Article
Phenyldihydropyrazolones as Novel Lead Compounds Against Trypanosoma cruzi
Registro en:
SIJM, Maarten et al. Phenyldihydropyrazolones as Novel Lead Compounds Against Trypanosoma cruzi. ACS Omega, v. 4, p. 6585-6596, 2019.
2470-1343
10.1021/acsomega.8b02847
Autor
Sijm, Maarten
Araújo, Julianna Siciliano de
Kunz, Stefan
Schroeder, Susane
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.
Soeiro, Maria Nazaré C.
Sterk, GeertJan
Esch, Iwan J. P. de
Leurs, Rob
Resumen
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.