The Chemistry of Pseudomonic Acid.† 18. Heterocyclic Replacement of the α,β-Unsaturated Ester: Synthesis, Molecular Modeling, and Antibacterial Activity1

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 Synthetic routes were developed to access a range of compounds where the α,β-unsaturated ester moiety had been replaced by a 5-membered ring heterocycle.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 α,β-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 μg mL-1, reflecting their poorer penetration into the bacterial cell.