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

doi:10.1021/acsomega.8b02847

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^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-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 language	English
Pages (from-to)	6585-6596
Number of pages	12
Journal	ACS Omega
Volume	4
Issue number	4
DOIs	https://doi.org/10.1021/acsomega.8b02847
Publication status	Published - 10 Apr 2019

Funding

*E-mail: [email protected] (R.L.). ORCID Rob Leurs: 0000-0003-1354-2848 Author Contributions Performing experimental work: Maarten Sijm, K.M.O., J.S.d.A., S.S., A.M., T.v.d.M., P.S., H.C., and I.C.; writing manuscript: M.S., M.d.N.C.S, R.L.; experimental design: M.S., E.E., Marco Siderius, L.M., D.G.B., J.J.M., M.d.N.C.S, G.S., I.J.P.d.E., and R.L.; funding: L.M., D.G.B., M.d.N.C.S, G.S., I.J.P.d.E., and R.L.; reviewing and editing manuscript: M.S., M.d.N.C.S, G.S., and R.L. All authors have given approval to the final version of the manuscript. Funding The PDE4NPD project was funded by the European Union under the FP-7-Health program, project ID: 602666. MNCS is a researcher with the CNPq and CNE/FAPERJ. Notes The authors declare no competing financial interest.

Funders	Funder number
FP-7-Health program
Seventh Framework Programme	602666
European Commission

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Sijm, M., Siciliano De Araújo, J., Kunz, S., Schroeder, S., Edink, E., Orrling, K. M., Matheeussen, A., Van De Meer, T., Sadek, P., Custers, H., Cotillo, I., Martin, J. J., Siderius, M., Maes, L., Brown, D. G., De Nazaré Correia Soeiro, M., Sterk, G. J., De Esch, I. J. P., & Leurs, R. (2019). Phenyldihydropyrazolones as Novel Lead Compounds Against Trypanosoma cruzi. ACS Omega, 4(4), 6585-6596. https://doi.org/10.1021/acsomega.8b02847

@article{8b319efff72243ccb7cfa9bee2d8c558,

title = "Phenyldihydropyrazolones as Novel Lead Compounds Against Trypanosoma cruzi",

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. ",

author = "Maarten Sijm and {Siciliano De Ara{\'u}jo}, Julianna and Stefan Kunz and Susanne Schroeder and Ewald Edink and Orrling, {Kristina M.} and An Matheeussen and {Van De Meer}, Tiffany and Payman Sadek and Hans Custers and Ignacio Cotillo and Martin, {Julio J.} and Marco Siderius and Louis Maes and Brown, {David G.} and {De Nazar{\'e} Correia Soeiro}, Maria and Sterk, {Geert Jan} and {De Esch}, {Iwan J.P.} and Rob Leurs",

year = "2019",

month = apr,

day = "10",

doi = "10.1021/acsomega.8b02847",

language = "English",

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pages = "6585--6596",

journal = "ACS Omega",

publisher = "American Chemical Society",

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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

TY - JOUR

T1 - Phenyldihydropyrazolones as Novel Lead Compounds Against Trypanosoma cruzi

AU - Sijm, Maarten

AU - Siciliano De Araújo, Julianna

AU - Kunz, Stefan

AU - Schroeder, Susanne

AU - Edink, Ewald

AU - Orrling, Kristina M.

AU - Matheeussen, An

AU - Van De Meer, Tiffany

AU - Sadek, Payman

AU - Custers, Hans

AU - Cotillo, Ignacio

AU - Martin, Julio J.

AU - Siderius, Marco

AU - Maes, Louis

AU - Brown, David G.

AU - De Nazaré Correia Soeiro, Maria

AU - Sterk, Geert Jan

AU - De Esch, Iwan J.P.

AU - Leurs, Rob

PY - 2019/4/10

Y1 - 2019/4/10

N2 - 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.

AB - 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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U2 - 10.1021/acsomega.8b02847

DO - 10.1021/acsomega.8b02847

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EP - 6596

JO - ACS Omega

JF - ACS Omega

IS - 4

ER -

Phenyldihydropyrazolones as Novel Lead Compounds Against Trypanosoma cruzi

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UN SDGs

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