Structure-activity relationship studies of a novel series of anthrax lethal factor inhibitors.
We report on the identification of a novel small molecule inhibitor of anthrax lethal factor using a high-throughput screening approach. Guided by molecular docking studies, we carried out structure-activity relationship (SAR) studies and evaluated activity and selectivity of most promising compounds in in vitro enzyme inhibition assays and cellular assays. Selected compounds were further analyzed for their in vitro ADME properties, which allowed us to select two compounds for further preliminary in vivo efficacy studies. The data provided represents the basis for further pharmacology and medicinal chemistry optimizations that could result in novel anti-anthrax therapies.
Burnham Institute for Medical Research, Cancer Research Center and Infectious and Inflammatory Disease Center, La Jolla, CA 92037, USA.
Sherida L
SL
Johnson
Li-Hsing
LH
Chen
Elisa
E
Barile
Aras
A
Emdadi
Mojgan
M
Sabet
Hongbin
H
Yuan
Jun
J
Wei
Donald
D
Guiney
Maurizio
M
Pellecchia
D000818:Animals; D000881:Anthrax / Q000188:drug therapy; D000942:Antigens, Bacterial / Q000737:chemistry*; D000992:Antitoxins / Q000737:chemistry* / Q000494:pharmacology*; D001408:Bacillus anthracis / Q000378:metabolism; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D000942:Antigens, Bacterial; D000992:Antitoxins; D001427:Bacterial Toxins; D011480:Protease Inhibitors; D013449:Sulfonamides; C030325:anthrax toxin