Compounds Against Trypanosoma cruzi' ACS Omega, vol. 4, no. 4, pp. 6585-6596. https://doi.org/10.1021/acsomega.8b02847

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; Cotillo, Ignacio; Martin, Julio J.; Siderius, Marco; Maes, Louis; Brown, David G.; De Nazaré Correia Soeiro, Maria; Sterk, Geert Jan; De Esch, Iwan J.P.; Leurs, Rob.

In: ACS Omega, Vol. 4, No. 4, 10.04.2019, p. 6585-6596.

Research output: Contribution to JournalArticleAcademicpeer-review

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AU - Edink, Ewald

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AU - Matheeussen, An

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Sijm M, Siciliano De Araújo J, Kunz S, Schroeder S, Edink E, Orrling KM et al. Phenyldihydropyrazolones as Novel Lead Compounds Against Trypanosoma cruzi. ACS Omega. 2019 Apr 10;4(4):6585-6596. https://doi.org/10.1021/acsomega.8b02847