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

Robert A. Fecik, Pratik Devasthale, Segaran Pillai, Ali Keschavarz-Shokri, Linus Shen, Lester A. Mitscher

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1229-1236
Number of pages8
JournalJournal of Medicinal Chemistry
Volume48
Issue number4
DOIs
StatePublished - Feb 24 2005

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