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 Online-Ressource | |
| Verfasst von: | Borsari, Chiara [VerfasserIn]  |
| Wade, Rebecca C. [VerfasserIn] | |
| Titel: | Profiling of flavonol derivatives for the development of antitrypanosomatidic drugs |
| Verf.angabe: | Chiara Borsari, Rosaria Luciani, Cecilia Pozzi, Ina Poehner, Stefan Henrich, Matteo Trande, Anabela Cordeiro-da-Silva, Nuno Santarem, Catarina Baptista, Annalisa Tait, Flavio Di Pisa, Lucia Dello Iacono, Giacomo Landi, Sheraz Gul, Markus Wolf, Maria Kuzikov, Bernhard Ellinger, Jeanette Reinshagen, Gesa Witt, Philip Gribbon, Manfred Kohler, Oliver Keminer, Birte Behrens, Luca Costantino, Paloma Tejera Nevado, Eugenia Bifeld, Julia Eick, Joachim Clos, Juan Torrado, María D. Jiménez-Antón, María J. Corral, José Ma Alunda, Federica Pellati, Rebecca C. Wade, Stefania Ferrari, Stefano Mangani, and Maria Paola Costi |
| E-Jahr: | 2016 |
| Jahr: | July 14, 2016 |
| Umfang: | 19 S. |
| Fussnoten: | Gesehen am 14.05.2020 |
| Titel Quelle: | Enthalten in: Journal of medicinal chemistry |
| Ort Quelle: | Washington, DC : ACS, 1959 |
| Jahr Quelle: | 2016 |
| Band/Heft Quelle: | 59(2016), 16, Seite 7598-7616 |
| ISSN Quelle: | 1520-4804 |
| Abstract: | Flavonoids represent a potential source of new antitrypanosomatidic leads. Starting from a library of natural products, we combined target-based screening on pteridine reductase 1 with phenotypic screening on Trypanosoma brucei for hit identification. Flavonols were identified as hits, and a library of 16 derivatives was synthesized. Twelve compounds showed EC50 values against T. brucei below 10 μM. Four X-ray crystal structures and docking studies explained the observed structure-activity relationships. Compound 2 (3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one) was selected for pharmacokinetic studies. Encapsulation of compound 2 in PLGA nanoparticles or cyclodextrins resulted in lower in vitro toxicity when compared to the free compound. Combination studies with methotrexate revealed that compound 13 (3-hydroxy-6-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one) has the highest synergistic effect at concentration of 1.3 μM, 11.7-fold dose reduction index and no toxicity toward host cells. Our results provide the basis for further chemical modifications aimed at identifying novel antitrypanosomatidic agents showing higher potency toward PTR1 and increased metabolic stability. |
| DOI: | doi:10.1021/acs.jmedchem.6b00698 |
| URL: | Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt. Volltext: https://doi.org/10.1021/acs.jmedchem.6b00698 |
| DOI: https://doi.org/10.1021/acs.jmedchem.6b00698 | |
| Datenträger: | Online-Ressource |
| Sprache: | eng |
| K10plus-PPN: | 1698257910 |
| Verknüpfungen: | → Zeitschrift |
