Phenyldihydropyrazolones as Novel Lead Compounds Against Trypanosoma cruzi
| Autor: | Julianna Siciliano de Araújo, Louis Maes, Maria de Nazaré Correia Soeiro, Ignacio Cotillo, Iwan J. P. de Esch, Payman Sadek, Geert Jan Sterk, Stefan Kunz, Julio Martin, An Matheeussen, David G. Brown, Kristina M. Orrling, Marco Siderius, Ewald Edink, Susanne Schroeder, Hans Custers, Rob Leurs, Tiffany van de Meer, Maarten Sijm |
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| Přispěvatelé: | Medicinal chemistry, AIMMS, Chemistry and Pharmaceutical Sciences |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Chagas disease
0303 health sciences biology 030306 microbiology General Chemical Engineering General Chemistry biology.organism_classification medicine.disease Virology 3. Good health lcsh:Chemistry 03 medical and health sciences Cyclic nucleotide chemistry.chemical_compound Chemistry chemistry SDG 3 - Good Health and Well-being lcsh:QD1-999 medicine Human medicine Trypanosoma cruzi Biology 030304 developmental biology |
| Zdroj: | ACS Omega, Vol 4, Iss 4, Pp 6585-6596 (2019) 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, vol. 4, no. 4, pp. 6585-6596 . https://doi.org/10.1021/acsomega.8b02847 ACS Omega, 4(4), 6585-6596. American Chemical Society ACS Omega |
| ISSN: | 2470-1343 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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