Phenethylthiazolylthiourea (PETT) compounds as a new class of HIV-1 reverse transcriptase inhibitors. 2. Synthesis and further structure-activity relationship studies of PETT analogs

Phenylethylthiazolylthiourea (PETT) derivatives have been identified as a new series of non-nucleoside inhibitors of HIV-1 RT. Structure-activity relationship studies of this class of compounds resulted in the identification of N-[2-(2-pyridyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea hydrochloride (trovirdine; LY300046.HCl) as a highly potent anti-HIV-1 agent. Trovirdine is currently in phase one clinical trials for potential use in the treatment of AIDS. Extension of these structure-activity relationship studies to identify additional compounds in this series with improved properties is ongoing. A part of this work is described here. Replacement of the two aromatic moieties of the PETT compounds by various substituted or unsubstituted heteroaromatic rings was investigated. In addition, the effects of multiple substitution in the phenyl ring were also studied. The antiviral activities were determined on wild-type and constructed mutants of HIV-1 RT and on wild-type HIV-1 and mutant viruses derived thereof, Ile100 and Cys181, in cell culture assays. Some selected compounds were determined on double-mutant viruses, HIV-1 (Ile 100/Asn103) and HIV-1 (Ile100/Cys181). A number of highly potent analogs were synthesized. These compounds displayed IC50's against wild-type RT between 0.6 and 5 nM. In cell culture, these agents inhibited wild-type HIV-1 with ED50's between 1 and 5 nM in MT-4 cells. In addition, these derivatives inhibited mutant HIV-1 RT (Ile 100) with IC50's between 20 and 50 nM and mutant HIV-1 RT (Cys 181) with IC50's between 4 and 10 nM, and in cell culture they inhibited mutant HIV-1 (Ile100) with ED50's between 9 and 100 nM and mutant HIV-1 (Cys181) with ED50's between 3 and 20 nM.     

Onset of mucosal, dermal, and general symptoms in relation to biomarkers and exposures in the dwelling: a cohort study from 1992 to 2002

We examined the associations between biomarkers of allergy and inflammation, indoor environment in dwellings, and incidence and remission of symptoms included in the sick building syndrome (SBS) and changes in the home environment of 452 adults who were followed from 1992 to 2002 within the Uppsala part of the European Community Respiratory Health Survey (ECRHS). The 10-year incidence (onset) of general, mucosal, and dermal symptoms was 8.5%, 12.7%, and 6.8%, respectively. Dampness or indoor molds at baseline was a predictor of incidence of general (relative risk [RR] = 1.98), mucosal (RR = 2.28), and dermal symptoms (RR = 1.91). Women had higher incidence of general (RR = 1.74) and mucosal symptoms (RR = 1.71). Indoor painting increased the incidence of general symptoms (RR = 1.62). Bronchial responsiveness (BR), eosinophil counts in blood, total IgE and eosinophilic cationic protein (ECP) in serum at baseline were predictors of incidence of SBS. At follow-up, BR, total IgE, and C-reactive protein (CRP ) were associated with increased incidence of SBS. Moreover, subjects with doctor-diagnosed asthma at baseline had a higher incidence of general (RR = 1.65) and mucosal symptoms (RR = 1.97). In conclusion, female gender, dampness or indoor molds, indoor painting, and biomarkers of allergy and inflammation were associated with a higher incidence of SBS symptoms, in particular mucosal symptoms. PRACTICAL IMPLICATIONS: The focus in Sweden on indoor environment issues over the last few decades has resulted in improvements in dwellings, and reduced tobacco smoking, which could be beneficial for public health. Reducing dampness and molds in the dwelling place is another important way of reducing occurrence of SBS symptoms in the general adult population. The association between the incidence of SBS symptoms and clinical biomarkers of allergy and inflammation suggests a common etiology between inflammatory diseases, including asthma, rhinitis, and SBS. Lastly, good agreement between self-reported and clinically diagnosed atopy indicates that questionnaire data on atopy can be used in epidemiological studies.     

Activation effects during hydrogen release and uptake of MgH2

Scandium(II)hydride, ScH₂, and scandium(III)chloride, ScCl₃, are explored as additives to facilitate hydrogen release and uptake for magnesium hydride. These additives are expected to form more homogeneous composites with Mg/MgH₂ as compared to metallic scandium. However, scandium(III)chloride, reacts with MgH₂ during mechano-chemical treatment and form ScH₂ and MgCl₂ (that later crystallise during heat treatment). The composite MgH₂−ScH₂ was investigated using in-situ synchrotron radiation powder X-ray diffraction during up to five cycles of continuous release and uptake of hydrogen at isothermal conditions at 320, 400 and 450 °C and p(H₂) = 100–150 or 10⁻² bar. The data were analysed by Rietveld refinement and no reaction is observed between either MgH₂/ScH₂ or Mg/ScH₂ during cycling. The extracted sigmoidal shaped curves for formation or decomposition of Mg/MgH₂ suggest that a nucleation process is preceding the crystal growth. The reaction rate increases with increasing number of cycles of hydrogen release and uptake at isothermal conditions possibly due to activation effects. This kinetic enhancement is strongest between the first cycles and may be denoted an activation effect.     

Synthesis and anti-HIV activities of urea-PETT analogs belonging to a new class of potent non-nucleoside HIV-1 reverse transcriptase inhibitors

A series of potent specific HIV-1 RT inhibitory compounds is described. The compounds are urea analogs of PETT (PhenylEthylThiazoleThiourea) derivatives and the series includes derivatives with an ethyl linker (1-6) and conformationally restricted analogs (7-13). The antiviral activity is determined both at the RT level and in cell culture on both native and mutant forms of HIV-1. Many compounds display activity in the nM range against wt-RT.     

Precipitation Kinetics During Post-heat Treatment of an Additively Manufactured Ferritic Stainless Steel

Metallurgical and Materials Transactions A - The microstructure response of laser-powder bed fusion (L-PBF)-processed ferritic stainless steel (AISI 441) during post-heat treatments is studied in...     

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Hydrogen storage properties of the pseudo binary laves phase (Sc1−xZrx)(Co1−yNiy)2 system

The (Sc_1−xZr_x)(Co_1−yNi_y)₂-H_z system has been studied using both experimental techniques and ab initio calculations. The material was synthesised through high temperature synthesis and characterised using powder XRD. Hydrogen absorption and desorption was studied in-situ using synchrotron radiation. Maximal storage capacity increased when Co replaced Ni and substitution of Sc for Zr increased the equilibrium pressure. Density functional based calculations reproduce the experimental trends in terms of cell parameters both for the non-hydrogenated systems as well as for the hydrogenated systems, and helped to quantitatively understand the observed hydrogen uptake properties.     

A techno-economic assessment of NuScale and DHR-400 reactors in a district heating and cooling grid

Many companies are developing small modular reactors (SMR), but only few are in a licensing or demonstration phase. Several papers have studied the economy of the SMRs, but district heating studies were carried out without a reference energy system that has a high impact on the results. We modeled NuScale CHP and DHR-400 (heat only) units as a part of a city-level district heating and cooling grid. In the studied reference system, NuScale CHP and DHR-400 look cost-efficient investments with internal rates of return from 7% to 20%. Modeled heat only reactor had better profitability than CHP reactor in almost all cases except when assuming higher than 50 €/MWh electricity prices. Large heat pumps with COP of 3.5 had similar economic performance than studied SMRs. Large heat pumps are less capital intensive than SMRs and easier to accept by public, but their potential is limited by the available heat sources.     

Hydrogen sorption properties of a Mg–Y–Ti alloy

The catalytic effect of titanium on the hydrogen sorption properties of a Mg–Y–Ti alloy has been investigated. The alloy is formed by a majority phase Mg_24+xY₅, a minor phase of solid solution of Y in Mg and Ti clusters randomly dispersed in the sample. During the first hydrogen absorption cycle 5.6 wt.% hydrogen was absorbed at temperatures above 613 K. The alloy decomposed almost completely to MgH₂ and YH₃. After hydrogen desorption pure Mg and YH₂ were formed. For further absorption/desorption cycles the material had a reversible hydrogen capacity of 4.8 wt.%. The MgH₂ decomposition enthalpy was determined to ?68 kJ/mol H₂, and the calculated activation energy of hydrogen desorption of MgH₂ was 150(±10) kJ/mol.