Immobilization of antimicrobial peptides (AMPs) holds potential for creating surfaces with bactericidal properties. In order to successfully incorporate AMPs into desired materials, increased fundamental understanding of the relationship between AMP immobilization and the efficacy of bound peptides as antibacterial agents is required. In this study, we characterize the relationship between surface binding of the AMP and subsequent ability of the peptide to kill bacteria. Surface immobilization of the AMP chrysophsin-1 (CHY1) via a flexible linker is studied in real-time, using a quartz crystal microbalance with dissipation monitoring (QCM-D). Depending on whether the AMP is physically adsorbed to the surface or attached covalently via a zero-length or flexible cross-linker, changes could be observed in AMP orientation, surface density, flexibility, and activity against bacteria. Covalent surface binding of CHY1 led to the formation of solvated monolayers of vertically positioned peptide molecules, while the physical adsorption of CHY1 led to the deposition of rigid monolayers of horizontally positioned peptide molecules on the sensor surface. Covalently bound peptides were not removed by extensive washing and did not leach from the surface. Zero-length immobilization of the peptide decreased its ability to kill E. coli to 34% ± 7% of added bacteria, while binding via a flexible linker resulted in 82% ± 11% of bacteria being killed by the AMP.

A total synthesis of the illudalane sesquiterpene illudinine was realized in eight steps and 14% overall yield from commercially available dimedone. The approach features tandem fragmentation/Knoevenagel-type condensation and microwave-assisted oxidative cycloisomerization to establish the isoquinoline core. Completion of the synthesis involves a recently reported cascade SAr/Lossen rearrangement on a densely functionalized aryl bromide and an optimized procedure for O-methylation of 8-hydroxyisoquinolines. The oxidative cycloisomerization proceeds by way of a novel inverse-demand intramolecular dehydro-Diels-Alder cycloaddition, which has a potentially broader appeal for preparing substituted isoquinolines.

A cascade (cyclo)isomerization/elimination process produces novel isoquinoline derivatives of potential interest for pharmaceutical, biomedical, and energy-related research. Mechanistic experiments support a putative allenylpyridine (reminiscent of the Garratt-Braverman cyclization) as a key intermediate in the cascade process.

A synergy between theory and experiments leads to a milder protocol for base‐mediated high‐temperature benzannulation of alkynylpyridine substrates. Computational analysis identifies mechanistic and energetic nuances in the previously postulated 1,3‐proton transfer isomerization which results in replacement of DBU with a bicyclic guanidine, 1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene (TBD). We have also outlined the general stereoelectronic and geometric hurdles for the design of 1,3‐proton transfer catalysts. Considerable reductions in time, temperature, and equivalents of base underscore the potential of computational analysis to impact experimental design in the laboratory.

Neopentylene ring fusions (ring-fused 4,4-dimethylcyclopentane polycycles) are found in many natural products, but they are largely absent from synthetic compound libraries and focused medicinal chemistry research. Here is reported a synthetic approach to one of the few non-natural product-based target compounds from medicinal chemistry that includes a neopentylene ring fusion: an analogue of ibuprofen referred to herein as “neoprofen”. The approach features ring-opening fragmentation reactions of dimedone derivatives coupled with transition metal-catalyzed benzannulation and hydrocarboxylation methods.