Synthesis and activity of nonhydrolyzable pseudomonic acid analogues.
Several series of pseudomonic acid analogues have been prepared that incorporate modified functionalities in place of the C1-C3 alpha,beta-unsaturated ester group. The inhibition of isoleucyl-tRNA synthetase and the in vitro activity of these compounds against various Gram-positive and Gram-negative strains are described. Several derivatives showed enzyme inhibition equivalent to or better than that of methyl pseudomonate (3), while lacking the hydrolyzable ester group at C1. These analogues include the corresponding phenyl ketone and the ether 12. The long-chain ketone 24 exhibited similar in vitro activity as the parent ester.
Klein
L L
LL
Anti-Infective Division, Abbott Laboratories, Abbott Park, Illinois 60064.
Yeung
C M
CM
Kurath
P
P
Mao
J C
JC
Fernandes
P B
PB
Lartey
P A
PA
Pernet
A G
AG
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D005227:Fatty Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000201:enzymology; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000201:enzymology; D007533:Isoleucine-tRNA Ligase / Q000037:antagonists & inhibitors; D008826:Microbial Sensitivity Tests; D016712:Mupirocin; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D005227:Fatty Acids; D016712:Mupirocin; D007533:Isoleucine-tRNA Ligase