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 aci d analogues were investigated. Synthetic routes were developed to acce ss a range of compounds where the alpha,beta-unsaturated ester moiety had been replaced by a 5-membered ring heterocycle.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 det ermined as was the minimum inhibitory concentration (MIG) of the test compounds against that organism. Compounds possessing a region of elec trostatic potential corresponding to that of the carbonyl group in the alpha,beta-unsaturated ester, and a low-energy unoccupied molecular o rbital in the region corresponding to the double bond, were found to h ave 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 mu g mL(-1), reflecting their poor er penetration into the bacterial cell.