Dane M. Springer

Design at the atomic level: design of biaryloxazolidinones as potent orally active antibiotics.

We have developed a first generation of hybrid sparsomycin-linezolid compounds into a new family of orally bioavailable biaryloxazolidinones that have activity against both linezolid-susceptible and -resistant gram-positive bacteria as well as the fastidious gram-negative bacteria Haemophilus influenzae and Moraxella catarrahalis. The convergent synthesis of these new compounds is detailed.

Design at the atomic level : Generation of novel hybrid biaryloxazolidinones as promising new antibiotics

From the X-ray crystal structures of linezolid and the non-selective antibiotic sparsomycin, we have derived a new family of hybrid oxazolidinones. From this initial compound set we have developed a new biaryloxazolidinone scaffold that shows both potent antimicrobial activity as well as selective inhibition of ribosomal translation. The synthesis of these compounds is outlined.

MILD, SELECTIVE DEPROTECTION OF THIOACETATES USING SODIUM THIOMETHOXIDE

Abstract A mild method for the deprotection of thioacetates is described. The reaction can be conveniently carried out at room temperature, and is compatible with a wide range of functionality. The procedure was shown to chemoselectively remove a thioacetate in the presence of an acetate.

Synthesis and activity of a C-8 keto pleuromutilin derivative

A C-8 keto pleuromutilin derivative has been synthesized from the biotransformation product 8-hydroxy mutilin. A key step in the process was the selective oxidation at C-8 of 8-hydroxy mutilin using tetrapropylammonium perruthenate. The presence of the C-8 keto group precipitated interesting intramolecular chemistry to afford a compound (10) with a novel pleuromutilin-derived ring system.

Anti-MRSA Cephems. Part 2: C-7 Cinnamic Acid Derivatives

Forty-five novel cephalosporin derivatives with activity against methicillin-resistant Staphylococcus aureus (MRSA) are described. The compounds contain novel cinnamic acid moieties at C-7 that were synthesized using a key Heck reaction followed by nucleophilic aromatic substitution reactions. The most active compound (41) displayed an MIC(90) against MRSA of 1.0 microg/mL, and a PD(50) of 0.8 mg/kg. Compound 14 was found to be very safe in a mouse model of acute toxicity.

Biaryl diacid inhibitors of human s-PLA2 with anti-inflammatory activity.

Twenty-four hydrophobic dicarboxylic acids are described which were evaluated as inhibitors of 14 kDa human platelet phospholipase A2 (HP-PLA2). In general, biarylacetic acid derivatives were found to be more active than biaryl acids or biarylpropanoic acids. More potent inhibitors were obtained when hydrophobic groups were attached to the biaryl acid nucleus using an olefin linkage as compared to an ether linkage. Compounds with larger hydrophobic groups were usually more potent inhibitors of HP-PLA2. Five of the compounds disclosed in this report (2, 4, 28, 36b and 36i) were found to possess significant anti-inflammatory activity in a phorbol ester induced mouse ear edema model of chronic inflammation.

Anti-MRSA cephems. Part 3: Additional C-7 acid derivatives

Twenty-seven novel cephalosporin derivatives with activity against methicillin-resistant Staphylococcus aureus (MRSA) are described. The compounds contain novel acid moieties at C-7 that were synthesized using nucleophilic aromatic substitution reactions and Stille couplings. The most interesting compound (6) displayed an MIC(90) against MRSA of 3.7 microg/mL, and an average PD(50) of 3.9 mg/kg.

A novel ring expansion of the pleuromutilin skeleton

An unprecedented cyclooctane to cyclononene ring expansion in the pleuromutilin skeleton, affording two main products, has been discovered. The process entails an intramolecular cyclization of an olefin onto an oxonium ion, followed by 1,2 migration of a carbon of the cyclooctane ring.

Dicarboxylic acid inhibitors of phospholipase A2

Abstract Ten diacids were synthesized via a simple regio- and stereoselective aldol reaction. All of these compounds were good to excellent inhibitors of 14 kDa human platelet PLA2, and many of these derivatives displayed activity in a phorbol-ester induced mouse ear edema assay. One of the new compounds reported here was selected for further development as a potential antipsoriasis agent.

A simple synthesis of biaryl phospholipase A2 inhibitors: Probing hydrophobic effects

Abstract A series of biaryl acids has been synthesized by treating diphenic anhydride with a variety of amines. The one step strategy allows the rapid interchange of groups for evaluating the hydrophobic constraints of inhibitors of phopholipase A 2 . The most active inhibitor synthesized displayed an IC 50 = 6 μM against human platelet phospholipase A 2 .