Glutamyl-gamma-boronate inhibitors of bacterial Glu-tRNA(Gln) amidotransferase.
Analogues of glutamyl-gamma-boronate (1) were synthesized as mechanism-based inhibitors of bacterial Glu-tRNA(Gln) amidotransferase (Glu-AdT) and were designed to engage a putative catalytic serine nucleophile required for the glutaminase activity of the enzyme. Although 1 provides potent enzyme inhibition, structure-activity studies revealed a narrow range of tolerated chemical changes that maintained activity. Nonetheless, growth inhibition of organisms that require Glu-AdT by the most potent enzyme inhibitors appears to validate mechanism-based inhibitor design of Glu-AdT as an approach to antimicrobial development.
Decicco
C P
CP
Department of Medicinal Chemistry, DuPont Pharmaceuticals Company, Experimental Station, PO Box 80400, Wilmington, DE 19880, USA. carl.p.decicco@dupontpharma.com
Nelson
D J
DJ
Luo
Y
Y
Shen
L
L
Horiuchi
K Y
KY
Amsler
K M
KM
Foster
L A
LA
Spitz
S M
SM
Merrill
J J
JJ
Sizemore
C F
CF
Rogers
K C
KC
Copeland
R A
RA
Harpel
M R
MR
D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology*; D001897:Boronic Acids / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D019884:Nitrogenous Group Transferases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D001897:Boronic Acids; D004791:Enzyme Inhibitors; C448820:glutamyl-gamma-boronate; C412016:Asp-tRNA(Asn) amidotransferase; D019884:Nitrogenous Group Transferases