NDLI: Efficient Dimerization Disruption of <i>Leishmania infantum</i> Trypanothione Reductase by Triazole-phenyl-thiazoles.

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Efficient Dimerization Disruption of Leishmania infantum Trypanothione Reductase by Triazole-phenyl-thiazoles.

Content Provider	Europe PMC
Author	Revuelto, Alejandro de Lucio, Héctor García-Soriano, Juan Carlos Sánchez-Murcia, Pedro A. Gago, Federico Jiménez-Ruiz, Antonio Camarasa, María-José Velázquez, Sonsoles
Copyright Year	2021
Abstract	Inhibitionof Leishmania infantum trypanothionedisulfide reductase (LiTryR) by disruptionof its homodimeric interface has proved to be an alternative and unexploitedstrategy in the search for novel antileishmanial agents. Proof ofconcept was first obtained by peptides and peptidomimetics. Buildingon previously reported dimerization disruptors containing an imidazole-phenyl-thiazolescaffold, we now report a new 1,2,3-triazole-based chemotype thatyields noncompetitive, slow-binding inhibitors of LiTryR. Several compounds bearing (poly)aromatic substituents dramaticallyimprove the ability to disrupt LiTryR dimerizationrelative to reference imidazoles. Molecular modeling studies identifiedan almost unexplored hydrophobic region at the interfacial domainas the putative binding site for these compounds. A subsequent structure-baseddesign led to a symmetrical triazole analogue that displayed evenmore potent inhibitory activity over LiTryR and enhancedleishmanicidal activity. Remarkably, several of these novel triazole-bearingcompounds were able to kill both extracellular and intracellular parasitesin cell cultures.
ISSN	00222623
Journal	Journal of Medicinal Chemistry
Volume Number	64
PubMed Central reference number	PMC8480782
Issue Number	9
PubMed reference number	33945281
e-ISSN	15204804
DOI	10.1021/acs.jmedchem.1c00206
Language	English
Publisher	American ChemicalSociety
Publisher Date	2021-05-04
Access Restriction	Open
Rights License	Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). © 2021 AmericanChemical Society
Content Type	Text
Resource Type	Article
Subject	Drug Discovery Molecular Medicine

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