| Heterocycles comprise the backbone of many medicinally significant structures; however, the synthesis of heterocycles provides a significant challenge as existing routes can be expensive, complicated and inconsistent. Research in our laboratory previously demonstrated the efficient preparation of substituted oxepanes, seven-membered oxygen-containing heterocycles, by cyclopropane fragmentation, a method that constructs a new bond by utilizing the significant strain energy contained in cyclopropane. An analogous strategy has been applied to seven-membered nitrogenous heterocycles, azepines. The formation of the heterocycle is accomplished by preparing a cyclic aminal, activating it to form an iminium species and cyclizing using a cyclopropanol unit, made by the Kulinkovich reaction. The synthesis of the azepine using the cyclopropane fragmentation approach has been achieved and further optimized to moderate success. Antimicrobial resistance is a growing concern for modern medicine, as existing antibiotic treatments are becoming less and less effective at killing infectious organisms. In addition, existing antibiotic treatments are generally ineffective against biofilms, complex communities of bacteria that exist in a self-produced matrix. This deficiency in current antibiotics opens a platform for development of a new generation of antibacterial and antibiofilm targets. Amphiphiles, compounds with both polar and non-polar regions, have long served as antimicrobial agents, and continuing research in amphiphilic structures has provided new insight into structural features that offer the most potent antimicrobial activity. This work explores the syntheses and biological application of two series of amphiphiles: the first series investigates a previously unreported set of bipyridinium amphiphiles; the second series extends the use of quaternary ammonium amphiphiles, already known to be potent antibacterial agents, to biofilm disruption. The results of biological testing are highlighted by some of the most potent antibiofilm and antibacterial compounds reported to date. |
