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

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.