Molecular recognition of tyrosinyl adenylate analogues by prokaryotic tyrosyl tRNA synthetases.

Molecular modelling and synthetic studies have been carried out on tyrosinyl adenylate and analogues to probe the interactions seen in the active site of the X-ray crystal structure of tyrosyl tRNA synthetase from Bacillus stearothermophilus, and to search for new inhibitors of this enzyme. Micromolar and sub-micromolar inhibitors of tyrosyl tRNA synthetases from both B. stearothermophilus and Staphylococcus aureus have been synthesised. The importance of the adenine ring to the binding of tyrosinyl adenylate to the enzyme, and the importance of water-mediated hydrogen bonding interactions, have been highlighted. The inhibition data has been further supported by homology modelling with the S. aureus enzyme, and by ligand docking studies.

The chemistry of pseudomonic acid. 18. Heterocyclic replacement of the alpha,beta-unsaturated ester: synthesis, molecular modeling, and antibacterial activity.

The electronic requirements around the C1-C3 region of pseudomonic acid analogues were investigated. Synthetic routes were developed to access a range of compounds where the alpha, beta-unsaturated ester moiety had been replaced by a 5-membered ring heterocycle. The inhibition of isoleucyl tRNA synthetase from Staphylococcus aureus NCTC 6571 was determined as was the minimum inhibitory concentration (MIC) of the test compounds against that organism. Compounds possessing a region of electrostatic potential corresponding to that of the carbonyl group in the alpha, beta-unsaturated ester, and a low-energy unoccupied molecular orbital in the region corresponding to the double bond, were found to have IC50 values of 0.7-5.3 ng mL-1. However the MIC values of these compounds were in the range 2.0-8.0 micrograms mL-1, reflecting their poorer penetration into the bacterial cell.

6-(substituted methylene)penems, potent broad spectrum inhibitors of bacterial beta-lactamase. IV. Kidney stability, serum binding and additional biological evaluation of racemic derivatives.

Sodium (5RS)-Z-6-(substituted methylene)penem-3-carboxylates (3) are extremely potent inhibitors of bacterial beta-lactamases, but some members of this group of compounds are highly bound to human serum, while others are readily degraded by renal dehydropeptidase I enzyme. Consequently, the stability of a variety of 6-(substituted methylene)penems (3) to human kidney homogenate, their binding to human serum and their activity in a mouse infection model was investigated at an early stage, and were instrumental in the selection of the 1,2,3-triazolylmethylene derivatives (e.g. 3k) as a class of compounds worthy of further evaluation.

6-(substituted methylene)penems, potent broad spectrum inhibitors of bacterial beta-lactamase. III. Structure-activity relationships of the 5-membered heterocyclic derivatives.

Sodium (5RS)-Z-6-(heterocyclylmethylene)penem-3-carboxylates (2) are a series of extremely potent inhibitors of bacterial beta-lactamases. A variety of 5-membered heteroaromatic derivatives have been prepared and structure-activity studies reveal a preferred substituent orientation. One of these derivatives, the 1-methyl-1,2,3-triazolyl compound (5m) is a more potent synergist of amoxycillin than clavulanic acid, sulbactam or tazobactam.

6-(substituted methylene)penems, potent broad spectrum inhibitors of bacterial beta-lactamase. I. Racemic 6-ethylidenepenems.

The dehydration of various 6-(1-hydroxyethyl)penems to give E- and Z-6-ethylidenepenems is described. Both isomers have been shown to be potent broad spectrum inhibitors of bacterial beta-lactamases capable of reducing the MIC values of beta-lactam antibiotics such as amoxycillin and cephaloridine against a wide range of resistant organisms.

6-(substituted methylene)penems, potent broad spectrum inhibitors of bacterial beta-lactamase. II. Racemic furyl and thienyl derivatives.

A series of racemic 6-(substituted methylene)penems have been prepared. These compounds contain a 5-membered monoheteroaromatic ring at C-8. The antibacterial/synergistic and beta-lactamase inhibitory activities of both E- and Z-isomers and 2-substituted derivatives are compared.

Structure--activity relationships in cephalosporins prepared from penicillins. 1. 7beta-Acylamino derivatives of 3-benzyl- and 3-(3-pyridylmethyl)ceph-3-em-4-carboxylic acids.

tert-Butyl 7beta-aminoceph-3-em-4-carboxylates carrying either benzyl or 3-pyridylmethyl substituents at position 3 have been prepared by a multistep modification of the penicillin nucleus. Acylation of either amine, followed by deprotection, gave a range of new cephalosporins. The relationship between structure and antibacterial activity is discussed. D-Phenylglycine proved to be a preferred side chain in both series.

Structure--activity relationships in cephalosporins prepared from penicillins. 2. Analogues of cephalexin substituted in the 3-methyl group.

A previously outlined general procedure for preparing various 3-substituted cephalosporins from the penicillin nucleus has been used, with modifications where required, to prepare a series of analogues of cephalexin with various substituents in the 3-methyl group. The 3-substituents most conducive to broad-spectrum antibacterial activity were 3-pyridylmethyl and m- or p-carboxybenzyl. The compounds were only poorly absorbed by the oral route in mice, but the 3-(carboxybenzyl) compounds gave more prolonged useful serum levels than the usual cephalosporins.