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 / Di Pisa, F.; Landi, G.; Dello Iacono, L.; Pozzi, C.; Borsari, C.; Ferrari, S.; Santucci, M.; Santarem, N.; Cordeiro-Da-Silva, A.; Moraes, C. B.; Alcantara, L. M.; Fontana, V.; Freitas-Junior, L. H.; Gul, S.; Kuzikov, M.; Behrens, B.; Pohner, I.; Wade, R. C.; Costi, M. P.; Mangani, S.. - In: MOLECULES. - ISSN 1420-3049. - 22:3(2017), pp. 426-442. [10.3390/molecules22030426]

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

Landi G.;Pozzi C.;Santucci M.
Methodology
;
Fontana V.;Costi M. P.
Funding Acquisition
;
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.
2017
22
3
426
442
Chroman-4-one derivatives targeting pteridine reductase 1 and showing anti-parasitic activity / Di Pisa, F.; Landi, G.; Dello Iacono, L.; Pozzi, C.; Borsari, C.; Ferrari, S.; Santucci, M.; Santarem, N.; Cordeiro-Da-Silva, A.; Moraes, C. B.; Alcantara, L. M.; Fontana, V.; Freitas-Junior, L. H.; Gul, S.; Kuzikov, M.; Behrens, B.; Pohner, I.; Wade, R. C.; Costi, M. P.; Mangani, S.. - In: MOLECULES. - ISSN 1420-3049. - 22:3(2017), pp. 426-442. [10.3390/molecules22030426]
Di Pisa, F.; Landi, G.; Dello Iacono, L.; Pozzi, C.; Borsari, C.; Ferrari, S.; Santucci, M.; Santarem, N.; Cordeiro-Da-Silva, A.; Moraes, C. B.; Alcantara, L. M.; Fontana, V.; Freitas-Junior, L. H.; Gul, S.; Kuzikov, M.; Behrens, B.; Pohner, I.; Wade, R. C.; Costi, M. P.; Mangani, S.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1208956
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