Synthesis and biological activity of 5-amino- and 5-hydroxyquinolones, and the overwhelming influence of the remote N1-substituent in determining the structure-activity relationship.
A series of 5-amino- and 5-hydroxyquinolone antibacterials substituted at C7 with a select group of common piperazinyl and 3-aminopyrrolidinyl side chains was prepared. These 5-substituted derivatives were compared to the analogous 5-hydrogen compounds for antiinfective activity by using DNA gyrase inhibition, minimum inhibitory concentrations against a variety of bacteria, and in vivo efficacy in the mouse infection model. The influence on the structure-activity relationships of varied substituents at C8 (H, F, Cl) and N1 (ethyl, cyclopropyl, difluorophenyl) was also studied. The results showed that several of the structure-activity conclusions regarding side-chain bulk at C7, the effect of halogen at C8, and the effect of the C5-amino group were greatly influenced by the choice of the N1-substituent. Several outstanding broad spectrum quinolones were identified in this work. In particular, the spectrum and potency of the 7-piperazinyl quinolones could be greatly enhanced by the judicious choice of C5-, C8-, and N1-substituents.
Domagala
J M
JM
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Bridges
A J
AJ
Culbertson
T P
TP
Gambino
L
L
Hagen
S E
SE
Karrick
G
G
Porter
K
K
Sanchez
J P
JP
Sesnie
J A
JA
Spense
F G
FG
D000478:Alkylation; D000634:Aminoquinolines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D001424:Bacterial Infections / Q000188:drug therapy; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006912:Hydroxyquinolines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry; D011759:Pyrrolidines / Q000737:chemistry; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000634:Aminoquinolines; D000900:Anti-Bacterial Agents; D006912:Hydroxyquinolines; D010879:Piperazines; D011759:Pyrrolidines; D059005:Topoisomerase II Inhibitors