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.

Chroman-4-one derivatives targeting pteridine reductase 1 and showing anti-parasitic activity / F. Di Pisa, G. Landi, L. Dello Iacono, C. Pozzi, C. Borsari, S. Ferrari, M. Santucci, N. Santarem, A. Cordeiro-Da-Silva, C.B. Moraes, L.M. Alcantara, V. Fontana, L.H. Freitas-Junior, S. Gul, M. Kuzikov, B. Behrens, I. Pohner, R.C. Wade, M.P. Costi, S. Mangani. - In: MOLECULES. - ISSN 1420-3049. - 22:3(2017), pp. 426.1-426.16. [10.3390/molecules22030426]

Chroman-4-one derivatives targeting pteridine reductase 1 and showing anti-parasitic activity

C. Borsari;
2017

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.
Chroman-4-one; Chromen-4-one; Crystallographic studies; Leishmania spp; Pteridine reductase 1; Trypanosoma brucei
Settore CHIM/08 - Chimica Farmaceutica
   New Medicines for Trypanosomatidic Infections
   NMTRYPI
   European Commission
   SEVENTH FRAMEWORK PROGRAMME
   603240
2017
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1017120
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