Tuberculosis (TB) is a devastating disease resulting in a death every 20s. Thus, new drugs are urgently needed. Herein we report ten classes of compounds—oxazoline, oxazole, thiazoline, thiazole, ...pyrazole, pyridine, isoxazole, imidazo1,2-apyridine, imidazo1,2-apyrimidine and imidazo1,2-cpyrimidine—which have good (micromolar) to excellent (sub-micromolar) antitubercular potency. The 5,6-fused heteroaromatic compounds were the most potent with MIC’s as low as <0.195μM (9 and 11). Overall, the imidazo1,2-apyridine class was determined to be most promising, with potency similar to isoniazid and PA-824 against replicating Mtb H37Rv, clinically relevant drug sensitive, multi- and extensively resistant Mtb strains as well as having good in vitro metabolic stability.
Scalability study of solid xenon Yoo, J.; Cease, H.; Jaskierny, W.F. ...
Journal of instrumentation,
04/2015, Letnik:
10, Številka:
4
Journal Article
Recenzirano
Odprti dostop
We report a demonstration of the scalability of optically transparent xenon in the solid phase for use as a particle detector above a kilogram scale. We employed a cryostat cooled by liquid nitrogen ...combined with a xenon purification and chiller system. A modified {\it Bridgeman's technique} reproduces a large scale optically transparent solid xenon.
A set of nine 2,7-dimethylimidazo1,2-apyridine-3-carboxamides and one 2,6-dimethylimidazo1,2-apyrimidine-3-carboxamide were synthesized. The compounds were evaluated for their in vitro ...antituberculosis activity versus replicating, nonreplicating, multi- and extensive drug resistant Mtb strains. The MIC90 values of seven of these agents were ≤1 μM against the various tuberculosis strains tested. A representative compound of this class (1) was screened against seven nontubercular strains as well as other nonmycobacteria organisms and demonstrated remarkable microbe selectivity. A transcriptional profiling experiment of Mtb treated with compound 1 was performed to give a preliminary indication of the mode of action. Lastly, the in vivo ADME properties of compounds 1, 3, 4, and 6 were assessed. The 2,7-dimethylimidazo1,2-apyridine-3-carboxamides are a druglike and synthetically accessible class of anti-TB agents that have excellent selective potency against multi- and extensive drug resistant TB and encouraging pharmacokinetics.
Antipseudomonal carbapenems are an important target for antimicrobial stewardship programs. We evaluated the impact of formulary restriction and preauthorization on relative carbapenem use for ...medical and surgical intensive care units at a large, urban academic medical center using interrupted time-series analysis.
A set of 5,6-fused bicyclic heteroaromatic scaffolds were investigated for their in vitro anti-tubercular activity versus replicating and non-replicating strains of Mycobacterium tuberculosis (Mtb) ...in an attempt to find an alternative scaffold to the imidazo1,2-apyridine and imidazo1,2-apyrimidines that were previously shown to have potent activity against replicating and drug resistant Mtb. The five new bicyclic heteroaromatic scaffolds explored in this study include a 2,6-dimethylimidazo1,2-bpyridazine-3-carboxamide (7), a 2,6-dimethyl-1H-indole-3-carboxamide (8), a 6-methyl-1H-indazole-3-carboxamide (9), a 7-methyl-1,2,4triazolo4,3-apyridine-3-carboxamide (10), and a 5,7-dimethyl-1,2,4triazolo1,5-apyrimidine-2-carboxamide (11). Additionally, imidazo1,2-apyridines isomers (2 and 12) and a homologous imidazo1,2-apyrimidine isomer (6) were prepared and compared. Compounds 2 and 6 were found to be the most potent against H37Rv Mtb (MIC's of 0.1 μM and 1.3 μM) and were inactive (MIC >128 μM) against Staphylococcus aureus, Escherichia coli and Candida albicans. Against other non-tubercular mycobacteria strains, compounds 2 and 6 had activity against Mycobacterium avium (16 and 122 μM, respectively), Mycobacterium kansasii (4 and 19 μM, respectively), Mycobacterium bovis BCG (1 and 8 μM, respectively) while all the other scaffolds were inactive (>128 μM).
The headmass is a key element in tonpilz transducer design. As an acoustic radiator, a successful headmass must be built from a material that is both light and stiff. To assess the suitability of ...ceramics for this application, the authors used the mechanical properties of candidate materials to perform a theoretical comparison based on the flexural behavior of square plates. Although not a comprehensive metric for identifying the best headmass materials, the headmass flexure may be usefully employed as a first-level selection criteria. A software routine based on thin plate and thick plate theory was created to evaluate the flexural behavior in candidate materials.
We describe the design and testing of the Cryogenic Flex Cable (CFC) delivered for the Near-Infrared Spectro-Photometer (NISP) instrument 1 for the ESA Euclid mission 2, 3. The Euclid spacecraft is ...scheduled for launch in the summer of 2022. It will observe ∼ 1/3 of the total sky using a telescope with 1.2m SiC primary mirror, passively cooled to ∼ 125K, and containing Visible Imager (VIS) 4 and NISP focal plane instruments, from an orbit at the Earth-Sun L2 lagrange point. At the heart of the NISP instrument is a 4X4 mosaic focal plane of Teledyne H2RG infrared detector arrays held at 100K. The CFC described here are designed to link each detector array to a dedicated packaged cryogenic electronics assembly held at ∼ 137K with minimal heat leak to the 100K stage and to withstand handling and launch vibrations. Prototype CFCs were developed and tested by Teledyne. The final 7-layer CFC flexible printed circuit boards and Airborn nanoconnectors were provided by Teledyne and assembled for flight at the Jet Propulsion Lab (JPL). Flight qualification CFC were made and subjected to thermal conductance, thermal emissivity, thermal cycle, survivability to bend, vibration and normal mode testing at JPL. The flight CFC were subject to bake out and thermal cycle at JPL and then tested with the flight detectors and electronics at Goddard Space Flight Centers Detector Characterization Lab. The results of the qualification tests as well as the measured characteristics of the 41 manufactured CFC are summarized.
A set of 14 imidazo1,2-apyridine-3-carboxamides was synthesized and screened against Mycobacterium tuberculosis H37Rv. The minimum inhibitory concentrations of 12 of these agents were ≤1 μM against ...replicating bacteria and 5 compounds (9, 12, 16, 17, and 18) had MIC values ≤0.006 μM. Compounds 13 and 18 were screened against a panel of MDR and XDR drug resistant clinical Mtb strains with the potency of 18 surpassing that of clinical candidate PA-824 by nearly 10-fold. The in vivo pharmacokinetics of compounds 13 and 18 were evaluated in male mice by oral (PO) and intravenous (IV) routes. These results indicate that readily synthesized imidazo1,2-apyridine-3-carboxamides are an exciting new class of potent, selective anti-TB agents that merit additional development opportunities.
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