Saturated N-heterocycles are prevalent in biologically active molecules and are increasingly attractive scaffolds in the development of new pharmaceuticals. Unlike their aromatic counterparts, there ...are limited strategies for facile construction of substituted saturated N-heterocycles by convergent, predictable methods. In this Synopsis, we discuss recent advances in the synthesis of these compounds, focusing on approaches that offer generality and convenience from widely available building blocks.
Interest in saturated N-heterocycles as scaffolds for the synthesis of bioactive molecules is increasing. Reliable and predictable synthetic methods for the preparation of these compounds, especially ...medium-sized rings, are limited. We describe the development of SnAP (Sn amino protocol) reagents for the transformation of aldehydes into seven-, eight- and nine-membered saturated N-heterocycles. This process occurs under mild, room-temperature conditions and offers exceptional substrate scope and functional-group tolerance. Air- and moisture-stable SnAP reagents are prepared on a multigram scale from inexpensive starting materials by simple reaction sequences. These new reagents and processes allow widely available aryl, heteroaryl and aliphatic aldehydes to be converted into diverse N-heterocycles, including diazepanes, oxazepanes, diazocanes, oxazocanes and hexahydrobenzoxazonines, by a single synthetic operation.
Substituted piperazines and morpholines are valuable structural motifs in biologically active compounds, but are not easily prepared by contemporary cross-coupling approaches. In this report, we ...introduce SnAP reagents for the transformation of aldehydes into N-unprotected piperazines and morpholines. This approach offers simple, mild conditions compatible with aromatic, heteroaromatic, aliphatic, and glyoxylic aldehydes and provides mono- and disubstituted N-heterocycles in a single step.
It's a SnAP! The transformation of aldehydes into N‐unsubstituted 3‐thiomorpholines provides a convenient alternative to metal‐catalyzed cross‐coupling reactions, which are generally unsuited to the ...functionalization of saturated N‐heterocycles. A copper‐mediated radical cyclization is the key to the mild conditions, high functional group tolerance, and broad substrate scope offered by these reagents.
Tuberculosis transmission continues to be a major public health challenge. In this cluster-randomized, controlled trial conducted in Vietnam, active community-wide screening for tuberculosis over 4 ...years is shown to decrease the prevalence of tuberculosis.
Mixed acetals and organotrifluoroborates undergo BF3·OEt2-promoted cross-couplings to give dialkyl ethers under simple, mild conditions. A survey of reaction partners identified a hydroxamate leaving ...group that improves the regioselectivity and product yield in the BF3·OEt2-promoted coupling reaction of mixed acetals and potassium alkynyl-, alkenyl-, aryl- and heteroaryltrifluoroborates to access substituted dialkyl ethers. This leaving group enables the reaction to proceed rapidly under mild conditions (0 °C, 5–60 min) and permits reactions with electron-deficient potassium aryltrifluoroborates that are less reactive with other acetal substrates. A study of the reaction mechanism and characterization of key intermediates by NMR spectroscopy and X-ray crystallography identified a role for the hydroxamate moiety as a reversible leaving group that serves to stabilize the key oxocarbenium intermediate and the need for a slight excess of organodifluoroborane to serve as a catalyst. A secondary role for the boron nucleophile as an activating ligand was also considered. These studies provide the basis for a general class of reagents that lead to dialkyl ethers by a simple, predictable cross-coupling reaction.
Introduction
Preterm birth is the most common cause of neonatal morbidity and mortality. Women with twin pregnancies and a short cervical length are at high risk for preterm birth. Vaginal ...progesterone and cervical pessary have been proposed as potential strategies to reduce preterm birth in this high‐risk population. Therefore, we aimed to compare the effectiveness of cervical pessary and vaginal progesterone in improving developmental outcomes of children born to women with twin pregnancies and mid‐trimester short cervical length.
Material and methods
This was a follow‐up study (NCT04295187) of all children at 24 months of age, born from women treated with cervical pessary or progesterone to prevent preterm birth in a randomized controlled trial (NCT02623881). We used a validated Vietnamese version of Ages & Stages Third Edition Questionnaires (ASQ‐3) and a red flag questionnaire. In surviving children, we compared the mean ASQ‐3 scores, abnormal ASQ‐3 scores, the number of children with any abnormal ASQ‐3 scores and red flag signs between the two groups. We reported the composite outcome of perinatal death or survival with any abnormal ASQ‐3 score in offspring. These outcomes were also calculated in a subgroup of women with a cervical length ≤28 mm (<25th percentile).
Results
In the original randomized controlled trial, we randomized 300 women to pessary or progesterone. After counting the number of perinatal deaths and lost to follow‐up, 82.8% parents in the pessary group and 82.5% parents in progesterone group returned the questionnaire. The mean ASQ‐3 scores of the five skills and red flag signs did not differ significantly between the two groups. However, the percentage of children having abnormal ASQ‐3 scores in fine motor skills was significantly lower in the progesterone group (6.1% vs 1.3%, P = 0.01). There were no significant differences in the composite outcome of perinatal death or survival with any abnormal ASQ‐3 score in unselected women and in those with cervical length ≤28 mm.
Conclusions
Cervical pessary and vaginal progesterone may have comparable effects on developmental outcomes in children at ≥24 months of age, born to women with twin pregnancies and short cervical length. However, this finding could be likely due to a lack of study power.
Vaginal progesterone and cervical pessary have been proposed as potential strategies to reduce preterm birth in women with twin pregnancies and a short cervix. Our results suggested that the impact of cervical pessary and progesterone on the brain development of young children via Red flag and Ages & Stages Third Edition Questionaires (ASQ‐3) are mostly comparable.
The main protease 3CL
pro
is one of the potential targets against coronavirus. Inhibiting this enzyme leads to the interruption of viral replication. Chalcone and its derivatives were reported to ...possess the ability to bind to 3CL
pro
protease in the binding pocket. This study explored an in-house database of 269 chalcones as 3CL
pro
inhibitors using in silico screening models, including molecular docking, molecular dynamics simulation, binding free energy calculation, and ADME prediction.
C264
and
C235
stand out as the two most potential structures. The top hit compound
C264
was with the Jamda score of −2.8329 and the MM/GBSA binding energy mean value of −28.23 ± 3.53 kcal/mol, which was lower than the reference ligand. Despite the lower mean binding energy (−22.07 ± 3.39 kcal/mol), in-depth analysis of binding interaction suggested
C235
could be another potential candidate. Further, in vitro and in vivo experiments are required to confirm the inhibitory ability.
Lichens produce secondary metabolites that have many pharmaceutical activities such as antimicrobial, antioxidant, antiviral, anticancer, antigenotoxic, anti-inflammatory, analgesic and antipyretic ...activities. However, there is limited research on their efflux pump inhibitory activities. Twelve phytochemicals were isolated from
, and their activity of AcrAB-TolC efflux pump inhibition was evaluated. Four potential compounds, which are diffractaic acid
, 8' -
- methylstictic acid
, 3-hydroxy-4-(methoxycarbonyl)-2,5-dimethylphenyl 2,4-dimethoxy-3,6-dimethylbenzoate (
and 3-hydroxy-4-(methoxycarbonyl)-2,5-dimethylphenyl 2-hydroxy-4-methoxy-3,6-dimethylbenzoate
, were found by virtual screening using pharmacophore and 2D-QSAR model. Compound
exhibited AcrB inhibition activity
with an accumulation H33342 percentage compared with untreated control of 202% at a concentration of 50 µM and increased the antibacterial activity of levofloxacin by four-fold at a concentration of 200 µM. By molecular docking and molecular dynamics (MD) simulation, the binding affinity of depside and depsidone derivatives to AcrB was also clarified. Despite the poor docking score to the AcrB binding site, compound
was the most stable among the four complexes at 20 ns of MD simulation. The analysis of long MD at 100 ns indicated that compound
interacts strongly with the residues in the distal pocket, creating a stable complex with
of
kcal.mol-1. According to the ADMETlab 2.0 web server's predictions of pharmacokinetics and toxicities, compound
has the potential for drug development.Communicated by Ramaswamy H. Sarma.
The high-performance liquid chromatography method coupled with diode array and mass spectrometric detector (HPLC-DAD-MS) method for quinonoid pigment identification and quantification in sea urchin ...samples was developed and validated. The composition and quantitative ratio of the quinonoid pigments of the shells of 16 species of sea urchins, collected in the temperate (Sea of Japan) and tropical (South-China Sea) climatic zones of the Pacific Ocean over several years, were studied. The compositions of the quinonoid pigments of sea urchins
,
,
and
were studied for the first time. A study of the composition of the quinonoid pigments of the coelomic fluid of ten species of sea urchins was conducted. The composition of quinonoid pigments of
jelly-like egg membrane, of
developing embryos and pluteus, was reported for the first time. In the case of
, we have shown that the compositions of pigment granules of the shell epidermis, coelomic fluid, egg membrane, developing embryos and pluteus are different, which should enable a fuller understanding of the functions of pigments at different stages of life.
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