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.

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 [10.3390/molecules22030426].

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

DI PISA, FLAVIO;LANDI, GIACOMO;DELLO IACONO, LUCIA;POZZI, CECILIA;MANGANI, STEFANO
2017-01-01

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.
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 [10.3390/molecules22030426].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/1006868