Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity

Di Pisa, Flavio, Landi, Giacomo, Dello Iacono, Lucia, Pozzi, Cecilia, Borsari, Chiara, Ferrari, Stefania, Santucci, Matteo, Santarem, Nuno, Cordeiro-da-Silva, Anabela, Moraes, Carolina B
et al (show 10 more authors) (2017) Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity. MOLECULES, 22 (3). E426-.

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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.

Item Type: Article
Uncontrolled Keywords: pteridine reductase 1, Trypanosoma brucei, Leishmania spp, chroman-4-one, chromen-4-one, crystallographic studies
Depositing User: Symplectic Admin
Date Deposited: 15 Mar 2018 15:26
Last Modified: 19 Jan 2023 06:38
DOI: 10.3390/molecules22030426
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