Design, synthesis and evaluation of halogenated phenazine antibacterial prodrugs targeting nitroreductase enzymes for activation.

It is of great importance to develop new strategies to combat antibiotic resistance. Our lab has discovered halogenated phenazine (HP) analogues that are highly active against multidrug-resistant bacterial pathogens. Here, we report the design, synthesis, and study of a new series of nitroarene-based HP prodrugs that leverage intracellular nitroreductase (NTR) enzymes for activation and subsequent release of active HP agents. Our goals of developing HP prodrugs are to (1) mitigate off-target metal chelation (potential toxicity), (2) possess motifs to facilitate intracellular, bacterial-specific HP release, (3) improve water solubility, and (4) prevent undesirable metabolism (e.g., glucuronidation of HP's phenol). Following the synthesis of HP-nitroarene prodrugs bearing a sulfonate ester linker, NTR-promoted release experiments demonstrated prodrug HP-1-N released 70.1% of parent HP-1 after 16 hours (with only 6.8% HP-1 release without NTR). In analogous in vitro experiments, no HP release was observed for control sulfonate ester compounds lacking the critical nitro group. When compared to parent HP compounds, nitroarene prodrugs evaluated during these studies demonstrate similar antibacterial activities in MIC and zone of inhibition assays (against lab strains and clinical isolates). In conclusion, HP-nitroarene prodrugs could provide a future avenue to develop potent agents that target antibiotic resistant bacteria.

Pyrazine and Phenazine Heterocycles: Platforms for Total Synthesis and Drug Discovery.

There are numerous pyrazine and phenazine compounds that demonstrate biological activities relevant to the treatment of disease. In this review, we discuss pyrazine and phenazine agents that have shown potential therapeutic value, including several clinically used agents. In addition, we cover some basic science related to pyrazine and phenazine heterocycles, which possess interesting reactivity profiles that have been on display in numerous cases of innovative total synthesis approaches, synthetic methodologies, drug discovery efforts, and medicinal chemistry programs. The majority of this review is focused on presenting instructive total synthesis and medicinal chemistry efforts of select pyrazine and phenazine compounds, and we believe these incredible heterocycles offer promise in medicine.

Scaled Synthesis of Polyamine-Modified Cellulose Nanocrystals from Bulk Cotton and Their Use for Capturing Volatile Organic Compounds.

We have previously demonstrated that cellulose nanocrystals modified with poly(ethylenimine) (PEI-f-CNC) are capable of capturing volatile organic compounds (VOCs) associated with malodors. In this manuscript, we describe our efforts to develop a scalable synthesis of these materials from bulk cotton. This work culminated in a reliable protocol for the synthesis of unmodified cellulose nanocrystals (CNCs) from bulk cotton on a 0.5 kg scale. Additionally, we developed a protocol for the modification of the CNCs by means of sequential 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) oxidation and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) coupling to modify their surface with poly(ethylenimine) on a 100 g scale. Subsequently, we evaluated the performance of the PEI-f-CNC materials that were prepared in a series of VOC capture experiments. First, we demonstrated their efficacy in capturing volatile fatty acids emitted at a rendering plant when formulated as packed-bed filter cartridges. Secondly, we evaluated the potential to use aqueous PEI-f-CNC suspensions as a spray-based delivery method for VOC remediation. In both cases, the PEI-f-CNC formulations reduced detectable malodor VOCs by greater than 90%. The facile scaled synthesis of these materials and their excellent performance at VOC remediation suggest that they may emerge as a useful strategy for the remediation of VOCs associated with odor.

Ring Distortion of Vincamine Leads to the Identification of Re-Engineered Antiplasmodial Agents.

There is a significant need for new agents to combat malaria, which resulted in ∼409,000 deaths globally in 2019. We utilized a ring distortion strategy to create complex and diverse compounds from vincamine with the goal of discovering molecules with re-engineered biological activities. We found compound 8 (V3b) to target chloroquine-resistant Plasmodium falciparum Dd2 parasites (EC50 = 1.81 ± 0.09 µM against Dd2 parasites; EC50 > 40 µM against HepG2 cells) and established structure-activity relationships for 25 related analogues. New analogue 30 (V3ss, Dd2, EC50 = 0.25 ± 0.004 µM; HepG2, EC50 > 25 µM) was found to demonstrate the most potent activity, which prevents exit on the parasite from the schizont stage of intraerythrocytic development and requires >24 h to kill P. falciparum Dd2 cells. These findings demonstrate the potential that vincamine ring distortion has toward the discovery of novel antimalarial agents and other therapies significant to human health.

Iodinated Polyesters with Enhanced X-ray Contrast Properties for Biomedical Imaging.

Synthetic materials exhibiting contrast imaging properties have become vital to the field of biomedical imaging. However, polymeric biomaterials are lacking imaging contrast properties for deep tissue imaging. This report details the synthesis and characterization of a suite of aryl-iodo monomers, which were used to prepare iodinated polyesters using a pre-functionalization approach. Commercially available 4-iodo-phenylalanine or 4-iodobenzyl bromide served as the starting materials for the synthesis of three iodinated monomeric moieties (a modified lactide, morpholine-2,5-dione, and caprolactone), which under a tin-mediated ring-opening polymerization (ROP), generated their respective polyesters (PE) or poly(ester amides) (PEA). An increase in X-ray intensity of all synthesized iodine-containing polymers, in comparison to non-iodinated poly(lactic acid) (PLA), validated their functionality as radio-opaque materials. The iodinated-poly(lactic acid) (iPLA) material was visualized through varying thicknesses of chicken tissue, thus demonstrating its potenial as a radio-opaque biomaterial.

Degradation of pesticides using amine-functionalized cellulose nanocrystals.

A series of amine-functionalized cellulose nanocrystal materials were successfully synthesized, characterized, and evaluated for the remediation of pesticide contaminants from organic and aqueous media. Their ability to degrade malathion in organic systems has been examined, resulting in up to 100% degradation of the compound into detectable lower molecular weight by-products. A poly(ethylenimine) cellulose nanocrystal (CNC-PEI) material was also capable of degrading aqueous solutions of malathion, deltamethrin, and permethrin with 100%, 95%, and 78% degradation, respectively. Thus, these materials can potentially serve as a new and viable remediation technique based on their ability to effectively degrade various pesticides. The reusability of the CNC-PEI was also explored. The CNC-PEI material maintained its ability to degrade malathion throughout two wash and re-use cycles.

One-Pot Absolute Stereochemical Identification of Alcohols via Guanidinium Sulfate Crystallization.

A novel technique for the absolute stereochemical determination of alcohols has been developed that uses crystallization of guanidinium salts of organosulfates. The simple one-pot, two-step process leverages facile formation of guandinium organosulfate single crystals for the straightforward determination of the absolute stereochemistry of enantiopure alcohols by means of X-ray crystallography. The strong hydrogen bonding network drives the stability of the crystal lattice and allows for a diverse range of organic alcohol substrates to be analyzed.

Recent Advances in Polyesters for Biomedical Imaging.

Several synthetic materials exhibiting contrast imaging properties have become vital to the field of biomedical imaging. Polymeric biomaterials and metals are commonly used imaging agents and can assist in the monitoring of therapy response, migration, degradation, changes in morphology, defects, and image-guided surgery. In comparison to metals, most bio and synthetic polymers lack inherent imaging properties. Polymeric biomaterials, specifically polyesters, have gained a considerable amount of attention due to their unique properties including biocompatibility, biodegradation, facile synthesis, and modification capability. Polyester implants and nanomaterials are available on the market or are in clinical trials for many applications including: dental implants, cranio-maxilofacial implants, soft tissue sutures and staples, abdominal wall repair, tendon and ligament reconstruction, fracture fixation devices, and coronary drug eluting stents. This review aims to provide a summary of the recent developments of polyesters with bioimaging contrast properties. The three main approaches to prepare bioimaging polyesters (coating, encapsulation, and functionalization) are discussed in depth. Furthermore, commonly used imaging modalities including X-ray computed tomography, magnetic resonance imaging, ultrasound, fluorescence, and radionucleotide polyester contrast agents are highlighted. In each section, examples of impactful bioimaging polyesters in the five major imaging modalities are evaluated.

Poly(amine) modified kaolinite clay for VOC capture.

Polyethylenimine (PEI) functionalized kaolinite clay was successfully prepared, characterized, and assessed for the remediation of volatile organic compounds (VOCs) comprising the aldehyde, carboxylic acid, and disulfide functional group classes. A gas chromatographic vapor capture assay evaluated the capability of unmodified and modified clay material to capture representative aldehyde, carboxylic acid, and disulfide VOCs in a laboratory setting. Unmodified kaolinite (Kao) clay was moderately or poorly effective at remediating these VOCs, while the poly(amine) functionalized Kao was capable of capturing VOCs in the vapor phase with reductions up to 100%. Sample cartridge tubes were packed with PEI-functionalized clay in order to assess their ability to reduce the detectable volatile fatty acid load at an open-air rendering plant in a relevant field test for applying these materials in a packed-bed scrubber application. The PEI-Kao packed cartridges were capable of significantly reducing the detectable concentration of volatile fatty acid effluent from the rendering operation. These volatile fatty acids are major contributors to nuisance odors associated with rendering.