Quinolone antibacterials: synthesis and biological activity of carbon isosteres of the 1-piperazinyl and 3-amino-1-pyrrolidinyl side chains.
A series of 6-fluoro-1,4-dihydro-4-oxo-3-quinoline- and 1,8-naphthyridinecarboxylic acids, substituted at the 7-position with carbon-linked side chains, was synthesized and evaluated for antibacterial activity and DNA-gyrase inhibition. Structural modifications focused on replacement of the heterocyclic nitrogen of the frequently found 1-piperazinyl and 3-amino-1-pyrrolidinyl side chains by an sp2- or an sp3-hybridized carbon. All new compounds displayed high in vitro and in vivo antibacterial activity. Potency relative to the standard nitrogenated agents was dependent on ring size and hybridization of the linking carbon atom of the side chain. Compounds with a 1,2,3,6-tetrahydro-4-pyridinyl substituent at C-7 were equipotent with their 1-piperazinyl analogs, whereas those having a 4-piperidinyl or a 3-amino-1-cyclopentenyl ring at C-7 were less active than the 1-piperazinyl or 3-amino-1-pyrrolidinyl substituted agents, respectively. This relative difference in antibacterial potency did not correlate with the observed activity against gyrase, where the majority of the new compounds were equally or more potent than their nitrogenated counterparts.
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105.
E
E
Laborde
J S
JS
Kiely
T P
TP
Culbertson
L E
LE
Lesheski
D042462:4-Quinolones; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D051379:Mice; D008826:Microbial Sensitivity Tests; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D042462:4-Quinolones; D000890:Anti-Infective Agents; D010879:Piperazines; D011759:Pyrrolidines; D059005:Topoisomerase II Inhibitors