Chiral DNA gyrase inhibitors. 3. Probing the chiral preference of the active site of DNA gyrase. Synthesis of 10-fluoro-6-methyl-6,7-dihydro-9-piperazinyl- 2H-benzo[a]quinolizin-20-one-3-carboxylic acid analogues.
In pursuit of an apparent literature anomaly, S- and R-6-methyl-6,7-dihydro-2H-benzo[a]quinolizin-2-one-3-carboxylic acids (12 and 22) were synthesized by an unambiguous route from optically active norephedrines, and their antibacterial potencies were measured. Against Gram-negative microorganisms and DNA gyrase a preference for S-absolute configuration was found whereas R-absolute stereochemistry was more active against Gram-positives. These results are in partial conflict with an earlier report. In an attempt to enhance potency, racemic 10-fluoro-9-piperazinyl (35) and related analogues were synthesized by a novel route. The latter analogues were surprisingly unimproved in potency. The implications of these findings are briefly discussed.
Fecik
Robert A
RA
Department of Medicinal Chemistry, University of Kansas, 4010 Malott Hall, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045-7582, USA.
Devasthale
Pratik
P
Pillai
Segaran
S
Keschavarz-Shokri
Ali
A
Shen
Linus
L
Mitscher
Lester A
LA
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D027081:DNA Gyrase / Q000737:chemistry*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011807:Quinolizines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000900:Anti-Bacterial Agents; D010879:Piperazines; D011807:Quinolizines; D059005:Topoisomerase II Inhibitors; D027081:DNA Gyrase