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

• Type: Article in International Scientific Journal
• Date: 2017

Authors

Di Pisa, F (Author) Other; Landi, G (Author) Other; Dello Iacono, L (Author) Other; Pozzi, C (Author) Other; Borsari, C (Author) Other; Ferrari, S (Author) Other; Santucci, M (Author) Other; Santarem, N (Author) Other; Anabela Cordeiro da Silva (Author) FFUP; Moraes, CB (Author) Other; Alcantara, LM (Author) Other; Fontana, V (Author) Other; Freitas Junior, LH (Author) Other; Gul, S (Author) Other; Kuzikov, M (Author) Other; Behrens, B (Author) Other; Poehner, I (Author) Other; Wade, RC (Author) Other; Costi, MP (Author) Other; Mangani, S (Author) Other

Journal

Title: Molecules

Vol. 22 No. 2

Final page: 426

ISSN: 1420-3049

Publisher: MDPI

Indexing

ISI Web of Knowledge - 6 Citations

Scopus - 20 Citations

Other information

Authenticus ID: P-00M-KXW

DOI: 10.3390/molecules22030426

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 16