Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs
| Autor: | Paloma Tejera Nevado, Anabela Cordeiro-da-Silva, María Jesús Corral, Gesa Witt, Catarina Baptista, Rebecca C. Wade, G. Landi, José Mª Alunda, Juan J. Torrado, Bernhard Ellinger, Maria Kuzikov, Maria Paola Costi, Julia Eick, Stefano Mangani, Jeanette Reinshagen, Eugenia Bifeld, Nuno Santarém, Sheraz Gul, Manfred Kohler, Stefania Ferrari, Joachim Clos, María Dolores Jiménez-Antón, Lucia Dello Iacono, Birte Behrens, Philip Gribbon, Cecilia Pozzi, Oliver Keminer, Markus Wolf, Luca Costantino, Stefan Henrich, Matteo Trande, Rosaria Luciani, Ina Poehner, Flavio Di Pisa, Annalisa Tait, Federica Pellati, Chiara Borsari |
|---|---|
| Přispěvatelé: | Publica |
| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular 0301 basic medicine Flavonols Stereochemistry Phenotypic screening Trypanosoma brucei brucei Trypanosoma brucei 01 natural sciences Flavonol Derivatives Drug Development Antitrypanosomatidic Drugs enzyme inhibition x-ray crystallography drug delivery Cell Line Mice Structure-Activity Relationship 03 medical and health sciences Parasitic Sensitivity Tests Drug Discovery Animals Humans Structure–activity relationship EC50 chemistry.chemical_classification Biological Products Mice Inbred BALB C Dose-Response Relationship Drug Molecular Structure biology Macrophages Drug Discovery3003 Pharmaceutical Science biology.organism_classification Trypanocidal Agents In vitro 0104 chemical sciences 3. Good health 010404 medicinal & biomolecular chemistry 030104 developmental biology chemistry Biochemistry Molecular Medicine Docking (molecular) Toxicity |
| Zdroj: | 'Journal of Medicinal Chemistry ', vol: 59, pages: 7598-7616 (2016) |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|