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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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 (<b>1</b>-<b>3</b>) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes (<i>Trypanosoma brucei</i> PTR1-<i>Tb</i>PTR1 and <i>Leishmania major-Lm</i>PTR1) and parasites (<i>Trypanosoma brucei</i> and <i>Leishmania infantum</i>). A crystal structure of <i>Tb</i>PTR1 in complex with compound <b>1</b> and the first crystal structures of <i>Lm</i>PTR1-flavanone complexes (compounds <b>1</b> and <b>3</b>) 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 <b>1</b> 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: 07 Feb 2024 15:48
DOI: 10.3390/molecules22030426
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3019074
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