ABSTRACT
Novel quinolone antibacterial agents bearing (3S)-amino-(4R)-ethylpiperidines were designed by using low energy conformation analysis and synthesized by applying a conventional coupling reaction of the quinolone nuclei with new piperidine side chains. These compounds were tested in MIC assays and found to be highly potent against Gram-positive and Gram-negative organisms. In particular, the new compounds exhibited high activity against the resistant pathogens Staphylococcus aureus (MRCR) and Streptococcus pneumoniae (PR). Importantly, when the (3S)-amino-(4R)-ethylpiperidinyl quinolones were compared with marketed quinolones sharing the same quinolone nuclei but different side chains at the C-7 position, the new quinolones showed superior activity against Gram-positive organisms, including resistant pathogens.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Bacteria/drug effects , Drug Resistance, Bacterial , Piperidines/chemical synthesis , Quinolones/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , DNA Gyrase/chemistry , DNA Gyrase/drug effects , DNA, Superhelical/chemistry , DNA, Superhelical/drug effects , Escherichia coli/enzymology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Models, Molecular , Molecular Conformation , Piperidines/chemistry , Piperidines/pharmacology , Quinolones/chemistry , Quinolones/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Quinolones without the usual 6-fluorine substituent have been recently described as potent antibacterial agents. A series of non-fluorinated analogues of the antibacterial quinolone Levofloxacin were synthesized and tested.
Subject(s)
Anti-Infective Agents/chemical synthesis , Bacteria/drug effects , Levofloxacin , Ofloxacin/analogs & derivatives , Ofloxacin/chemical synthesis , Animals , Anti-Infective Agents/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Escherichia coli/drug effects , Microbial Sensitivity Tests , Molecular Conformation , Ofloxacin/pharmacology , Structure-Activity Relationship , Topoisomerase II InhibitorsABSTRACT
[reaction: see text] trans-(3S)-Amino piperidines bearing various alkyl and aryl substituents at the C-4 position were synthesized via a ring-closing metathesis reaction. The absolute stereochemistry was controlled using a protected D-serine as a starting material. Stereoselective hydrogenation of allylamines provided trans-(3S)-amino-(4R)-alkyl- and -(4S)-aryl-piperidines. This procedure presents the first method for the asymmetric synthesis of 4-substituted 3-amino piperidines.
