Journal of Medicinal Chemistry p. 7598 - 7616 (2016)
Update date:2022-08-15
Topics:
Borsari, Chiara
Lucian, Rosaria
Pozzi, Cecilia
Poehner, Ina
Henrich, Stefan
Trande, Matteo
Cordeiro-Da-silva, Anabela
Santarem, Nuno
Baptista, Catarina
Tait, Annalisa
Di Pisa, Flavio
Iacono, Lucia Dello
Landi, Giacomo
Gul, Sheraz
Wolf, Markus
Kuzikov, Maria
Ellinger, Bernhard
Reinshagen, Jeanette
Witt, Gesa
Gribbon, Philip
Kohler, Manfred
Keminer, Oliver
Behrens, Birte
Costantino, Luca
Nevado, Paloma Tejera
Bifeld, Eugenia
Eick, Julia
Clos, Joachim
Torrado, Juan
Jiménez-Antón, María D.
Corral, María J.
Alunda, José Ma
Pellati, Federica
Wade, Rebecca C.
Ferrari, Stefania
Mangani, Stefano
Costi, Maria Paola
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.
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