A series of spirocyclic analogues as potent inhibitors of bacterial phenylalanyl-tRNA synthetases.
We have identified a series of spirocyclic furan and pyrrolidine inhibitors of Enterococcus faecalis and Staphylococcus aureus phenylalanyl-tRNA synthetases. The most potent analogue 1b showed IC50=5 nM (E. faecalis PheRS) and IC50=2 nM (S. aureus PheRS) with high selectivity over the human enzyme. The crystal X-ray structure of analogue 1b was determined.
Department of Medicinal Chemistry, Cubist Pharmaceuticals Inc., 65 Hayden Avenue, Lexington, MA 02421, USA. xyu@activbiotics.com
Xiang Y
XY
Yu
John
J
Finn
Jason M
JM
Hill
Zhong G
ZG
Wang
Dennis
D
Keith
Jared
J
Silverman
N
N
Oliver
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005663:Furans / Q000737:chemistry / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D010652:Phenylalanine-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology; D012329:RNA, Bacterial / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D005663:Furans; D006571:Heterocyclic Compounds; D011759:Pyrrolidines; D012329:RNA, Bacterial; D010652:Phenylalanine-tRNA Ligase