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 | |
| Publication status | Published - 10 Apr 2019 |
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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; 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 Journal › Article › Academic › peer-review
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
M3 - Article
VL - 4
SP - 6585
EP - 6596
JO - ACS Omega
JF - ACS Omega
SN - 2470-1343
IS - 4
ER -