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.

This project is to synthesize a known nanomolar inhibitor of dehydroquinate synthase for evaluation as an antimicrobial agent in collaboration with TCU's Biology Professor McGillivray. It is estimated that nearly 10 million individuals could die per year due to antimicrobial resistance by the year 2050 (1). The focus will be two-fold: first, the improved synthesis of alkenylphosphonate 1, and then its elaboration into various prodrugs to improve its activity in vivo. The in vitro activity of 1 on dehydroquinate synthase is Ki = 0.29 nM, while the enzyme's substrate has Km = 4 microM (2). Dehydroquinate synthase is an enzyme that is part of the aromatic amino acid biosynthetic pathway, which is essential to bacteria and plants but does not exist in mammals - which is why we must eat vegetables and fruits. Thus, the toxicity to humans of antibacterial compounds targeting this pathway should be minimized.

Compound 1 was synthesized previously (2), but improvements to its synthesis must be made since it will be the starting material for the preparation of prodrugs. Prodrugs are compounds that are precursors of 1 but where the charge is masked. Because inhibitor 1 is highly hydrophilic, this prodrug strategy should be necessary to achieve biological activity in vivo. Initial work will aim at the large-scale preparation of 1 and particularly eliminate as much as possible the need for purification by chromatography.

Lab safety across independent academic and research labs for undergraduate and graduate students is critical to creating a successful chemistry experience. Many students at Texas Christian University (TCU) are heading into the medical field where healthcare professionals work in sensitive and controlled environments every day. Others are moving to research and industrial labs where safety is a critical component of success. Safety concerns constantly arise within these environments. Understanding how to manage a hazard or safety concern is a critical skill that translates to a successful professional skillset and creates a positive professional environment. TCU is offering a groundbreaking safety course for undergraduates and graduate students starting Fall 2024. Students in the course will focus on learning objectives from American Chemical Society’s, “Guidelines for Chemical Laboratory Safety in Academic Institutions”. The TCU Chemistry Club is working to complement this new course with a campus awareness campaign and include local elementary schools that work with Chemistry Club. We will be discussing the various awareness strategies that the Chemistry Club has implemented to achieve awareness at various campuses.

Predicting pKa and pH-dependent speciation is an important aspect of drug design. Often, pKa behaviors govern various properties including solubility, docking poses, and membrane permeability of drug molecules. Understanding these properties is critical for synthesizing an applicable drug molecule for a given ailment. Traditionally, fairly accurate computational pKa predictions are achievable for small rigid gas-phase molecules with a single acid/base site. However, the same level of accuracy has not been reached for larger, macrocyclic molecules that more closely resemble pharmaceuticals. To predict the pKa for their large, flexible, polybasic molecules in water, new workflows were developed to account for solvation and conformational dynamics incurred by these larger molecules in solution. We evaluated a series of flexible tetra-aza macrocyclic small molecules derived from pyclen using conformational analysis alongside continuum solvent models and DFT calculations to obtain pKa predictions. Utilizing a linear fit we can obtain an RMSD of 0.9 pKa units which is competitive with the best physics-based methods in the SAMPL6 benchmark for pKa predictions. This presentation will focus on the development of the workflow, benchmarking, and results.

Superoxide dismutase (SOD) enzymes are a major defense against superoxide, which is a potent reactive oxygen species. SOD mimics have potential clinical relevance as treatments for neurodegenerative diseases. The Green group at TCU synthesized tetra-aza macrocycle copper complexes since they serve as promising SOD mimics. The redox potential of these complexes is a critical factor in their antioxidant activity, as it determines their ability to bind and transfer electrons. However, the vast number of possible tetra-aza macrocycles presents a challenge for experimental synthesis and testing. To address this, we perform computational simulations to predict the redox potential of un-synthesized tetra-aza macrocycles, helping to identify the most promising candidates for further study. This work, in combination with other predictive models for properties such as pKa, solubility, permeability, and metal binding, accurate redox potential simulations can help focus experimental efforts on the most viable SOD mimics, accelerating the development of effective treatments.

Liquid Phase Deposition of Nickel Oxide as a Hole Transport Layer for TEMPO-Mediated Oxidation

Favor Igwilo, Texas Christian University, Class of 2026
Laboratory of Dr. Benjamin Sherman, PhD;
Department of Chemistry and Biochemistry

Efficient positive charge (hole) transport is essential in photoelectrochemical systems for driving oxidation reactions. In our target process, 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO), a stable free radical mediator, drives the redox reaction of benzyl alcohol to benzaldehyde, a reaction with significant applications in industrial processes and synthetic chemistry. TEMPO-mediated oxidation offers a sustainable alternative to conventional oxidation methods that generate hazardous waste, highlighting the need to enhance its viability in photoelectrochemical applications. Nickel oxide (NiO), a p-type semiconductor, is suited for this role due to its hole transport ability, abundance and cost-effectiveness compared to conventional alternatives such as TiO₂. To integrate NiO as a hole transport layer in TEMPO-mediated oxidation, we developed a liquid phase deposition (LPD) protocol for fabricating uniform NiO films on fluorine-doped tin oxide (FTO) glass. These films were incorporated into FTO|WO3-BiVO4 photoanodes to improve charge separation and hole extraction under light conditions.

Our experiments indicates that the uniformity and quality of NiO films are affected by deposition parameters, including the pH of the boric acid (H₃BO₃) solution, the type of base employed for pH adjustment (NH₄OH vs. NaOH)), and the temperature of nickel(II) fluoride tetrahydrate (NiF₂·4H₂O) to H₃BO₃ precursors. Characterization by profilometry reveals that maintaining a pH between 7.5 and 8 consistently produces uniform films with thicknesses in the range of 100–200 nm. UV–Vis spectroscopic analysis confirms the expected optical absorption of NiO in the near-ultraviolet region, while further electrochemical characterizations via cyclic voltammetry and chronoamperometry will further assess hole transport efficiency. This work establishes a scalable approach for NiO film fabrication that will enhance the performance of WO₃–BiVO₄ photoanodes in TEMPO-mediated oxidation processes, advancing sustainable, solar-driven alcohol oxidation with reduced environmental impact.

Emma Kulla, ¹Emily Rathke, ¹Braden Chadwick, Shauna M McGillivray, and Jean-Luc Montchamp*

¹Contributed equally

"Synthesis of Penicillin G Prodrugs and Assessment of Antibiotic Activity"

ABSTRACT
The goal of our project is to synthesize and evaluate prodrugs for phosphorus-containing antibiotics. To begin, we evaluated common prodrug moieties. This is because the preparation of phosphorus prodrugs is significantly more complex than that of carboxylic acids. In an attempt at determining the best prodrug moieties or at least establish if there are significant differences among the various bacterial strains, a series of compounds was synthesized. Penicillin G (potassium salt) was chosen as the model compound since it is a well-established antibiotic, and since there is only a carboxylate group needing derivatization. The potassium salt of penicillin G (PenCOOK) was esterified directly to PenCOOR by alkylation in DMF. The following R groups have been prepared: CH₂OC(O)t-Bu, CH₂C₆H₄(4-OAc), CH₂C₆H₄(4-NO₂), and CH₂C₆H₅. The former two compounds should be triggered by bacterial esterases, whereas the nitrobenzyl ester should be triggered by bacterial nitrogenases. The benzyl ester provides a control for the para-substituted benzyl derivatives. These compounds were then tested against the gram-positive pathogen, Bacillus anthracis Sterne. We find that the minimum inhibitor concentration (MIC) of the control (non-derivatized) penicillin-G was 120 μM (approximately 40 μg/ml), which is consistent with our previous studies. The addition of the prodrug moieties substantially increased the effectiveness of penicillin for all 4 pro-drugs. This result was most striking with EK31 (R = CH₂OC(O)t-Bu), which lowered the MIC to 3.75 μM (1.25 μg/ml). These results may be confounded by the lack of solubility of these prodrugs in aqueous media as EK31 also had the best solubility of the prodrugs tested. Future experiments will be needed to address this challenge and optimize the prodrugs, but our results indicate this is an effective approach.

Oxidative stress through the production of reactive oxygen species (ROS) has been shown to damage molecules in the brain and lead to the neuronal damage characteristic of AD. Additionally, metal ions like iron, copper, and zinc have been shown to not only bind to amyloid beta proteins and induce their aggregation, one hallmark of AD, but these metals also stimulate the production of ROS. To effectively fight AD, therapeutics should not only be able to chelate these metals and reduce oxidative stress but also prevent the aggregation of amyloid beta proteins. The Green Lab has produced ligands that both effectively chelate metals and reduce oxidative stress through interacting with ROS, but these ligands simply prevent the progression of the disease without affecting amyloid-beta protein aggregation directly. In this presentation, a synthetic scheme is proposed for the creation of a Green Lab ligand with the KLVFF peptide attached. The KLVFF peptide in the past has been shown to prevent amyloid-beta plaques from aggregating in vitro. Additionally, research has also been done showing that KLVFF, when attached to nanoparticles, can pass through RAGE receptors that are produced in the brains of AD patients. Through the addition of this peptide to the ligand, a small molecule that can chelate transition metals, reduce the effects of ROS, and prevent amyloid-beta aggregation will have been synthesized, providing a potential new therapeutic solution for Alzheimer's Disease treatment.

Salt-induced diffusiophoresis is the migration of a charged nanoparticle in water, induced by an imposed directional gradient of salt concentration. This transport phenomenon has emerged as a valuable tool for particle manipulation inside porous materials and microfluidics. Micelles represent a common example of nanoparticles with the crucial ability of hosting small guest molecules. Thus, micelle diffusiophoresis is important in the manipulation of small molecules. Micelle diffusiophoresis depends on micelle Brownian mobility or diffusion coefficient. This transport parameter describes the intrinsic ability of a micelle to randomly move (diffuse) in water. The poster reports diffusion-coefficient measurements carried out on aqueous solutions of the surfactant, hexadecylpyridinium chloride (CPC), in the presence of aqueous NaCl by dynamic light scattering. The effect of surfactant and salt concentrations on the diffusion coefficient of CPC micelles is discussed. These data are used to characterize salt-induced diffusiophoresis of charged micelles.

In this work, a single-layer tungsten oxide (WO₃) film on fluorine-doped tin oxide (FTO) coated glass was successfully prepared by the dip-coating method, followed by thermal treatment at 450°C. The structure and electrochemical properties of the WO₃ film were then determined via UV-Vis spectroscopy, IR absorption, surface profilometry, and XRD analysis. The result suggests that the films have consistent thickness and uniformity, with future investigations needed to explore how they interact with the addition of a nickel oxide layer and bismuth vanadate layer determined by electrochemical measurements such as cyclic voltammetry, chronoamperometry under light and dark conditions. WO₃ electrode can be used as the base layer to make FTO-WO₃-Bismuth Van(BiVO₄)-Nickel Oxide (NiO) electrode ,which has the potential to improve the photochemical performance in photoelectrochemical cells.