Alpha-substituted hydroxamic acids as novel bacterial deformylase inhibitor-based antibacterial agents.
We report the synthesis and biological activity of analogues of VRC3375 (N-hydroxy-3-R-butyl-3-[(2-S-(tert-butoxycarbonyl)-pyrrolidin-1-ylcarbonyl]propionamide), an orally active peptide deformylase inhibitor. This study explores the structure-activity relationship of various chelator groups, alpha substituents, P(2)' and P(3)' substituents in order to achieve optimal antibacterial activity with minimal toxicity liability.
Jain
R
R
Vicuron Pharmaceuticals (formerly Versicor Inc), 34790 Ardentech Court, Fremont, CA 94555, USA.
Sundram
A
A
Lopez
S
S
Neckermann
G
G
Wu
C
C
Hackbarth
C
C
Chen
D
D
Wang
W
W
Ryder
N S
NS
Weidmann
B
B
Patel
D
D
Trias
J
J
White
R
R
Yuan
Z
Z
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects*; D002614:Chelating Agents / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry*; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D010446:Peptide Fragments; C481668:VRC3375; D011392:Proline; D000581:Amidohydrolases; C084507:peptide deformylase