Gerald Brooks

Pleuromutilins. Part 1. The identification of novel mutilin 14-carbamates.

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.

Penem inhibitors of bacterial signal peptidase

Abstract C(3)-Penem esters and amides having the (5S)-configuration at the bridgehead are inhibitors of Escherichia coli leader peptidase, the best activity being seen with a 6-(1-acetoxyethyl) derivative having the (5S, 6S, 8R)-stereochemistry. These compounds represent the first examples of potent inhibitors of bacterial signal peptidase.

Novel hydroxyl tricyclics (e.g., GSK966587) as potent inhibitors of bacterial type IIA topoisomerases

During the course of our research to find novel mode of action antibacterials, we discovered a series of hydroxyl tricyclic compounds that showed good potency against Gram-positive and Gram-negative pathogens. These compounds inhibit bacterial type IIA topoisomerases. Herein we will discuss structure-activity relationships in this series and report advanced studies on compound 1 (GSK966587) which demonstrates good PK and in vivo efficacy properties. X-ray crystallographic studies were used to provide insight into the structural basis for the difference in antibacterial potency between enantiomers.

Novel amino-piperidines as potent antibacterials targeting bacterial type IIA topoisomerases.

We have identified a series of amino-piperidine antibacterials with a good broad spectrum potency. We report the investigation of various subunits in this series and advanced studies on compound 8. Compound 8 possesses good pharmacokinetics, broad spectrum antibacterial activity and demonstrates oral efficacy in a rat lung infection model.

Novel cyclohexyl-amides as potent antibacterials targeting bacterial type IIA topoisomerases

As part of our wider efforts to exploit novel mode of action antibacterials, we have discovered a series of cyclohexyl-amide compounds that has good Gram positive and Gram negative potency. The mechanism of action is via inhibition of bacterial topoisomerases II and IV. We have investigated various subunits in this series and report advanced studies on compound 7 which demonstrates good PK and in vivo efficacy properties.

Synthesis of derivatives of muramic acid and C-1 homologated α-D-glucose as potential inhibitors of bacterial transglycosylase

Abstract Phosphate derivatives of muramic acid, incorporating a lipid-like group, have been synthesised as potential inhibitors of bacterial transglycosylase. The Lewis acid catalysed addition of unsaturated alkyl silanes to methyl α-D-glucopyranoside, followed by an oxidative cleavage, has been used to provide a route to C-1 homologues of glucose. Conversion of α-D-glucose methanephosphonic acid to esters derived from lipid-like groups is also described.

Novel tricyclics (e.g., GSK945237) as potent inhibitors of bacterial type IIA topoisomerases.

During the course of our research on the lead optimisation of the NBTI (Novel Bacterial Type II Topoisomerase Inhibitors) class of antibacterials, we discovered a series of tricyclic compounds that showed good Gram-positive and Gram-negative potency. Herein we will discuss the various subunits that were investigated in this series and report advanced studies on compound 1 (GSK945237) which demonstrates good PK and in vivo efficacy properties.

Synthesis of ethyl 3-methyl-7-oxo-4-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate and the reaction of 4-acetoxyazetidin-2-one with ethyl α-diazoacetoacetate

Ethyl 3-methyl-7-oxo-4-oxa-1-azobicylco[3.2.0]-hept-2-ene-2-carboxylate (4) has been obtained by a four-step synthesis from 4-methylthioazetidin-2-one and has been compared with the products obtained from the rhodium(II) acetate-catalysed reaction of 4-acetoxy-azetidin-2-one with ethyl α-diazoacetoacetate; this latter reaction did not give compound (4), as was previously claimed, but yielded ethyl 2-(4-acetoxy-2-oxoazetidinyl)-3-oxobutyrate as the major β-lactam product.

A new total synthesis of (±)-clavulanic acid

Abstract Regioselective reactions at the terminal double bond of the racemic azetidinone dienylether (4), provides a source of clavulanic acid and several analogues.

Total synthesis of (±)-clavulanic acid

A formal total synthesis of racemic clavulanic acid has been achieved commencing with (±)-4-methylthioazetidin-2-one (3).