Synthesis of Indole-3-Acetic Acid Derivatives and a Urea Carboxylic Acid Derivative by Propylphosphonic Anhydride (T3P)

The purpose of medicinal chemistry is to efficiently create a variety of compounds with potential for pharmacological efficacy. To promote this diversity, indole-3-acetic acid, a common plant hormone, was used as the starting material for various reactions. The coupling reagent used for these reactions was propylphosphonic anhydride, or T3P, since it has demonstrated efficiency in selective amide formation under mild conditions and it is readily soluble. In the case of multiple viable reaction sites, the intended product will dimerize, as was the case in the synthesis of the compound labeled amide 2 when T3P coupled with both sites of piperazine. N-Hydroxysuccinimide, also referred to as HOSu and NHS, was used to decrease the reactivity of the carboxylic acid—T3P mixed anhydride, so it less readily formed the dimer. This increased the yield of the monomer. Pharmacological efficacy is more probable when synthesizing a chemotype with a known structure-activity relationship, or SAR. Urea carboxylic acid has been found to have antischistosomal activity. In an effort to synthesize a drug candidate with greater likelihood of pharmacological activity, a compound was synthesized from a urea carboxylic acid using T3P by the same method used to synthesize products from indole-3-acetic acid. Five compounds were synthesized using the T3P reagent in an attempt to expand the repository of potential drug candidates. The method for each compound was made largely similar, but it differed in the work-up and purification stages, as the acidity and polarity of the systems varied.https://digitalcommons.unmc.edu/surp2021/1061/thumbnail.jp

Multi-element fingerprinting of waters to evaluate connectivity among depressional wetlands

Establishing the connectivity among depressional wetlands is important for their proper management, conservation and restoration. In this study, the concentrations of 38 elements in surface water and porewater of depressional wetlands were investigated to determine chemical and hydrological connectivity of three hydrological types: recharge, flow-through, and discharge, in the Prairie Pothole Region of North America. Most element concentrations of porewater varied significantly by wetland hydrologic type (p \u3c 0.05), and increased along a recharge to discharge hydrologic gradient. Significant spatial variation of element concentrations in surface water was observed in discharge wetlands. Generally, higher element concentrations occurred in natural wetlands compared to wetlands with known disturbances (previous drainage and grazing). Electrical conductivity explained 42.3% and 30.5% of the variation of all element concentrations in porewater and surface water. Non-metric multidimensional scaling analysis showed that the similarity decreased from recharge to flowthrough to discharge wetland in each sampling site. Cluster analysis confirmed that element compositions in porewater of interconnected wetlands were more similar to each other than to those of wetlands located farther away. Porewater and surface water in a restored wetland showed similar multi-element characteristics to natural wetlands. In contrast, depressional wetlands connected by seeps along a deactivated drain-tile path and a grazed wetland showed distinctly different multi-element characteristics compared to other wetlands sampled. Our findings confirm that the multi-element fingerprinting method can be useful for assessing hydro-chemical connectivity across the landscape, and indicate that element concentrations are not only affected by land use, but also by hydrological characteristics

21cm signal sensitivity to dark matter decay

The redshifted 21cm signal from the Cosmic Dawn is expected to provide unprecedented insights into early Universe astrophysics and cosmology. Here we explore how dark matter can heat the intergalactic medium before the first galaxies, leaving a distinctive imprint in the 21cm power spectrum. We provide the first dedicated Fisher matrix forecasts on the sensitivity of the Hydrogen Epoch of Reionization Array (HERA) telescope to dark matter decays. We show that with 1000 hours of observation, HERA has the potential to improve current cosmological constraints on the dark matter decay lifetime by up to three orders of magnitude. Even in extreme scenarios with strong X-ray emission from early-forming, metal-free galaxies, the bounds on the decay lifetime would be improved by up to two orders of magnitude. Overall, HERA shall improve on existing limits for dark matter masses below 2 GeV/c 2 for decays into e+e- and below few MeV/c 2 for decays into photons. © 2024 IOP Publishing Ltd and Sissa Medialab

The synthetic peroxide OZ78 is effective against Echinostoma caproni and Fasciola hepatica

Objectives: The trematocidal properties of a synthetic peroxide, 1,2,4-trioxolane (OZ78) were determined both in vivo and in vitro. Methods: Two weeks post-infection Echinostoma caproni-infected mice were administered single oral doses of 400-1000 mg/kg OZ78. Fasciola hepatica-infected rats were treated orally with 50-400 mg/kg OZ78 3 and 8-9 weeks post-infection. Worm burden reductions were assessed against untreated control animals. Adult F. hepatica were observed by scanning electron microscopy (SEM) after recovery from the bile duct of a rat 3 days after administration of a single oral dose of 100 mg/kg OZ78 and after in vitro exposure to concentrations of 1, 10 and 100 μg/mL OZ78. Results: In the E. caproni-mouse model 100% worm burden reductions were achieved with a single oral dose of 1000 mg/kg OZ78. A single dose of 100 mg/kg OZ78 resulted in worm burden reductions of 100% against juvenile and adult F. hepatica. F. hepatica recovered from rats 3 days post-treatment displayed feeble activity and some flukes had died. Typical features revealed by SEM included extensive blebbing and sloughing. Exposure of F. hepatica to 10-100 μg/mL OZ78 in vitro resulted in the death of all trematodes. F. hepatica showed focal blebbing and sloughing of the tegument at all concentrations investigated. Conclusions: Our data indicate that OZ78 is highly efficacious against F. hepatica and E. caproni and provide a sound platform for identification of a synthetic peroxide drug development candidate against major trematode infection

Activity of artemether and OZ78 against triclabendazole-resistant Fasciola hepatica

Triclabendazole is the drug of choice against Fasciola hepatica infections in humans and animals. However, parasite resistance against triclabendazole is spreading in the veterinary field, and there are no drugs of comparable activity currently available for the treatment and control of fascioliasis. We investigated the efficacy of single oral doses of artemether and OZ78 against adult triclabendazole-resistant F. hepatica harboured in rats, and compared the results with triclabendazole administered at two different doses. Single oral doses of 100 mg/kg OZ78 and 200 mg/kg artemether resulted in worm burden reductions of 100%. Whereas a single 10 mg/kg dose of triclabendazole achieved a worm burden reduction of only 4.0%, a five-fold higher dose yielded a significant worm burden reduction of 60.9%. However, the lower dose of triclabendazole administered to rats harbouring a triclabendazole-sensitive F. hepatica isolate resulted in a worm burden reduction of 95.3%. Our findings confirm that artemether and OZ78 possess good fasciocidal properties, even against a triclabendazole-resistant F. hepatica isolate, and hence these drugs might become useful in areas where triclabendazole resistance is commo

Hyperelastic Material Properties of Mouse Skin under Compression

The skin is a dynamic organ whose complex material properties are capable of withstanding continuous mechanical stress while accommodating insults and organism growth. Moreover, synchronized hair cycles, comprising waves of hair growth, regression and rest, are accompanied by dramatic fluctuations in skin thickness in mice. Whether such structural changes alter skin mechanics is unknown. Mouse models are extensively used to study skin biology and pathophysiology, including aging, UV-induced skin damage and somatosensory signaling. As the skin serves a pivotal role in the transfer function from sensory stimuli to neuronal signaling, we sought to define the mechanical properties of mouse skin over a range of normal physiological states. Skin thickness, stiffness and modulus were quantitatively surveyed in adult, female mice (Mus musculus). These measures were analyzed under uniaxial compression, which is relevant for touch reception and compression injuries, rather than tension, which is typically used to analyze skin mechanics. Compression tests were performed with 105 full-thickness, freshly isolated specimens from the hairy skin of the hind limb. Physiological variables included body weight, hair-cycle stage, maturity level, skin site and individual animal differences. Skin thickness and stiffness were dominated by hair-cycle stage at young (6–10 weeks) and intermediate (13–19 weeks) adult ages but by body weight in mature mice (26–34 weeks). Interestingly, stiffness varied inversely with thickness so that hyperelastic modulus was consistent across hair-cycle stages and body weights. By contrast, the mechanics of hairy skin differs markedly with anatomical location. In particular, skin containing fascial structures such as nerves and blood vessels showed significantly greater modulus than adjacent sites. Collectively, this systematic survey indicates that, although its structure changes dramatically throughout adult life, mouse skin at a given location maintains a constant elastic modulus to compression throughout normal physiological stages

Chiral symmetry breaking for deterministic switching of perpendicular magnetization by spin-orbit torque

Symmetry breaking is a characteristic to determine which branch of a bifurcation system follows upon crossing a critical point. Specifically, in spin-orbit torque (SOT) devices, a fundamental question arises: how to break the symmetry of the perpendicular magnetic moment by the in-plane spin polarization? Here, we show that the chiral symmetry breaking by the DMI can induce the deterministic SOT switching of the perpendicular magnetization. By introducing a gradient of saturation magnetization or magnetic anisotropy, non-collinear spin textures are formed by the gradient of effective SOT strength, and thus the chiral symmetry of the SOT-induced spin textures is broken by the DMI, resulting in the deterministic magnetization switching. We introduce a strategy to induce an out-of-plane (z) gradient of magnetic properties, as a practical solution for the wafer-scale manufacture of SOT devices.Comment: 16 pages, 4 figure

Aryl hydantoin Ro 13-3978, a broad-spectrum antischistosomal

Objectives Praziquantel is the only drug available for the treatment of schistosomiasis and the state of the exhausted drug discovery pipeline is alarming. We restarted investigations on the abandoned antischistosomal Ro 13-3978, an aryl hydantoin discovered in the early 1980s by Hoffmann La-Roche. Methods Newly transformed schistosomula and adult Schistosoma mansoni were studied in the presence of Ro 13-3978 in vitro. The metabolic stability of Ro 13-3978 was determined in vitro using human and mouse liver S9 fractions. Dose-response relationship, stage specificity, hepatic shift and scanning electron microscopy studies were carried out in S. mansoni-infected mice. In addition, efficacy experiments were conducted in rodents infected with Echinostoma caproni and Fasciola hepatica as well as in S. mansoni-infected immunocompromised nude (Foxn1nu) mice. Results Ro 13-3978 showed minor in vitro activity and no damage to the tegument was found. No cytotoxicity was detected for Ro 13-3978. Ro 13-3978 was metabolically stable. ED50 values of 138.9 and 14.6 mg/kg were calculated for the treatment of juvenile and adult S. mansoni infections, respectively, with a single oral dose of Ro 13-3978. SEM studies revealed severe damage to the worms 48 h post-treatment of infected mice. A single oral dose of Ro 13-3978 (100 mg/kg) administered to S. mansoni-infected (Foxn1nu) mice reduced the worm burden by 88%. Ro 13-3978 was not active against E. caproni and F. hepatica in vivo. Conclusions Ro 13-3978 has excellent antischistosomal properties in vivo. Structure-activity relationship studies with the aryl hydantoins have been launched in order to elucidate active pharmacophores, further investigate the mechanism of action and to identify a derivative with minimal antiandrogenic effect

Dispiro-1,2,4-trioxane Analogues of a Prototype Dispiro-1,2,4-trioxolane: Mechanistic Comparators for Artemisinin in the Context of Reaction Pathways with Iron(II)

Single electron reduction of the 1,2,4-trioxane heterocycle of artemisinin (1) forms primary and secondary carbon-centered radicals. The complex structure of 1 does not lend itself to a satisfactory dissection of the electronic and steric effects that influence the formation and subsequent reaction of these carbon-centered free radicals. To help demarcate these effects, we characterized the reactions of achiral dispiro-1,2,4-trioxolane 4 and dispiro-1,2,4-trioxanes 5−7 with ferrous bromide and 4-oxo-TEMPO. Our results suggest a small preference for attack of Fe(II) on the nonketal peroxide oxygen atom of 1. For 4, but not for 5 and 6, there was a strong preference for attack of Fe(II) on the less hindered peroxide bond oxygen atom. The steric hindrance afforded by a spiroadamantane in a five-membered trioxolane is evidently much greater than that for a corresponding six-membered trioxane. Unlike 1, 5−7 fragment by entropically favored β-scission pathways forming relatively stable α-oxa carbon-centered radicals. These data suggest that formation of either primary or secondary carbon-centered radicals is a necessary but insufficient criterion for antimalarial activity of 1 and synthetic peroxides