The study presented here aimed at identifying a new class of compounds acting against Leishmania parasites, the causative agent of Leishmaniasis. For this purpose, the thioether derivatives of our in-house library have been evaluated in whole-cell screening assays in order to determine their in vitro activity against Leishmania protozoan. Among them, promising results have been achieved with compound RDS 777 (6-(sec-butoxy)-2-((3-chlorophenyl)thio)pyrimidin-4-amine) (IC50¼29.43 mM), which is able to impair the mechanism of the parasite defence against the reactive oxygen species by inhibiting the trypanothione reductase (TR) with high efficiency (Ki 0.25 ± 0.18 mM). The X-ray structure of L. infantum TR in complex with RDS 777 disclosed the mechanism of action of this compound that binds to the catalytic site and engages in hydrogen bonds the residues more involved in the catalysis, namely Glu466', Cys57 and Cys52, thereby inhibiting the trypanothione binding and avoiding its reduction.

Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives / Saccoliti, Francesco; Angiulli, Gabriella; Pupo, Giovanni; Pescatori, Luca; Madia, VALENTINA NOEMI; Messore, Antonella; Colotti, Gianni; Fiorillo, Annarita; Scipione, Luigi; Gramiccia, Marina; Di Muccio, Trentina; DI SANTO, Roberto; Costi, Roberta; Ilari, Andrea. - In: JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY. - ISSN 1475-6366. - STAMPA. - 32:1(2017), pp. 304-310. [10.1080/14756366.2016.1250755]

Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives

SACCOLITI, FRANCESCO;ANGIULLI, GABRIELLA;PUPO, GIOVANNI;PESCATORI, LUCA;MADIA, VALENTINA NOEMI;MESSORE, ANTONELLA;FIORILLO, ANNARITA;SCIPIONE, Luigi;DI SANTO, Roberto;COSTI, Roberta
;
ILARI, ANDREA
2017

Abstract

The study presented here aimed at identifying a new class of compounds acting against Leishmania parasites, the causative agent of Leishmaniasis. For this purpose, the thioether derivatives of our in-house library have been evaluated in whole-cell screening assays in order to determine their in vitro activity against Leishmania protozoan. Among them, promising results have been achieved with compound RDS 777 (6-(sec-butoxy)-2-((3-chlorophenyl)thio)pyrimidin-4-amine) (IC50¼29.43 mM), which is able to impair the mechanism of the parasite defence against the reactive oxygen species by inhibiting the trypanothione reductase (TR) with high efficiency (Ki 0.25 ± 0.18 mM). The X-ray structure of L. infantum TR in complex with RDS 777 disclosed the mechanism of action of this compound that binds to the catalytic site and engages in hydrogen bonds the residues more involved in the catalysis, namely Glu466', Cys57 and Cys52, thereby inhibiting the trypanothione binding and avoiding its reduction.
2017
Diaryl sulfide derivatives; Leishmania infantum; trypanothione reductase; trypanothione reductase inhibition; X-ray crystal structure
01 Pubblicazione su rivista::01a Articolo in rivista
Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives / Saccoliti, Francesco; Angiulli, Gabriella; Pupo, Giovanni; Pescatori, Luca; Madia, VALENTINA NOEMI; Messore, Antonella; Colotti, Gianni; Fiorillo, Annarita; Scipione, Luigi; Gramiccia, Marina; Di Muccio, Trentina; DI SANTO, Roberto; Costi, Roberta; Ilari, Andrea. - In: JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY. - ISSN 1475-6366. - STAMPA. - 32:1(2017), pp. 304-310. [10.1080/14756366.2016.1250755]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/929856
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