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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2017-03, Vol.22 (3), p.426
• Main Authors: 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, Alcantara, Laura M, Fontana, Vanessa, Freitas-Junior, Lucio H, Gul, Sheraz, Kuzikov, Maria, Behrens, Birte, Pöhner, Ina, Wade, Rebecca C, Costi, Maria Paola, Mangani, Stefano
• Format: Article
• Language: English
• Subjects: Antiparasitic agents; Antiparasitic Agents - chemical synthesis; Antiparasitic Agents - chemistry; Antiparasitic Agents - pharmacology; Binding Sites; Chromans - chemical synthesis; Chromans - chemistry; Chromans - pharmacology; Crystal structure; Design optimization; Drug development; Enzyme Activation - drug effects; Enzymes; Flavonoids; Inhibitory Concentration 50; Leishmania major - drug effects; Leishmania major - enzymology; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Oxidoreductases - antagonists & inhibitors; Oxidoreductases - chemistry; Parasites; Protein Binding; Protozoa; Reductase; Reductases; Scaffolds; Selectivity; Toxicity; Trypanosoma brucei; Trypanosoma brucei brucei - drug effects; Trypanosoma brucei brucei - enzymology
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules22030426

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 ( - ) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes ( PTR1- PTR1 and PTR1) and parasites ( and ). A crystal structure of PTR1 in complex with compound and the first crystal structures of PTR1-flavanone complexes (compounds and ) 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 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.