Abstract

The World Health Organization recognizes antimicrobial resistance as a global problem caused by the decreasing effectiveness of conventional antibacterial drugs. Estimates are that by 2050, 10 million lives a year would be at risk from drug-resistant infections. The Wolfe research group works to develop novel antibiotics through the isolation, extraction, and characterization of secondary metabolites produced by bacteria, and by leveraging antibiotic scaffolds provided by nature to synthesize and optimize antibacterial activity through medicinal chemistry techniques. Empetroxepin A and B, isolated from the black crowberry tree, Empetrum nigrum L. (Ericaceae), exhibited weak antimycobacterial activity against M. tuberculosis H37Ra (MIC = 100 μg/mL, IC50 =25.7 μg/mL and IC50 = 28.5 μg/mL) and selectivity against human embryonic kidney 293 cells (IC50 45.6 μg/mL and IC50 96.7 μg/mL). Prior research resulted in a synthetic strategy for both empetroxepin analogs by forming an alkene bridge between a triphenylphosphate salt and a trimethylsilane (TMS) protected salicylaldehyde followed by cyclization using potassium carbonate and a copper oxide catalyst. This research introduced an alternate strategy using an Ullman type reaction for cyclization and transfer hydrogenation to reduce an aromatic alkene, increasing overall yields from 0.5% to over 13%. The effects of new ligands on the empetroxepin core were investigated by introducing commercially available substituted salicylaldehydes chosen for their influence on steric and electrochemical properties. Results revealed deprotected analogs to have cell death activity against Gram-positive S. aureus (0.46 to 0.92 mg/mL) but not Gram-negative E. coli bacteria. Cell wall viability assays revealed broad spectrum activity, indicating empetroxepin acts to inhibit bacterial cell walls and that activity was significantly affected by substituent type and position.

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