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.

Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs / Borsari, Chiara; Luciani, Rosaria; Pozzi, Cecilia; Poehner, Ina; Henrich, Stefan; Trande, Matteo; Cordeiro da Silva, Anabela; Santarem, Nuno; Baptista, Catarina; Tait, Annalisa; Di Pisa, Flavio; Dello, Iacono; Lucia, Landi; Giacomo, ; Gul, Sheraz; Wolf, Markus; Kuzikov, Maria; Ellinger, Bernhard; Reinshagen, Jeanette; Witt, Gesa; Gribbon, Philip; Kohler, Manfred; Keminer, Oliver; Behrens, Birte; Costantino, Luca; Tejera Nevado, Paloma; Bifeld, Eugenia; Eick, Julia; Clos, Joachim; Torrado Santiago, Juan; Jiménez Antón, María D.; Corral, María J.; Alunda, José Ma; Pellati, Federica; Wade, Rebecca C.; Ferrari, Stefania; Mangani, Stefano; Costi, Maria Paola. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - ELETTRONICO. - 59:16(2016), pp. 7598-7616. [10.1021/acs.jmedchem.6b00698]

Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs

BORSARI, CHIARA;LUCIANI, Rosaria;TRANDE, MATTEO;TAIT, Annalisa;COSTANTINO, Luca;PELLATI, Federica;FERRARI, Stefania;COSTI, Maria Paola
2016

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.
2016
5-ago-2016
59
16
7598
7616
Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs / Borsari, Chiara; Luciani, Rosaria; Pozzi, Cecilia; Poehner, Ina; Henrich, Stefan; Trande, Matteo; Cordeiro da Silva, Anabela; Santarem, Nuno; Baptista, Catarina; Tait, Annalisa; Di Pisa, Flavio; Dello, Iacono; Lucia, Landi; Giacomo, ; Gul, Sheraz; Wolf, Markus; Kuzikov, Maria; Ellinger, Bernhard; Reinshagen, Jeanette; Witt, Gesa; Gribbon, Philip; Kohler, Manfred; Keminer, Oliver; Behrens, Birte; Costantino, Luca; Tejera Nevado, Paloma; Bifeld, Eugenia; Eick, Julia; Clos, Joachim; Torrado Santiago, Juan; Jiménez Antón, María D.; Corral, María J.; Alunda, José Ma; Pellati, Federica; Wade, Rebecca C.; Ferrari, Stefania; Mangani, Stefano; Costi, Maria Paola. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - ELETTRONICO. - 59:16(2016), pp. 7598-7616. [10.1021/acs.jmedchem.6b00698]
Borsari, Chiara; Luciani, Rosaria; Pozzi, Cecilia; Poehner, Ina; Henrich, Stefan; Trande, Matteo; Cordeiro da Silva, Anabela; Santarem, Nuno; Baptista...espandi
File in questo prodotto:
File Dimensione Formato  
36_JMC_2016_flavonoidi.pdf

Open access

Descrizione: Articolo
Tipologia: Versione pubblicata dall'editore
Dimensione 8.24 MB
Formato Adobe PDF
8.24 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1107045
Citazioni
  • ???jsp.display-item.citation.pmc??? 15
  • Scopus 42
  • ???jsp.display-item.citation.isi??? 42
social impact