Chroman-4-one derivatives targeting pteridine reductase 1 and showing anti-parasitic activity

• Verfasst von: Pisa, Flavio Di [VerfasserIn]
• Verfasst von: Pöhner, Ina [VerfasserIn]
• Verfasst von: Wade, Rebecca C. [VerfasserIn]
• Titel: Chroman-4-one derivatives targeting pteridine reductase 1 and showing anti-parasitic activity
• Verf.angabe: Flavio Di Pisa, Giacomo Landi, Lucia Dello Iacono, Cecilia Pozzi, Chiara Borsari, Stefania Ferrari, Matteo Santucci, Nuno Santarem, Anabela Cordeiro-da-Silva, Carolina Moraes, Laura Alcantara, Vanessa Fontana, Lucio Freitas-Junior, Sheraz Gul, Maria Kuzikov, Birte Behrens, Ina Pöhner, Rebecca Wade, Maria Costi and Stefano Mangani
• E-Jahr: 2017
• Jahr: 8 March 2017
• Umfang: 16 S.
• Teil: volume:22
• Teil: year:2017
• Teil: number:3
• Teil: elocationid:426
• Teil: extent:16
• Fussnoten: Gesehen am 18.10.2018
• Titel Quelle: Enthalten in: Molecules
• Ort Quelle: Basel : MDPI, 1996
• Jahr Quelle: 2017
• Band/Heft Quelle: 22(2017), 3, Artikel-ID 426
• ISSN Quelle: 1420-3049
• DOI: doi:10.3390/molecules22030426
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: <i>Leishmania</i> spp.
• Sach-SW: <i>Trypanosoma brucei</i>
• Sach-SW: chroman-4-one
• Sach-SW: chromen-4-one
• Sach-SW: crystallographic studies
• Sach-SW: pteridine reductase 1
• K10plus-PPN: 1582083665

Abstract

Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three chroman-4-one analogues (1-3) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes (Trypanosoma brucei PTR1-TbPTR1 and Leishmania major-LmPTR1) and parasites (Trypanosoma brucei and Leishmania infantum). A crystal structure of TbPTR1 in complex with compound 1 and the first crystal structures of LmPTR1-flavanone complexes (compounds 1 and 3) were solved. The inhibitory activity of the chroman-4-one and chromen-4-one derivatives was explained by comparison of observed and predicted binding modes of the compounds. Compound 1 showed activity both against the targeted enzymes and the parasites with a selectivity index greater than 7 and a low toxicity. Our results provide a basis for further scaffold optimization and structure-based drug design aimed at the identification of potent anti-trypanosomatidic compounds targeting multiple PTR1 variants.