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.
|Titolo:||Chroman-4-one derivatives targeting pteridine reductase 1 and showing anti-parasitic activity|
MANGANI, STEFANO (Corresponding)
|Citazione:||DI PISA, F., Landi, G., DELLO IACONO, L., Pozzi, C., Borsari, C., Ferrari, S., et al. (2017). Chroman-4-one derivatives targeting pteridine reductase 1 and showing anti-parasitic activity. MOLECULES, 22(3), 1-16.|
|Appare nelle tipologie:||1.1 Articolo in rivista|