Journal of Medicinal Chemistry · 1997 · 80 citations · 9 references
PharmacyMedicinal ChemistryMicrobiologyDrug DesignDrug DiscoveryStructure-activity RelationshipsAntibacterial AgentsAntibacterial PharmacologyAntibacterial ResistanceAntibiotic ResistanceEnzyme InhibitionHeterocyclic ChemistryAntibacterial Drug DevelopmentAntibiotic DiscoveryChemical Synthesis Of AnaloguesMinimum Inhibitory Concentration DeterminationMolecular Electrostatic PotentialNovel Antibacterial AgentsNovel Antibacterial Drug DiscoverySynthetic Analogues
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 Synthetic routes were developed to access a range of compounds where the alpha, beta-unsaturated ester moiety had been replaced by a 5-membered ring heterocycle.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.
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