title: Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs.
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.
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia , Via G. Campi 103, 41125 Modena, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Borsari
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia , Via G. Campi 103, 41125 Modena, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Luciani
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena , Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Pozzi
authors.affiliation: Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies , 69118 Heidelberg, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Poehner
authors.affiliation: Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies , 69118 Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Henrich
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia , Via G. Campi 103, 41125 Modena, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Trande
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto and Institute for Molecular and Cell Biology , 4150-180 Porto, Portugal.
authors.forename: Anabela
authors.initials: A
authors.lastname: Cordeiro-da-Silva
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto and Institute for Molecular and Cell Biology , 4150-180 Porto, Portugal.
authors.forename: Nuno
authors.initials: N
authors.lastname: Santarem
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto and Institute for Molecular and Cell Biology , 4150-180 Porto, Portugal.
authors.forename: Catarina
authors.initials: C
authors.lastname: Baptista
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia , Via G. Campi 103, 41125 Modena, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Tait
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena , Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Di Pisa
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena , Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Dello Iacono
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena , Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Landi
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort , Schnackenburgallee 114 D-22525, Hamburg, Germany.
authors.forename: Sheraz
authors.initials: S
authors.lastname: Gul
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort , Schnackenburgallee 114 D-22525, Hamburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Wolf
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort , Schnackenburgallee 114 D-22525, Hamburg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Kuzikov
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort , Schnackenburgallee 114 D-22525, Hamburg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ellinger
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort , Schnackenburgallee 114 D-22525, Hamburg, Germany.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Reinshagen
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort , Schnackenburgallee 114 D-22525, Hamburg, Germany.
authors.forename: Gesa
authors.initials: G
authors.lastname: Witt
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort , Schnackenburgallee 114 D-22525, Hamburg, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Gribbon
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort , Schnackenburgallee 114 D-22525, Hamburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kohler
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort , Schnackenburgallee 114 D-22525, Hamburg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Keminer
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort , Schnackenburgallee 114 D-22525, Hamburg, Germany.
authors.forename: Birte
authors.initials: B
authors.lastname: Behrens
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia , Via G. Campi 103, 41125 Modena, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Costantino
authors.affiliation: Bernhard Nocht Institute for Tropical Medicine , D-20359 Hamburg, Germany.
authors.forename: Paloma
authors.initials: P
authors.lastname: Tejera Nevado
authors.affiliation: Bernhard Nocht Institute for Tropical Medicine , D-20359 Hamburg, Germany.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Bifeld
authors.affiliation: Bernhard Nocht Institute for Tropical Medicine , D-20359 Hamburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Eick
authors.affiliation: Bernhard Nocht Institute for Tropical Medicine , D-20359 Hamburg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Clos
authors.affiliation: Complutense University of Madrid , 28040 Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Torrado
authors.affiliation: Complutense University of Madrid , 28040 Madrid, Spain.|Instituto de Investigación Hospital 12 de Octubre , 28041 Madrid, Spain.
authors.forename: María D
authors.initials: MD
authors.lastname: Jiménez-Antón
authors.affiliation: Complutense University of Madrid , 28040 Madrid, Spain.|Instituto de Investigación Hospital 12 de Octubre , 28041 Madrid, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Corral
authors.affiliation: Complutense University of Madrid , 28040 Madrid, Spain.|Instituto de Investigación Hospital 12 de Octubre , 28041 Madrid, Spain.
authors.forename: José Ma
authors.initials: JM
authors.lastname: Alunda
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia , Via G. Campi 103, 41125 Modena, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Pellati
authors.affiliation: Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies , 69118 Heidelberg, Germany.|Center for Molecular Biology (ZMBH), DKFZ-ZMBH Alliance, Heidelberg University , 69120 Heidelberg, Germany.|Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University ,69120 Heidelberg, Germany.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Wade
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia , Via G. Campi 103, 41125 Modena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Ferrari
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena , Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Mangani
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia , Via G. Campi 103, 41125 Modena, Italy.
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Costi
mesh_terms: D000818:Animals; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D044948:Flavonols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects*
chemical_list: D001688:Biological Products; D044948:Flavonols; D014344:Trypanocidal Agents