Heterocalixarenes. Part 3: Bis-oxo-bridged calix[1]cyclicurea[3]arene and calix[1]cyclicurea[1]pyridine[2]arenes. Synthesis, X-Ray crystal structure and conformational analysis

The Friedel-Crafts aroylations of 2- and 4-methylanisole with isophthaloyl dichloride or pyridine-2,6-dicarbonyl dichloride provide respective diones, which on bromination with NBS provide corresponding bisbromomethyl derivatives that undergo simple cyclocondensations with embedded cyclicurea-containing heterocycles, viz. benzimidazol-2(1H)-one, 5-nitrobenzimidazol-2(1H)-one, 5,6-dinitrobenzimidazol-2(1H)-one, uracil and quinazoline-2,4(1H,3H)-dione to form 11 new bis-oxo-bridged heterocalix[4]arenes ( 11-19, 24, 25). The X-ray crystal structure of the 11-benzene complex, 1H-1H COSY spectra and energy-minimization studies assign partial cone conformations to these heterocalix[4]arenes. The variation in the cyclicurea moiety controls the flexibility of these heterocalix[4]arenes

Heterocalixarenes part 4. Synthesis of oxocalix [1] heterocycle [2]-arenes: a unique H-bonding network in calix [1] benzimidazol-2-one [2] arene &#189; H<SUB>2</SUB>O

The Friedel.Crafts aroylation of 2-methylanisole with 3-methylbenzoyl chloride followed by NBS bromination and cyclizations with 1,3-dihydrobenzimidazol-2-one, 1,3-dihydro-5,6-dinitrobenzimidazol-2-one, uracil, 6-methyluracil and quinazoline-2,4(1H,3H)-dione provide respective oxocalix[1]heterocycle[2]arenes 5.9. The X-ray crystal structure (solid) and 1H NMR spectral (solution) studies show them to have by and large inwardly flattened partial cone conformations which vary in torsion angles between the rings. The calix[1]benzimidazol-2-one[2]arene &#189; H2O complex shows a unique array of H-bonds in which three of the four CH and the imide oxygen of the benzimidazol-2-one unit, carbonyl oxygen and water molecule are involved in H-bonding with surrounding calixarene molecules. This heterocalixarene, in contrast to earlier reported benzimidazol-2-one-based calixarenes, does not show heterocyclic &#960;-&#960; stacking

Sinteza i farmakološko vrednovanje 2-supstituiranih-6-fenil-4,5-dihidropiridazin-3(2H)-ona kao snažnih srčanih stimulatora

The present study describes the synthesis and pharmacological evaluation of 2-substituted-6-(4-acylaminophenyl)-4,5-dihydropyridazin-3(2H)-ones as potent inodilating agents. The synthesis of target compounds 2-4 and 7-11 was acieved by Friedel-Crafts acylation of an appropriate anilide derivative with succinic anhydride or methylsuccinic anhydride and subsequent cyclization of intermediary keto acids with various hydrazine derivatives. The newly synthesized pyridazinone derivatives were evaluated for cardiotonic activity using isolated rat atria and for vasorelaxant activity using descending thoracic aortic rings of Wistar rats precontracted with phenylephrine (106 mol L1). 6-(4-Methanesulfonamidophenyl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one (7) exhibited significant inodilatory properties and showed vasorelaxant activity in a nanomolar range (IC50 = 0.08 0.01 μmol L1).U radu je opisana sinteza i framakološko vrednovanje 2-supstituiranih-6-(4-acilaminofenil)-4,5-dihidropiridazin-3(2H)-ona kao snažnih srčanih stimulatora. Spojevi 2-4 i 7-11 sintetizirani su Friedel-Craftsovim acilaranjem odgovarajućeg anilida s anhidridom jantarne ili anhidridom metiljantarne kiseline te ciklizacijom intermedijarnih keto kiselina s različitim derivatima hidrazina. Kardiotonično djelovanje novosintetiziranih derivata piridazinona ispitano je na izoliranim atrijima štakora, a vazodilatirajuće djelovanje na silaznim torakalnim prstenima aorte prethodno kontrahiranim fenilefrinom (106 mol L1). 6-(4-Metansulfonamidofenil)-2-fenil-4,5-dihidropiridazin-3(2H)-on (7) pokazao je značajno stimulativno i vazodilatirajuće djelovanje u nanomolarnim koncentracijama (IC50 = 0,08 0,01 μmol L1)

Cytochromec−Crown Ether Complexes as Supramolecular Catalysts: Cold-Active Synzymes for Asymmetric Sulfoxide Oxidation in Methanol

A series of supramolecular complexes of various cytochrome c proteins with 18-crown-6 derivatives behave as cold-active synzymes in the H_2O_2 oxidation of racemic sulfoxides. This interesting behavior contrasts with native functionality, where the employed proteins act as electron transfer carriers. ESI-MS, UV, CD, and Raman spectroscopic characterizations reveal that four or five 18-crown-6 molecules strongly bind to the surface of the cytochrome c and also that nonnatural low-spin hexacoordinate heme structures are induced in methanol. Significantly, crown ether complexation can convert catalytically inactive biological forms to catalytically active artificial forms. Horse heart, pigeon breast, and yeast cytochromes c all stereoselectively oxidize (S)-isomers of methyl tolyl sulfoxide and related sulfoxides upon crown ether complexation. These supramolecular catalysts show the highest efficiency and enantiomer selectivity at −40 °C in the H_2O_2-dependent sulfoxide oxidation, while oxidative decomposition of the heme moieties predominantly occurs at room temperature. The oxidation reactivity of the employed sulfoxides is apparently related to steric constraints and electrochemical oxidation potentials of their S O bonds. Among the cytochrome c complexes, yeast cytochrome c demonstrates the lowest catalytic activity and degradation reactivity. It has a significantly different protein sequence, suggesting that crown ether complexation effectively activates heme coordination but may additionally alter the native backbone structure. The proper combination of cytochrome c proteins, 18-crown-6 receptors, and external circumstances can be used to successfully generate “protein-based supramolecular catalysts” exhibiting nonbiological reactivities

Deep Chandra Observations of Abell 2199: the Interplay between Merger-Induced Gas Motions and Nuclear Outbursts in a Cool Core Cluster

We present new Chandra observations of Abell 2199 that show evidence of gas sloshing due to a minor merger, as well as impacts of the radio source, 3C 338, hosted by the central galaxy, NGC 6166, on the intracluster gas. The new data are consistent with previous evidence of a Mach 1.46 shock 100" from the cluster center, although there is still no convincing evidence for the expected temperature jump. Other interpretations of this feature are possible, but none is fully satisfactory. Large scale asymmetries, including enhanced X-ray emission 200" southwest of the cluster center and a plume of low entropy, enriched gas reaching 50" to the north of the center, are signatures of gas sloshing induced by core passage of a merging subcluster about 400 Myr ago. An association between the unusual radio ridge and low entropy gas are consistent with this feature being the remnant of a former radio jet that was swept away from the AGN by gas sloshing. A large discrepancy between the energy required to produce the 100" shock and the enthalpy of the outer radio lobes of 3C 338 suggests that the lobes were formed by a more recent, less powerful radio outburst. Lack of evidence for shocks in the central 10" indicates that the power of the jet now is some two orders of magnitude smaller than when the 100" shock was formed.Comment: 17 pages, 20 figures, accepted for publication in Ap

AGN Feedback in Galaxy Group 3C 88: Cavities, Shock and Jet Reorientation

We present results from the deep Chandra observation (105 ksec), together with new Giant Metrewave Radio Telescope and Very Large Array data of the AGN outburst in the radio-loud galaxy group 3C 88. The system shows a prominent X-ray cavity on the eastern side with a diameter of $\sim$50 kpc at $\sim28$ kpc from the nucleus. The total enthalpy of the cavity is $3.8\times10^{58}$ erg and the average power required to inflate the X-ray bubble is $\sim2.0\times10^{43}$ erg s^-1. From surface brightness profiles we detect a shock with a Mach number of $M=1.4\pm0.2$, consistent with the value obtained from temperature jump. The shock energy is estimated to be $1.9\times10^{59}$ erg. The size and total enthalpy of the cavity in 3C 88 are the largest known in galaxy groups, as well as the shock energy. The eastern X-ray cavity is not aligned with the radio jet axis. This factor, combined with the radio morphology, strongly suggests jet reorientation in the last tens of million years. The bright rim and arm features surrounding the cavity show metallicity enhancement, suggesting they originated as high metallicity gas from the group center, lifted by the rising X-ray bubbles. Our Chandra study of 3C 88 also reveals that galaxy groups with powerful radio AGN can have high cavity power, although deep X-ray observations are typically required to confirm the cavities in galaxy groups.Comment: 18 pages, 15 figures, MNRAS accepte

Evaluation of biophysical, anatomical and biochemical traits of resistance to Sitophilus oryzae L (Coleoptera: Curculionidae) in stored maize

Sitophilus oryzae L is the most destructive insect pest of stored maize and is widely distributed in tropical regions. In the present study, eighteen maize genotypes were screened for several susceptibility parameters against S. oryzae by using «No Choice method». Biophysical traits (test weight, thousand kernel weight, kernel hardness), anatomical fractions (tip cap, germ, pericarp, endosperm), biochemical variants (starch, protein, oil, sugar) were correlated with insect susceptibility parameters. There is significant relationship among test weight, kernel hard- ness, and insect susceptibility parameters. Pericarp was positively correlated while endosperm, starch content were negatively correlated with median development period but were non-significant. Majority of the maize geno- types containing harder kernels and thick pericarp showed less susceptibility to S. oryzae. The results indicated that the biophysical, anatomical and biochemical traits are responsible for varying levels of resistance to S. oryzae

Time course evaluation of provitamin A carotenoids stored under different storage regimens in maize

Yellow maize is natural source of provitamin A components. However, the provitamin A carotenoids are known to degrade fast as a result of oxidation and isomerization due to exposure to heat and oxygen during storage. Keeping this in view, here, we evaluated the provitamin A carotenoids in maize stored under different storage conditions. For this purpose, F2 grains of six hybrids consisting of two provitamin A rich, two QPM and two normal maize were stored in earthen pot, aluminium box, cotton cloth and jute bag for a period of 6 months under ambient temperature and carotenoid components were estimated at monthly interval. Provitamin A components are found to reduce significantly within two to six months under various storage conditions. However, the samples stored in aluminium box exhibited least degradation of β-carotene (73%) and β-cryptoxanthin (81%), whereas those stored in earthen pot exhibited highest degradation of β-carotene (86%) and β-cryptoxanthin (90%), after six months of storage. The provitamin A rich hybrids especially APH27 retained highest concentration of provitamin A carotenoids after six months of storage. The least losses observed in the samples stored in aluminium box may be attributed to reduced oxidation and least light penetration

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570