Andrew Keith Forrest

Analogues of SB-203207 as Inhibitors of tRNA Synthetases

SB-203207 and 10 analogues have been prepared, by elaboration of altemicidin, and evaluated as inhibitors of isoleucyl, leucyl and valyl tRNA synthetases (IRS, LRS, and VRS, respectively). Substituting the isoleucine residue of SB-203207 with leucine and valine increased the potency of inhibition of LRS and VRS, respectively. The leucine derivative showed low level antibacterial activity, while several of the compounds inhibited IRS from Staphylococcus aureus WCUH29 more strongly than rat liver IRS.

Aminoalkyl adenylate and aminoacyl sulfamate intermediate analogues differing greatly in affinity for their cognate Staphylococcus aureus aminoacyl tRNA synthetases

Aminoalkyl adenylates and aminoacyl sulfamates derived from arginine, histidine and threonine, have been prepared and tested as inhibitors of their cognate Staphylococcus aureus aminoacyl tRNA synthetases. The arginyl derivatives were both potent nanomolar inhibitors of the Class I arginyl tRNA synthetase whereas for the Class II histidyl and threonyl tRNA synthetases, the acyl sulfamates were potent inhibitors but the adenylates had very little affinity.

Optimisation of aryl substitution leading to potent methionyl tRNA synthetase inhibitors with excellent gram-positive antibacterial activity

Optimisation of the left-hand-side aryl moiety of a file compound screening hit against Staphylococcus aureus methionyl tRNA synthetase led to the identification of a series of potent nanomolar inhibitors. The best compounds showed excellent antibacterial activity against staphylococcal and enterococcal pathogens, including strains resistant to clinical antibiotics.

The preparation and lithiation of bromofluorofurans via a novel fluorodecarboxylation

Abstract The fluorodecarboxylation of bromofuroic acids using Selectfluor TM reagent 1 gives bromofluorofurans which can be lithiated and reacted with electrophiles to yield 3- or 5- substituted 2-fluorofurans.

Synthesis and activity of analogues of the isoleucyl tRNA synthetase inhibitor SB-203207

Twenty two analogues of SB-203207 have been prepared by total synthesis, and evaluated as inhibitors of a range of tRNA synthetases. Changes to the bicyclic core, removing either the terminal amino substituent or the sulfonyl group from the side chain, and altering either the carbon skeleton or stereochemistry of the isoleucine residue, decreases the potency of inhibition of isoleucyl tRNA synthetase. Substituting the isoleucine residue with other amino acids produces inhibitors of the corresponding synthetases. In particular, a methionine derivative is 50-100 times more potent against methionyl tRNA synthetase than against any of the corresponding isoleucyl, leucyl, valyl, alanyl and prolyl synthetases.

A versatile approach to the total synthesis of the pseudomonic acids

The total synthesis of pseudomonic acid C is described using an approach which gives access to analogues and putative biosynthetic precursors; the key step is installation of the C7 side-chain via alkylation of a trisubstituted δ-lactone with complete stereocontrol and in 85% yield under conditions which avoid the possible competing elimination of a protected hydroxy group β to the carbonyl.

CLEAVAGE OF THE 5-AMINO-5-CARBOXY-2-OXAPENTANOYL SIDE CHAIN FROM ENZYMATICALLY SYNTHESISED PENICILLINS AND CEPHALOSPORINS

Abstract Both 5R- and 5S-5-amino-5-carboxy-2-oxapentanoyl side chains can substitute for the L-δ-α-aminoadipoyl side chain in the isopenicillin N synthase catalysed formation of penicillins from tripeptides. The 5R- side chain analogue can be cleaved from penicillins and cephalosporins by treatment with D-amino acid oxidase followed by oxidative decarboxylation and decarboxylative elimination.

The chemistry of pseudomonic acid part 13. Modifications at C-12 to C-14☆

Abstract The novel antibiotic, pseudomonic acid, binds tightly to its target enzyme, isoleucyl t-RNA synthetase. The C12 to C14 region of the molecule is thought to bind to the isoleucine binding site of the enzyme. Semisynthetic analogues in which functionality present in this region have been systematically modified are reported here: all the derivatives prepared showed weak enzyme binding.

The chemistry of pseudomonic acid. Part 12. Preparation of diazole and triazole derivatives

The preparations of examples of normonyl †; imidazoles, pyrazoles and triazoles are described. Most derivatives were formed by treatment of monic acid amides with triphenylphosphine based dehydrating agents, resulting in cyclisation or cycloaddition of the intermediate dipolar species. One example is the novel one pot reduction–cyclisation of an α-acylamino nitrite to an imidazole.