Synthesis and Evaluation of Amino Acid Ester Substituted Pseudopyronine Derivatives

Stephanie Holz

Chemistry/Biochemistry

Amanda Wolfe

As antibiotic resistance continues to be an increasing problem worldwide, the synthesis and evaluation of novel antibiotic compounds is becoming necessary. Natural products have become a promising source of exploration, as many of these compounds have not been used clinically, and therefore bacterial pathogens have no associated resistance mechanisms. Pseudopyronines A and B of the α-pyrone class have been isolated and seen to exhibit both antibacterial and anticancer activities. Previous research by Fields et al. has demonstrated that the α-pyrone core has potential inhibitory effects on efflux pumps, which are commonly overexpressed in many Gram-negative bacteria. Additionally, Rath et al. determined that the addition of bulky amino acid substituents to natural compounds also increases inhibition of NorA efflux activity in Gram-positive bacteria. Finally, Bouthillette et al. determined through SAR study of pseudopyronine that specific chain alterations allow for specificity in antibacterial activity against Gram-negative and -positive bacteria. Based on this prior work, this research aims to synthesize short chain pseudopyronine derivatives in which previous methods were used to substitute the hydroxyl group of the α-pyrone core using various L-amino acid methyl esters. Based on these methods being mostly ineffective, the site of amino acid addition has been changed to a carbonyl present on the alkyl chain at the C6 position of the α-pyrone core. These synthesized compounds were tested biologically using a cell death assay in determination of whether they stand alone as antibiotic compounds themselves. Further testing will be required to discern if these compounds are more suited as an adjuvant therapy.

Jan-9-2024