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.