Chroman-4-one derivatives targeting pteridine reductase 1 and showing anti-parasitic activity
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 evalua...
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| Main Authors: | , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
8 March 2017
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| In: |
Molecules
Year: 2017, Volume: 22, Issue: 3 |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules22030426 |
| Online Access: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.3390/molecules22030426 Verlag, kostenfrei, Volltext: https://www.mdpi.com/1420-3049/22/3/426 
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| Author Notes: | 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 |
| Summary: | 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. |
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| Item Description: | Gesehen am 18.10.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules22030426 |