The WHO has declared antimicrobial resistance a top 10 global threat. New antimicrobials with novel modes of action are therefore desperately needed. One such mode of action would be to target the aromatic amino acid biosynthesis pathway. Several extremely potent inhibitors of Dehydroquinate Synthase have been previously synthesized. One of those, a vinylphosphonate compound, was selected as the lead compound for this study. In this project, the inhibitor was re-synthesized and several methods to prepare prodrugs have been investigated. The synthesis of prodrugs of other related compounds was also explored.

Alzheimer’s Disease (AD) is a neurodegenerative terminal disease that affects 11% of Americans who are 65+ years old. The progression of AD has been associated with the dysregulation of reactive oxygen species (ROS) via multiple mechanisms, resulting in oxidative stress and neuronal damage. One of the focuses of the Green Lab at TCU is the development of PyN3 pyridinophanes that act as antioxidants to counter the effects caused by unregulated ROS. While most compounds synthesized within the lab both have antioxidant characteristics and activate the Nrf2 pathway, they face the issue of having poor permeability to the Blood Brain Barrier (BBB), making them unable to deliver the therapeutic effects to the diseased neurons. To counter this deficit, the series of molecules proposed herein aim to increase the lipophilicity of the base PyN3 molecules while maintaining or increasing their antioxidant potential. In pursuit of these aims, we aimed to utilize Suzuki-Miyara-like carbon-carbon bond formation to add aromatic, lipophilic, antioxidant moieties to the para position of the parent PyN3 molecule. Computational studies, including the BOILED-Egg plot, were used to identify these synthetic targets for probable BBB permeability with the goal of highlighting a new route in drug synthesis to increase the delivery of active compounds to target tissues past the BBB.

Macrocycles are promising drug design frameworks because their folding can enhance stability, solubility, and membrane permeability. Recently, triazine macrocycles derived from two monomers were reported. The cyclization is quantitative, but the role of chirality in macrocycle formation remains unclear. To address this issue, triazine macrocycles were synthesized from Fmoc-protected amino acids to test whether chiral sorting occurs. Chiral sorting refers to the tendency of amino acid precursors to selectively pair as homochiral species (D-D or L-L) or heterochiral species (D-L). Understanding this behavior can dictate macrocycle folding and stability. Preliminary results with valine and isoleucine suggest strong chiral sorting favoring homochiral species. In contrast, chiral sorting does not appear to occur alanine or isovaline, both of which follow the expected 1:2:1 distribution of DD, DL, and LL. These findings highlight stereochemical influences on macrocycle formation and provide insights for designing macrocycles with improved therapeutic potential.

Reactive Oxygen Species (ROS) are associated with a broad spectrum of diseases, ranging from bone loss to cancer. One strategy to combat ROS is to treat sources of such species in the body with materials capable of generating hydrogen and reacting with ROS to neutralize it. This project involves incorporating an H₂-generating material known as Calcium Disilicide (CaSi₂) into membranes of another H₂-generating material known as porous silicon for tandem antioxidant drug delivery. Porous silicon (pSi) is an important substrate in drug delivery as its nano-network of pores allows controlled loading of drugs. Our approach centers on the use of spark ablation to deposit CaSi₂ into the pSi. Both porous silicon and CaSi₂ are nontoxic and can be resorbed over time in vivo.

To prepare CaSi₂/pSi, a piece of pSi membrane is fixed to substrate with a small drop of nail polish, and CaSi₂ powder is added. A capillary tube is placed on the pSi and spark ablated with a high-voltage Tesla coil, causing Si atoms on the porous membrane to vaporize along with CaSi₂ and the mixture resettles upon cooling. Scanning Electron Microscopy (SEM) is used to characterize morphology, and in situ Energy Dispersive X-ray Spectroscopy (EDX) to determine the percentage of calcium in the sample. We use the criterion of highest CaSi₂ loading percentage to determine the conditions for most efficient addition of CaSi₂ into the membrane. We have successfully incorporated calcium disilicide into porous Si membranes; current experiments are attempting to measure the amount of hydrogen produced synergistically to improve the performance of porous silicon as a means to treat in situ ROS production.

Density Functional Theory (DFT) is a method for simulating molecules by approximating their electron densities, with various functionals available to
model these systems. M11plus is one such functional, a range-separated hybrid meta functional that combines long-range non-local Hartree–Fock
exchange with the non-local Rung 3.5 correlation, which has demonstrated effectiveness across a broad range of chemical databases. This work
implements the M11plus functional into the PySCF open-source Python library.​

Salt-induced diffusiophoresis is the movement of a charged nanoparticle in water, driven by an imposed directional gradient of salt concentration. This transport phenomenon has become an important tool for manipulating the motion of charged nanoparticles within porous materials and microfluidic systems. Micelles are valuable nanoparticles with the ability to host small guest molecules in aqueous media. Therefore, understanding micelle diffusiophoresis is also crucial for transport of small molecules. This poster reports experimental diffusiophoresis coefficients for the cationic micelle of hexadecylpyridinium chloride (CPC) in water the presence of NaCl and KCl. Thermodynamic parameters characterizing micelle-salt interactions were also experimentally determined. We find that micelle-salt interaction is the essentially the same for both salts. In contrast, we find that diffusiophoresis of CPC micelles occurs from high to low salt concentration in the NaCl case, while it occurs in the opposite direction in the KCl case. A model describing micelle-salt interactions and micelle diffusiophoresis based on theory of electric double layer is reported. This work offers new insights into diffusiophoresis of charged nanoparticles with potential applications for enhanced-oil recovery from porous rocks, micellar ultrafiltration for the purification of industrial water, and diffusion-based mixing inside microfluidics.

This research aims to develop and characterize synthetic riboswitches for creatinine and trimethylamine N-oxide (TMAO), metabolic biomarkers for kidney and cardiovascular dysfunctions. Riboswitches are structured RNA elements located in the 5’-untranslated regions (UTRs) of bacterial mRNAs that regulate downstream gene expression through ligand-induced conformational changes with high affinity and selectivity. To select for the synthetic riboswitches specific to creatinine, the glycine riboswitch library was subjected to a dual genetic selection. In the positive selection, the riboswitches that bind to creatinine or any endogenous molecules will produce the CAT-UPP fusion protein, allowing the host cells to survive in the presence of chloramphenicol. The negative selection is carried out in media containing 5-fluorouracil (5-FU) in the absence of creatinine. Any riboswitches activated by endogenous ligands will die in the presence of 5-FU. The surviving cells should contain the riboswitches that are activated only by creatinine. After several repeated selection steps, including increased concentrations of chloramphenicol and 5-FU, no glycine riboswitch variants were identified to show chloramphenicol resistance in the presence of creatinine. We will continue the project with different riboswitch libraries. We identified a synthetic riboswitch to TMAO, a riboswitch that was derived from the genetic selection of the theophylline riboswitch library that clearly shows chloramphenicol resistance only in the presence of TMAO. We will further test this TMAO riboswitch by colorimetric or fluorescence assays using β-galactosidase and green fluorescence protein, respectively, in the presence of varying concentrations of TMAO.

Sustainable synthetic approaches to drug delivery carriers such as porous silicon are becoming increasingly important for biomedical applications such as drug delivery, where extreme electronic-grade purity is not required, even though silicon remains a critical material in electronics and energy technologies. This work develops a green, self-propagating high-temperature synthesis (SHS) approach to produce high-surface-area porous silicon using plant-derived silicon dioxide (SiO₂) as the precursor, magnesium (Mg) as the reductant, and sodium chloride (NaCl) as a thermal moderator. The exothermic magnesiothermic reaction is initiated using a controlled electrical input of less than (or equal to) 9V, enabling silicon formation while significantly reducing external energy requirements compared to conventional high-temperature silicon production methods.

In practice, Mg and SiO₂ reactants are exposed to a finite voltage for approximately 10–15 minutes to allow the SHS reaction to propagate. After synthesis, the crude product is purified by dissolving reaction byproducts in concentrated hydrochloric acid, leaving behind porous silicon. X-ray powder diffraction (XRD) is used to evaluate crystallinity and phase composition. While XRD analysis confirms the formation of silicon, persistent crystalline silica peaks indicate incomplete reduction and phase coexistence that currently limits effective separation. Ongoing work focuses on optimizing reaction conditions and refining reaction kinetics to improve phase selectivity and identify optimal synthesis parameters. Despite these challenges, the low-energy synthesis strategy and use of accessible raw materials highlight the potential of SHS-derived porous silicon as a scalable and sustainable platform for future drug delivery applications, particularly in resource-limited settings.

Oxidative stress plays a significant role in the progression of Alzheimer’s disease, making cellular antioxidant pathways attractive therapeutic targets. The Keap1–Nrf2 signaling pathway regulates the cellular response to oxidative stress, and inhibition of the Keap1 protein can activate Nrf2, promoting neuroprotective antioxidant responses. In this study, a series of quinoline-modified macrocyclic compounds were designed and synthesized to evaluate their potential as Keap1 inhibitors.
Computational and experimental approaches were employed to investigate the interaction of these compounds with the Keap1 protein. In-silico studies were conducted to analyze the binding affinity of the synthesized compounds using molecular docking, molecular dynamics simulations, and machine learning–based prediction of IC₅₀ values. These analyses provided insight into the stability of the ligand–protein complexes and the structural features that influence binding interactions.
The computational results indicate that compounds containing polar substitutions on the upper synthon exhibit stronger binding affinity and form more stable complexes with the Keap1 protein. Additionally, modification of the macrocyclic scaffold with quinoline substitution on the side nitrogen was found to enhance interactions with the protein binding pocket, suggesting a favorable structural motif for Keap1 inhibition.
Together, these findings provide insight into structure–activity relationships for this class of compounds and highlight promising molecular features for the development of Keap1 inhibitors as potential therapeutic leads for Alzheimer’s disease.

Chemotherapy relies on two therapeutic paradigms. The classic approach, most often used, employs small molecules to specifically target enzyme active sites, as represented by the new generation of kinase inhibitors. A secondary approach relies on interfering with protein-protein interactions thus requiring the use of larger compounds. While this latter strategy is garnering the attention of the pharmaceutical community, the rules for the design of these larger molecules, which are often cyclic, are not understood. The compact shape of small molecules leads to predictable behaviors including oral availability and cell uptake. For larger molecules that adopt multiple shapes, understanding the factors that control their shape and dynamic motion provides opportunities to predict similar behaviors that are critical for rational drug design. Here, the synthesis and characterization of a library of large, cyclic molecules (macrocycles) is described. The macrocycles of interest result from the dimerization of monomers. A total of 50 monomers containing different drug-like groups were synthesized. Reaction of a single monomer yields a homodimer, while combination of two different monomers leads to a 1:1:2 mixture of homodimers and a heterodimer. These combinations ultimately lead to a library of 1,275 different compounds. Liquid chromatography-mass spectrometry confirms that >99.9% of the reactions were successful. To investigate the biological activity of these compounds, we have provided this library to high throughput drug-screening facilities at Vanderbilt University and Scripps Florida. Of the several compounds created, macrocycles containing hydroxylamine groups are of special interest for two reasons. First, these molecules are similar to Hydrea, a widely-used, FDA-approved cancer drug. Second, unlike most macrocycles, both the shape and dynamics of these molecules are well understood so critical parameters such as oral availability and membrane transit can be predicted.