title: Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives.
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) (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 (Ki0.25 ± 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.
authors.affiliation: a Istituto Pasteur-Fondazione Cenci Bolognetti , Dipartimento di Chimica e Tecnologie del Farmaco , "Sapienza" Università di Roma , Roma , Italia.
authors.forename: Francesco
authors.initials: F
authors.lastname: Saccoliti
authors.affiliation: b Istituto di Biologia e Patologia Molecolari - CNR , and Dipartimento di Scienze Biochimiche , " Sapienza" Università di Roma , Roma , Italia.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Angiulli
authors.affiliation: a Istituto Pasteur-Fondazione Cenci Bolognetti , Dipartimento di Chimica e Tecnologie del Farmaco , "Sapienza" Università di Roma , Roma , Italia.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pupo
authors.affiliation: a Istituto Pasteur-Fondazione Cenci Bolognetti , Dipartimento di Chimica e Tecnologie del Farmaco , "Sapienza" Università di Roma , Roma , Italia.
authors.forename: Luca
authors.initials: L
authors.lastname: Pescatori
authors.affiliation: a Istituto Pasteur-Fondazione Cenci Bolognetti , Dipartimento di Chimica e Tecnologie del Farmaco , "Sapienza" Università di Roma , Roma , Italia.
authors.forename: Valentina Noemi
authors.initials: VN
authors.lastname: Madia
authors.affiliation: a Istituto Pasteur-Fondazione Cenci Bolognetti , Dipartimento di Chimica e Tecnologie del Farmaco , "Sapienza" Università di Roma , Roma , Italia.
authors.forename: Antonella
authors.initials: A
authors.lastname: Messore
authors.affiliation: b Istituto di Biologia e Patologia Molecolari - CNR , and Dipartimento di Scienze Biochimiche , " Sapienza" Università di Roma , Roma , Italia.
authors.forename: Gianni
authors.initials: G
authors.lastname: Colotti
authors.affiliation: b Istituto di Biologia e Patologia Molecolari - CNR , and Dipartimento di Scienze Biochimiche , " Sapienza" Università di Roma , Roma , Italia.
authors.forename: Annarita
authors.initials: A
authors.lastname: Fiorillo
authors.affiliation: a Istituto Pasteur-Fondazione Cenci Bolognetti , Dipartimento di Chimica e Tecnologie del Farmaco , "Sapienza" Università di Roma , Roma , Italia.
authors.forename: Luigi
authors.initials: L
authors.lastname: Scipione
authors.affiliation: c Dipartimento di Malattie Infettive, Parassitarie e Immunomediate , Istituto Superiore di Sanità , Roma , Italia.
authors.forename: Marina
authors.initials: M
authors.lastname: Gramiccia
authors.affiliation: c Dipartimento di Malattie Infettive, Parassitarie e Immunomediate , Istituto Superiore di Sanità , Roma , Italia.
authors.forename: Trentina
authors.initials: T
authors.lastname: Di Muccio
authors.affiliation: a Istituto Pasteur-Fondazione Cenci Bolognetti , Dipartimento di Chimica e Tecnologie del Farmaco , "Sapienza" Università di Roma , Roma , Italia.
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Santo
authors.affiliation: a Istituto Pasteur-Fondazione Cenci Bolognetti , Dipartimento di Chimica e Tecnologie del Farmaco , "Sapienza" Università di Roma , Roma , Italia.
authors.forename: Roberta
authors.initials: R
authors.lastname: Costi
authors.affiliation: b Istituto di Biologia e Patologia Molecolari - CNR , and Dipartimento di Scienze Biochimiche , " Sapienza" Università di Roma , Roma , Italia.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ilari
mesh_terms: D018360:Crystallography, X-Ray; D018314:Leishmania infantum / Q000201:enzymology*; D008958:Models, Molecular; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013440:Sulfides / Q000494:pharmacology*
chemical_list: D013440:Sulfides; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase
keywords: Diaryl sulfide derivatives; Leishmania infantum; X-ray crystal structure; trypanothione reductase; trypanothione reductase inhibition