title: Rhodanine derivatives as selective protease inhibitors against bacterial toxins.
abstract: In this study, we analyzed a series of rhodanine derivatives, as potential inhibitors of bacterial toxins, namely the proteases anthrax lethal factor and the botulinum neurotoxin type A. Conducting an extensive structure-activity relationship study on rhodanine derivatives, we profiled their selectivity against the two bacterial toxins and two related human metalloproteases using in vitro assays. In addition, we examined initial in vitro ADME-Tox properties of selected compounds and their ability to protect lethal factor-induced cell death of macrophages. These data allowed the selection of one additional drug candidate for which preliminary in vivo efficacy studies against anthrax spores were conducted. Integration of these results with our structure-activity relationship studies provides a framework for the development of potential drug candidates against anthrax and botulinum.
authors.affiliation: Infectious and Inflammatory Disease Center and Cancer Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Rd, La Jolla, CA 92037, USA.
authors.forename: Sherida L
authors.initials: SL
authors.lastname: Johnson
authors.forename: Li-Hsing
authors.initials: LH
authors.lastname: Chen
authors.forename: Rebecca
authors.initials: R
authors.lastname: Harbach
authors.forename: Mojgan
authors.initials: M
authors.lastname: Sabet
authors.forename: Alexei
authors.initials: A
authors.lastname: Savinov
authors.forename: Naomi J H
authors.initials: NJ
authors.lastname: Cotton
authors.forename: Alex
authors.initials: A
authors.lastname: Strongin
authors.forename: Donald
authors.initials: D
authors.lastname: Guiney
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D000942:Antigens, Bacterial; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D045726:Metalloproteases / Q000187:drug effects; D011480:Protease Inhibitors / Q000737:chemistry*; D012236:Rhodanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D011480:Protease Inhibitors; C030325:anthrax toxin; D012236:Rhodanine; D045726:Metalloproteases; D019274:Botulinum Toxins, Type A