ABSTRACT
A series of novel 5-aryl-4-aryloxymethyl-3-diazotetrahydrofuran-2-ones (12, 24, and 35a/b) have been prepared and found to undergo regio- and stereoselective C-H insertion reactions to afford 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane-8-ones (18, 26, and 36a/b) with endo,exo stereochemistry. Subsequent reduction of the lactone ring and cyclization of the resulting diols 27 and 37a/b permitted the synthesis of three endo,exo-furofuran lignans: asarinin (2), fargesin (3), and epimagnolin A (4). En route to the key diazo compounds 24 and 35a/b, a modified procedure for the Ghosez keteniminium-olefin cyclization was developed, which was required to minimize the decomposition of acid-sensitive functional groups such as electron-rich benzylic ethers that were present in the target compounds 2-4.
Subject(s)
Dioxoles/chemical synthesis , Lignans/chemical synthesis , Lignin/analogs & derivatives , Lignin/chemical synthesis , Anti-Allergic Agents/chemical synthesis , Anticholesteremic Agents/chemical synthesis , Antihypertensive Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Antioxidants/chemical synthesis , Drugs, Chinese Herbal/chemical synthesis , Furans/chemical synthesis , Platelet Aggregation Inhibitors/chemical synthesisABSTRACT
A novel series of mutilin 14-carbamates has been discovered as a result of structure-activity studies on the naturally occurring antibiotic pleuromutilin (1). In particular, the 4-methoxybenzoylcarbamate, SB-222734 (15o) displays potent antibacterial activity against a number of bacterial pathogens which are resistant to currently used agents and shows enhanced metabolic stability when compared to earlier pleuromutilin derivatives. Such derivatives therefore have the potential to provide a new class of antibacterial agents for human therapy which address the threat of bacterial resistance.
Subject(s)
Anti-Bacterial Agents/pharmacology , Diterpenes/chemical synthesis , Diterpenes/pharmacology , Haemophilus influenzae/drug effects , Staphylococcus/drug effects , Anti-Bacterial Agents/chemical synthesis , Biological Factors/chemistry , Biological Factors/pharmacology , Carbamates/chemical synthesis , Carbamates/pharmacology , Drug Resistance, Microbial/genetics , Drug Resistance, Microbial/physiology , Microbial Sensitivity Tests/standards , Polycyclic Compounds , PleuromutilinsABSTRACT
The synthesis, antibacterial activity, and stability to human dehydropeptidase-1 (DHP-1) of a novel series of (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-heterocyclylcarbapen-2-em-3-carb oxylates are described. Of the compounds investigated 1,5-disubstituted pyrazol-3-yl and 3-substituted isoxazol-5-yl derivatives have the best combination of antibacterial activity and stability to DHP-1. They are particularly active against community-acquired respiratory tract pathogens and have stabilities to DHP-1 superior to that of meropenem.
Subject(s)
Carbapenems/chemical synthesis , Carbapenems/pharmacology , Carbapenems/chemistry , Chromatography, High Pressure Liquid , Drug Stability , Humans , Microbial Sensitivity Tests , Spectrophotometry , Structure-Activity RelationshipABSTRACT
The synthesis, antibacterial activity and stability to human dehydropeptidase-1 (DHP-1) of three small series of carbapenems carrying carbon-linked substituents at C-2 are described. C-2 Ethenyl carbapenems showed moderate antibacterial activity but poor stability to DHP-1, C-2 Oxyiminomethyl carbapenems demonstrated variable activity and stability C-2 alpha-(Hydroxy)benzyl carbapenems were the most promising and showed good potency and DHP-1 stability.
Subject(s)
Carbapenems/chemical synthesis , Carbapenems/pharmacology , Humans , Structure-Activity RelationshipABSTRACT
A series of carbapenems containing novel C-2 semisaturated heterocyclic substituents were synthesised by 1,3 dipolar cycloaddition reactions of nitrile oxides, nitrile imines and a nitrone to 2-vinylcarbapenem. The isoxazoline and isoxazolidine compounds showed potent antibacterial activity but moderate stability to human dehydropeptidase 1 (DHP-1). Stability to DHP-1 was improved by methyl substitution in the isoxazoline ring, but at the expense of antibacterial activity. The pyrazolines exhibited excellent stability to DHP-1, but reduced potency against Gram-negative organisms.