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

DOI: 10.3390/molecules22030426 DOI Help

Authors: Flavio Di Pisa (University of Siena) , Giacomo Landi (University of Siena) , Lucia Dello Iacono (University of Siena) , Cecilia Pozzi (University of Siena) , Chiara Borsari (University of Modena and Reggio Emilia) , Stefania Ferrari (University of Modena and Reggio Emilia) , Matteo Santucci (University of Modena and Reggio Emilia) , Nuno Santarem (Universidade do Porto and Institute for Molecular and Cell Biology) , Anabela Cordeiro-da-silva (Universidade do Porto and Institute for Molecular and Cell Biology) , Carolina Moraes (Centro Nacional de Pesquisa em Energia e Materiais (CNPEM)) , Laura Alcantara (Centro Nacional de Pesquisa em Energia e Materiais (CNPEM)) , Vanessa Fontana (Centro Nacional de Pesquisa em Energia e Materiais (CNPEM)) , Lucio Freitas-junior (Centro Nacional de Pesquisa em Energia e Materiais (CNPEM); GARDE, Instituto Butantan) , Sheraz Gul (Fraunhofer Institute for Molecular Biology and Applied Ecology Screening Port) , Maria Kuzikov (Fraunhofer Institute for Molecular Biology and Applied Ecology Screening Port) , Birte Behrens (Fraunhofer Institute for Molecular Biology and Applied Ecology Screening Port) , Ina Pöhner (Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies) , Rebecca Wade (Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies; Center for Molecular Biology (ZMBH), DKFZ-ZMBH Alliance; Heidelberg University) , Maria Costi (University of Modena and Reggio Emilia) , Stefano Mangani (University of Siena; University of Florence)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecules , VOL 22

State: Published (Approved)
Published: March 2017
Diamond Proposal Number(s): 8574

Open Access Open Access

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 (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.

Journal Keywords: pteridine reductase 1, Trypanosoma brucei, Leishmania spp., chroman-4-one, chromen-4-one, crystallographic studies

Subject Areas: Chemistry, Medicine, Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography

Other Facilities: Elettra Synchrotron Trieste

Documents:
molecules-22-00426.pdf