title: N-methyldihydroquinazolinone derivatives of Retro-2 with enhanced efficacy against Shiga toxin.
abstract: The Retro-2 molecule protects cells against Shiga toxins by specifically blocking retrograde transport from early endosomes to the trans-Golgi network. A SAR study has been carried out to identify more potent compounds. Cyclization and modifications of Retro-2 led to a compound with roughly 100-fold improvement of the EC50 against Shiga toxin cytotoxicity measured in a cell protein synthesis assay. We also demonstrated that only one enantiomer of the dihydroquinazolinone reported herein is bioactive.
authors.affiliation: CEA, iBiTec-S/SCBM, CEA-Saclay, LabEx LERMIT, F-91191 Gif-sur-Yvette, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Noel
authors.forename: Neetu
authors.initials: N
authors.lastname: Gupta
authors.forename: Valérie
authors.initials: V
authors.lastname: Pons
authors.forename: Amélie
authors.initials: A
authors.lastname: Goudet
authors.forename: Maria Daniela
authors.initials: MD
authors.lastname: Garcia-Castillo
authors.forename: Aurélien
authors.initials: A
authors.lastname: Michau
authors.forename: Jennifer
authors.initials: J
authors.lastname: Martinez
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Buisson
authors.forename: Ludger
authors.initials: L
authors.lastname: Johannes
authors.forename: Daniel
authors.initials: D
authors.lastname: Gillet
authors.forename: Julien
authors.initials: J
authors.lastname: Barbier
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Cintrat
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000494:pharmacology; D022621:Shiga Toxin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D022603:Shiga Toxins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000494:pharmacology
chemical_list: C549073:2-(((5-methyl-2-thienyl)methylene)amino)-N-phenylbenzamide; D001549:Benzamides; D052999:Quinazolinones; D022603:Shiga Toxins; D013876:Thiophenes; D022621:Shiga Toxin