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Profiling of flavonol derivatives for the development of antitrypanosomatidic drugs

DOI: 10.1021/acs.jmedchem.6b00698 DOI Help

Authors: Chiara Borsari (University of Modena and Reggio Emilia) , Rosaria Luciani (University of Modena and Reggio Emilia) , Cecilia Pozzi (University of Siena) , Ina Poehner (Heidelberg Institute for Theoretical Studies) , Stefan Henrich (Heidelberg Institute for Theoretical Studies) , Matteo Trande (University of Modena and Reggio Emilia) , Anabela Cordeiro-Da-Silva (Universidade do Porto and Institute for Molecular and Cell Biology) , Nuno Santarem (Universidade do Porto and Institute for Molecular and Cell Biology) , Catarina Baptista (Universidade do Porto and Institute for Molecular and Cell Biology) , Annalisa Tait (University of Modena and Reggio Emilia) , Flavio Di Pisa (University of Siena) , Lucia Dello Iacono (University of Siena) , Giacomo Landi (University of Siena) , Sheraz Gul (Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort) , Markus Wolf (Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort) , Maria Kuzikov (Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort) , Bernhard Ellinger (Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort) , Jeanette Reinshagen (Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort) , Gesa Witt (Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort) , Philip Gribbon (Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort) , Manfred Kohler (Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort) , Oliver Keminer (Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort) , Birte Behrens (Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort) , Luca Costantino (University of Modena and Reggio Emilia) , Paloma Tejera Nevado (Bernhard Nocht Institute for Tropical Medicine) , Eugenia Bifeld (Bernhard Nocht Institute for Tropical Medicine) , Julia Eick (Bernhard Nocht Institute for Tropical Medicine) , Joachim Clos (Bernhard Nocht Institute for Tropical Medicine) , Juan Torrado (Complutense University of Madrid) , María D. Jiménez-Antón (Complutense University of Madrid, Instituto de Investigación Hospital 12 de Octubre) , María J. Corral (Complutense University of Madrid, Instituto de Investigación Hospital 12 de Octubre) , José M Alunda (Complutense University of Madrid, Instituto de Investigación Hospital 12 de Octubre) , Federica Pellati (University of Modena and Reggio Emilia) , Rebecca C. Wade (Heidelberg University) , Stefania Ferrari (University of Siena) , Stefano Mangani (University of Siena) , Maria Paola Costi (mariapaola.costi@unimore.it.)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: August 2016
Diamond Proposal Number(s): 11690

Open Access Open Access

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.

Journal Keywords: Flavonoids; Toxicological synergy; Hydroxyls; Inhibitors; Inhibition

Diamond Keywords: Sleeping Sickness

Subject Areas: Chemistry, Medicine, Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Other Facilities: ID30A-1 at ESRF

Added On: 23/08/2016 07:24

Documents:
acs.jmedchem.6b00698.pdf

Discipline Tags:

Infectious Diseases Disease in the Developing World Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)