Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs

被引：42

作者：

Borsari, Chiara ^{[1
]}

Luciani, Rosaria ^{[1
]}

Pozzi, Cecilia ^{[2
]}

Poehner, Ina ^{[3
]}

Henrich, Stefan ^{[3
]}

Trande, Matteo ^{[1
]}

Cordeiro-da-Silva, Anabela ^{[4
,5
]}

Santarem, Nuno ^{[4
,5
]}

Baptista, Catarina ^{[4
,5
]}

Tait, Annalisa ^{[1
]}

Di Pisa, Flavio ^{[2
]}

Dello Iacono, Lucia ^{[2
]}

Landi, Giacomo ^{[2
]}

Gul, Sheraz ^{[6
]}

Wolf, Markus ^{[6
]}

Kuzikov, Maria ^{[6
]}

Ellinger, Bernhard ^{[6
]}

Reinshagen, Jeanette ^{[6
]}

Witt, Gesa ^{[6
]}

Gribbon, Philip ^{[6
]}

Kohler, Manfred ^{[6
]}

Keminer, Oliver ^{[6
]}

Behrens, Birte ^{[6
]}

Costantino, Luca ^{[1
]}

Nevado, Paloma Tejera ^{[10
]}

Bifeld, Eugenia ^{[10
]}

Eick, Julia ^{[10
]}

Clos, Joachim ^{[10
]}

Torrado, Juan ^{[7
]}

Jimenez-Anton, Maria D. ^{[7
,11
]}

Corral, Maria J. ^{[7
,11
]}

Ma Alunda, Jose ^{[7
,11
]}

Pellati, Federica ^{[1
]}

Wade, Rebecca C. ^{[3
,8
,9
]}

Ferrari, Stefania ^{[1
]}

Mangani, Stefano ^{[2
]}

Costi, Maria Paola ^{[1
]}

机构：

[1] Univ Modena & Reggio Emilia, Dept Life Sci, Via G Campi 103, I-41125 Modena, Italy

[2] Univ Siena, Dept Biotechnol Chem & Pharm, Via Aldo Moro 2, I-53100 Siena, Italy

[3] Heidelberg Inst Theoret Studies, Mol & Cellular Modeling Grp, D-69118 Heidelberg, Germany

[4] Univ Porto, Inst Invest & Inovacao Saude, P-4150180 Oporto, Portugal

[5] Inst Mol & Cell Biol, P-4150180 Oporto, Portugal

[6] Fraunhofer Inst Mol Biol & Appl Ecol ScreeningPor, Schnackenburgallee 114, D-22525 Hamburg, Germany

[7] Univ Complutense Madrid, E-28040 Madrid, Spain

[8] Heidelberg Univ, DKFZ ZMBH Alliance, Ctr Mol Biol ZMBH, D-69120 Heidelberg, Germany

[9] Heidelberg Univ, Interdisciplinary Ctr Sci Comp IWR, D-69120 Heidelberg, Germany

[10] Bernhard Nocht Inst Trop Med, D-20359 Hamburg, Germany

[11] Inst Invest Hosp 12 Octubre, Madrid 28041, Spain

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 16期

关键词：

PTERIDINE REDUCTASE INHIBITORS; NATURAL-PRODUCTS; GENETIC ALGORITHM; ACCURATE DOCKING; IN-VITRO; DISCOVERY; LEISHMANIA; CHEMOTHERAPY; DISEASES; GLIDE;

D O I：

10.1021/acs.jmedchem.6b00698

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 mu M. 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 mu M 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.

引用

页码：7598 / 7616

页数：19

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