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

Abstract

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 Synthetic routes were developed to access a range of compounds where the alpha, beta-unsaturated ester moiety had been replaced by a 5-membered ring heterocycle.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.

Structural Basis for the Recognition of Isoleucyl-Adenylate and an Antibiotic, Mupirocin, by Isoleucyl-tRNA Synthetase

“…It has already been reported that when the conjugated system and the nonanoic acid moiety are replaced by proper chemical groups that maintain both the electrostatic potential and the unoccupied molecular orbital features, the inhibitory activities do not change (29). The present crystal structure of the IleRS⅐mupirocin complex suggests that the hydrogen bond between the carbonyl oxygen attached to C-1 and the main chain amide group of Ile-584 mainly contribute to the electrostatic potential and that the interaction between the C-1 to C-3-conjugated system and the side chains of Leu-583 mainly contribute to the unoccupied molecular orbital.…”

Conversion of 2(3H)‐furanones into 1,3,4‐oxadiazoles

“…2-Aryl-5-alkenyl-1,3,4-oxadiazoles have been reported to show antibacterial [1,2], antifungal [3], analgesic, antiinflammatory [4,5], and hypoglycemic [2] activity. The most popular synthesis of 2,5-disubstituted-1,3,4-oxadiazoles is based on the thermal or acid-catalyzed cyclization of 1,2-diacylhydrazines [6].…”

“…The most popular synthesis of 2,5-disubstituted-1,3,4-oxadiazoles is based on the thermal or acid-catalyzed cyclization of 1,2-diacylhydrazines [6]. Ring closure usually proceeds in the presence of hot phosphorus, using phosphorus oxychloride [2,3,[7][8][9][10], although an improved method by triphenylphosphine/carbon tetrachloride/triethylamine reagent has also been reported [1]. These results promoted us to convert 2(3H)-furanones 1a-f into 1,3,4-oxadiazoles 4a-f.…”

Synthesis of 2-(substituted-phenyl)-5-(aminomethyl)- and (thiomethyl)-1,3,4-oxadiazoles. Oxidation of thiomethyl-oxadiazole derivatives by dimethyldioxirane

“…1 Since many of them display a remarkable biological activity, their synthesis and transformations have been received particular interest for a long time. The 2-aryl-5-(substituted methyl)-1,3,4-oxadiazoles have been reported to show antibacterial, 2,3 antifungal, 4 analgesic and antiinflammatory 5,6 , and hypoglycemic 3 activity. Their synthetic usefulness has also been demonstrated.…”