ABSTRACT
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.
Subject(s)
Anti-Infective Agents/chemical synthesis , Piperazines/chemical synthesis , Pyrrolidines/chemical synthesis , 4-Quinolones , Animals , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Female , Mice , Microbial Sensitivity Tests , Piperazines/chemistry , Piperazines/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Structure-Activity Relationship , Topoisomerase II InhibitorsABSTRACT
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.
Subject(s)
Aminoquinolines/chemistry , Anti-Bacterial Agents/chemistry , Hydroxyquinolines/chemistry , Alkylation , Aminoquinolines/pharmacology , Aminoquinolines/therapeutic use , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Bacterial Infections/drug therapy , Chemical Phenomena , Chemistry , Female , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Hydroxyquinolines/pharmacology , Hydroxyquinolines/therapeutic use , Mice , Microbial Sensitivity Tests , Molecular Structure , Piperazines/chemistry , Pyrrolidines/chemistry , Structure-Activity Relationship , Topoisomerase II InhibitorsABSTRACT
A series of quinolone and naphthyridine antibacterial agents possessing as the C7-heterocycle bicyclic 2,5-diazabicyclo[n.2.m]alkanes, where n = 2, 3 and m = 1, 2, and a series including 4-aminopiperidine and 3-amino-8-azabicyclo[3.2.1]octanes have been prepared and evaluated in vitro and in vivo for antibacterial activity against a variety of Gram-negative and Gram-positive organisms. These compounds were also tested against the target enzyme bacterial DNA gyrase. All the examples investigated are nearly equipotent with the parent 7-piperazinyl analogues. Only endo-7-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-1-cyclopropyl-6,8-difluoro- 1,4- dihydro-4-oxo-3-quinolinecarboxylic acid displays activity that surpasses that of the piperazine parent.
Subject(s)
Anti-Infective Agents/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Piperazines/chemical synthesis , 4-Quinolones , Animals , Anti-Infective Agents/pharmacology , Bridged Bicyclo Compounds/pharmacology , Chemical Phenomena , Chemistry , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Mice , Microbial Sensitivity Tests , Piperazines/pharmacology , Structure-Activity RelationshipABSTRACT
A series of fluoroquinolone antibacterials having the 7-position (10-position of pyridobenzoxazines) substituted with 2,7-diazaspiro[4.4]nonane (4b), 1,7-diazaspiro[4.4]nonane (5a), or 2,8-diazaspiro[5.5]undecane (6b) was prepared, and their biological activities were compared with piperazine and pyrrolidine substituted analogues. Most exhibited potent Gram-positive and Gram-negative activity, especially when side chain 4b was N-alkylated.
