Every 65 seconds, someone develops Alzheimer's disease, which is the seventh leading cause of death in the United States. A major barrier to potential therapeutics is the permeability of these molecules across the blood-brain barrier. We have developed small molecules with strong reactivity to combat the oxidative stress known to cause Alzheimer’s disease. However, the permeability is less than ideal. As a result, my goal is to produce a molecule that has enhanced permeability but retains the reactivity of the parent molecules. To achieve this, the BOILED-Egg model assessed different derivatives of our parent molecule, Py2N2. This model showed the differences in lipophilicity among different Py2N2 compounds and how they impact permeability into the blood-brain barrier and gastrointestinal tract. Background information on our parent molecule and its function regarding Alzheimer's development will be outlined to give a scope of what these compounds can target and how they function. Compounds with high lipophilicity reflected in the model will have schemes of synthetic synthesis for future directions.

In the pursuit of new ways to develop libraries of compounds for pharmaceutical drug discovery, the utilization of a robust and tunable macrocycle synthetic scaffold has led to the discovery of persistent and structurally well-defined conformational isomers. Targeting these macrocycles that exist as an ensemble of preorganized conformations represents a compromise between the pursuit of flexible molecules of undefined structure and rigid molecules biased towards a single conformation. This system is based on the quantitative dimerization of a monomer to afford macrocycle. When a single monomer is used, six unique structures are obtained. When two monomers are used, twenty unique structures are obtained. These different structures (conformational isomers) are accessed via hindered bond rotation with a barrier of ~18 kcal/mol and are observable by ¬1H NMR. Current drug discovery methods heavily rely on screening large chemical libraries of small, ridged molecules against protein targets and typically sacrifice entropy in favor of stronger ligand-target binding. Using our system, synthesis of 50 monomers allows for the generation of a library of over 10,000 structurally unique macrocycles. The goal of this work is to provide new chemical libraries for drug discovery.

EUK-134 is a manganese-salen complex widely used in anti-aging skincare formulations due to its potent antioxidant activity resulting from catalytic decomposition of reactive oxygen species. Despite its popularity, the fundamental kinetic properties that govern its efficacy and recyclability are not well understood, limiting its optimization in skincare products. As a result, the study presented here investigates the efficiency, sustained activity, and selectivity of EUK-134 in comparison to the Green lab ligand library by evaluating its turnover number (TON), turnover frequency (TOF), and reaction rate. Results indicate that while EUK-134 demonstrates high catalase-type activity and selectivity, the activity decreases with continuous exposure to H₂O₂, suggesting a need for re-application in real-world scenarios to achieve long-term protection. Additionally, selectivity studies show that peroxidase activity was observed, which may impact the stability of sensitive ingredients in formulations. These findings provide essential kinetic benchmarks to compare future small molecules and optimize EUK-134’s use in antioxidant skincare products. Without a clear understanding of these fundamental properties, we lack benchmarks to compare future small molecules that compete with EUK-134.

Perfluoroalkyl substances (PFAS), known as "forever chemicals", are ubiquitous environmental contaminants whose remarkable persistence poses significant risks to human health and ecosystems. Thus, it is important to develop analytical assays to determine PFAS concentrations based on widely accessible, readily available instrumentation, such as UV-VIS spectrophotometry. Tetrasodium tetraphenylporphyrintetrasulfonate (TPPS) is a water-soluble porphyrin known for its spectrophotometric property in water. It is also known that TPPS binds to the protein bovine serum albumin (BSA). We investigated the effect of BSA on the absorption spectrum of TPPS and how PFAS presence impacts BSA-TPPS interaction in water. Interestingly, we found that BSA induces TPPS precipitation. As BSA concentration increases, TPPS solubility first dramatically decreases, then increases, ultimately leading to the formation of homogeneous solutions at relatively high BSA concentration. Furthermore, addition of two different PFAS, sodium perfluorohexanoate and potassium perfluorobutanesulfonate salts, to homogeneous BSA-TPPS mixtures appreciably alter TPPS spectra. Our results show that these mixtures can be used to produce calibration curves relevant to the determination of PFAS concentrations in water.

Some of the most effective drugs from Nature are large and ring-shaped, so-called macrocycles. Macrocycles are interesting because they can interfere with protein-protein interactions, a different strategy for therapy than that used by small molecules (like aspirin). The challenge with the design of macrocycle drugs is that they are difficult to make and behave unpredictably. Here, an efficient strategy to make macrocycles is described. These molecules behave consistently (with preserved shapes) and can be tailored to optimize binding (a hallmark of drug design). The two macrocycles described differ in the choice of one group with significant (and predictable) consequences. Both groups mimic amino acid sidechains that are implicated in protein-protein interactions. One amine, N-methylbenzylamine, yields a macrocycle that will adopt six conformations in solution (an advantage when looking for drugs). The second amine, isobutylamine, gives more than eight conformations. Structural analysis was accomplished by NMR spectroscopy.