The effect of remote chirality on the antibacterial activity of indolinyl, tetrahydroquinolyl and dihydrobenzoxazinyl oxazolidinones.
The oxazolidinones are promising agents for the treatment of infections caused by gram-positive bacteria, including multidrug-resistant strains. In ongoing studies we have discovered that a strategically placed chiral center of appropriate absolute configuration improves the antibacterial activity of indolinyl oxazolidinone analogues (gram-positive MIC's<0.5 microg/mL for the most potent congeners). The design, synthesis, antibacterial activity and pharmacokinetic profile of a selected series of alpha-methylated indoline derivatives and a related set of tetrahydroquinolyl and dihydrobenzoxazinyl analogues are discussed.
Ciske
Fred L
FL
Pfizer, 7000 Portage Road, Kalamazoo, MI 49001, USA.
Barbachyn
Michael R
MR
Genin
Michael J
MJ
Grega
Kevin C
KC
Lee
Chi Sing
CS
Dolak
Lester A
LA
Seest
Eric P
EP
Watt
William
W
Adams
Wade J
WJ
Friis
Janice M
JM
Ford
Charles W
CW
Zurenko
Gary E
GE
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006873:Hydroquinones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D010078:Oxazines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D023303:Oxazolidinones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D006873:Hydroquinones; D007211:Indoles; D010078:Oxazines; D023303:Oxazolidinones