TY - JOUR
T1 - Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives
AU - Saccoliti, Francesco
AU - Angiulli, Gabriella
AU - Pupo, Giovanni
AU - Pescatori, Luca
AU - Madia, Valentina Noemi
AU - Messore, Antonella
AU - Colotti, Gianni
AU - Fiorillo, Annarita
AU - Scipione, Luigi
AU - Gramiccia, Marina
AU - Di Muccio, Trentina
AU - Di Santo, Roberto
AU - Costi, Roberta
AU - Ilari, Andrea
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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) (IC50=29.43 µM), 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 µM). 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.
AB - 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) (IC50=29.43 µM), 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 µM). 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.
KW - Diaryl sulfide derivatives
KW - Leishmania infantum
KW - trypanothione reductase
KW - trypanothione reductase inhibition
KW - X-ray crystal structure
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U2 - 10.1080/14756366.2016.1250755
DO - 10.1080/14756366.2016.1250755
M3 - Article
C2 - 28098499
AN - SCOPUS:85013797723
VL - 32
SP - 304
EP - 310
JO - Journal of Enzyme Inhibition and Medicinal Chemistry
JF - Journal of Enzyme Inhibition and Medicinal Chemistry
SN - 1475-6366
IS - 1
ER -