ABSTRACT
In an era of increasing resistance to classical antibacterial agents, the synthetic oxazolidinone series of antibiotics has attracted much interest. Zyvoxtrade mark was the first oxazolidinone to be approved for clinical use against infections caused by multi-drug resistant Gram-positive bacteria. In the course of studies directed toward the discovery of novel antibacterial agents, a new series of synthetic phenyl-isoxazolinone agents that displayed potent activity against Gram-positive bacterial strains was recently discovered at Bristol-Myers Squibb. Extensive investigation of various substitutions on the phenyl ring was then undertaken. We report here, the synthesis and antibacterial activity of a series of biaryl isoxazolinone compounds.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Isoxazoles/chemistry , Isoxazoles/pharmacology , Animals , Haemophilus influenzae/drug effects , Rats , Structure-Activity RelationshipABSTRACT
A series of potential antimicrobial derivatives possessing bioisosteric replacements for the central oxazolidinone ring found in oxazolidinone antibacterials have been prepared. The design concept involved replacement of the requisite sp(3)-hybridized stereogenic center found at the 5-position of the oxazolidinone with a nitrogen atom. The synthesis and antibacterial activity of three such ring systems, the benzisoxazolinones, pyrroles, and isoxazolinones is described.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Isoxazoles/chemistry , Nitrogen/chemistry , Oxazolidinones/chemistry , Oxazolone/analogs & derivatives , Oxazolone/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Isoxazoles/chemical synthesis , Isoxazoles/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Oxazolone/chemical synthesis , Oxazolone/pharmacology , Pyrroles/chemical synthesis , Pyrroles/chemistry , Pyrroles/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Compounds based on sordaricin were prepared via organometallic addition onto a fully protected sordaricin aldehyde. The fungal growth inhibition profiles for these compounds were established and the results are presented here. The synthesis of homologated sordaricin as well as ether and ester derivatives is presented, and structural rearrangement products upon oxidation. These compounds were evaluated as agents to inhibit fungal growth.
