Competing Domino Knoevenagel-Cyclization Sequences with N-Arylcinnamylamines.

Domino Knoevenagel-cyclization reactions of N-arylcinnamylamines were carried out with active methylene reagents, which took place with five competing cyclization mechanisms: intramolecular hetero Diels-Alder reaction, stepwise polar [2 + 2] cycloaddition, styryl or aza-Diels-Alder reactions followed by rearomatization, and [1,5]-hydride shift-6-endo cyclization. In the stepwise aza-Diels-Alder reaction, the N-vinylpyridinium moiety acted as an azadiene, producing a condensed heterocycle with tetrahydroquinolizinium and tetrahydroquiniline subunits. Antiproliferative activity with low micromolar IC50 values was identified for some of the novel scaffolds.

VCD Analysis of Axial Chirality in Synthetic Stereoisomeric Biaryl-Type bis-Isochroman Heterodimers with Isolated Blocks of Central and Axial Chirality.

Optically active heterodimeric 5,5'-linked bis-isochromans, containing a stereogenic ortho-trisubstituted biaryl axis and up to four chirality centers, were synthesized stereoselectively by using a Suzuki-Miyaura biaryl coupling reaction of optically active isochroman and 1-arylpropan-2-ol derivatives, providing the first access to synthetic biaryl-type isochroman dimers. Enantiomeric pairs and stereoisomers up to seven derivatives were prepared with four different substitution patterns, which enabled us to test how OR, ECD, and VCD measurements and DFT calculations can be used to determine parallel central and axial chirality elements in three isolated blocks of chirality. In contrast to natural penicisteckins A-D and related biaryls, the ECD spectra and OR data of (aS) and (aR) atropodiastereomers did not reflect the opposite axial chirality, but they were characteristic of the central chirality. The atropodiastereomers showed consistently near-mirror-image VCD curves, allowing the determination of axial chirality with the aid of DFT calculation or by comparison of characteristic VCD transitions.

Secondary infections and long-term outcomes among hospitalized elderly and non-elderly patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and treated with baricitinib: a comparative study from the national centre of Hungary.

Baricitinib is considered a first-line treatment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected adult patients with an associated cytokine storm syndrome (CSS). Our objective was to compare rates of secondary infections and long-term outcomes of elderly and non-elderly patients who received baricitinib for COVID-19. We conducted a single-centre observational study between November 2020 and September 2023, focusing on hospitalized adult SARS-CoV-2 patients with CSS, categorized as elderly (≥ 65 years) and non-elderly (< 65 years). Enrolment, severity stratification, and diagnosis of infectious complications followed predefined criteria. Outcomes of all-cause mortality and rates of non-severe and severe secondary infections were assessed at 1-year post-treatment initiation. Kaplan-Meier analysis was performed for survival analysis. In total, 490 patients were enrolled (median age 65 ± 23 (21-100) years (years, median ± IQR, min-max); 49.18% elderly; 59.59% male). Elderly patients were admitted to the hospital significantly earlier (7 ± 5 days vs. 8 ± 4 days; p = 0.02), experienced a higher occurrence of severe COVID-19 (121/241, 50.21% vs. 98/249, 39.36%; p = 0.02), and required the use of non-invasive ventilation at baseline (167/225, 74.22% vs. 153/236, 64.83%; p = 0.03). At 1 year, all-cause mortality was significantly higher in the elderly subgroup (111/241, 46.06% vs. 29/249, 11.65%; p < 0.01). At 90 days and 1 year, rates of any severe secondary infection were also more prevalent among the elderly (56/241, 23.24% vs. 37/249 14.86%; p = 0.02 and 58/241, 24.07% vs. 39/249, 15.66%; p = 0.02). In conclusion, elderly SARS-CoV-2-infected patients experience a more severe clinical course, higher secondary infection rates, and increased risk for long-term mortality, regardless of immunomodulatory therapy.

Outcomes of high-risk adult outpatients treated with early remdesivir therapy during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron era: experiences from the national centre of Hungary.

Emerging evidence suggests that remdesivir might improve clinical outcome of high-risk outpatients with coronavirus disease 2019 (COVID-19). Our aim was to evaluate characteristics and outcomes of nonhospitalised adults diagnosed with COVID-19 and treated with early remdesivir therapy during the omicron wave. A single-centre prospective cohort study was performed among adult patients between February and June 2022, during the circulation of phylogenetic assignment of named global outbreak (PANGO) subvariants BA.2, BA.4, and BA.5 in Hungary. Patients were enrolled based on pre-defined criteria. Clinical characteristics (demography, comorbidities, vaccination status, imaging, treatment, and disease course) and outcomes (COVID-19 related hospitalisation, oxygen supplementation, intensive care support, and all-cause death) were assessed at 28 days post-treatment. A subgroup analysis of patients with and without active haematological malignancies was also carried out. Altogether, 127 patients were enrolled: 51.2% (65/127) were female with a median age of 59 (IQR: 22, range: 21‒92) years, and 48.8% (62/127) had active haematological malignancy. At 28 days post-treatment, 7.1% (9/127) of patients required COVID-19-related hospitalisation, 2.4% (3/127) required oxygen supplementation, 1.6% (2/127) required intensive care, and 0.8% (1/127) died due to a non-COVID-19-related secondary infection at the intensive care unit, all with haematological malignancies. Early remdesivir treatment might be a feasible strategy among high-risk outpatients with COVID-19 during the omicron wave.

Behaviour of some 1-C-acceptor-substituted glycals under azidohydroxylation conditions.

Azidohydroxylation of 1-carbamoyl, 1-methoxycarbonyl and 1-cyano substituted d-lyxo and d-arabino configured O-peracylated glycals was studied and the reaction conditions were optimized. Under these conditions (3 equiv. NaN3/2 equiv. PIFA/0.3 equiv. TEMPO/50 equiv. H2O/dry DCM/0 °C/Ar) the expected 3-azido-3-deoxy ulopyranosonic acid derivatives were isolated in good yield with α-d-galacto configuration exclusively from the reaction of the 1-carbamoyl and 1-methoxycarbonyl substituted d-lyxo configured O-peracetylated glycals, while the transformation of the 1-cyano derivative gave a 2,3-vicinal diazide in low yield. The 1-carbamoyl d-arabino configured O-perbenzoylated glycal gave a mixture of α-d-gluco and α-d-manno configured azidohydroxylated products with d-gluco preference. The analogous 1-methoxycarbonyl derivative gave an inseparable product mixture and no transformation was detected with the respective 1-cyano glycal.

α-Azido ketones. Part 7: synthesis of 1,4-disubstituted triazoles by the "click" reaction of various terminal acetylenes with phenacyl azides or α-azidobenzo(hetera)cyclanones.

Copper(I)-catalyzed alkyne-azide 1,3-cycloaddition reaction (CuAAC, Sharpless-Meldal reaction) of various α-azido ketones such as substituted 2-azidoacetophenones, 2-azidobenzosuberone and 3-azido(thio)chromanones with terminal alkynes was studied. The reaction resulted in the formation of the expected 1,2,3-triazoles in moderate to good yields although the reactivity was somewhat lower than in the case of simple azides. Reaction of ethynylchromones as alkynes gave interesting dichromonoid systems bridged by a triazole unit.

[Central nervous system tuberculosis in adult patients]. / Felnottek központi idegrendszeri tuberkulózisa.

UNLABELLED: Central nervous system tuberculosis is the fifth most frequent and at the same time most severe form of extrapulmonary tuberculosis diseases. It presents with no typical signs, thus early diagnosis and treatment is of high importance concerning the outcome. Authors present the characteristics, diagnostic and therapeutic alternatives of central nervous system tuberculosis through a case report and a retrospective study of 15 patients. PATIENTS AND METHODS: Authors performed a retrospective analysis of medical records of patients with central nervous system tuberculosis in an academic teaching hospital (Department of Neurology and Infectious Diseases, United Szent István-Szent László Hospital, Budapest, Hungary). RESULTS: Median age of patients was 54.5 years, and 6 (40%) were females. Cerebrospinal fluid findings at admission showed elevated protein (1.54 g/l; 95% confidence interval (CI): 1.01-2.05), cell count (mean: 337/µl; CI: 171.9-502.5), and decreased glucose index (0.32; CI: 0.15-0.52). 14 patients (93.3%) had hyponatremia. Average duration of symptoms were 16.3 days (1-40). On physical examination meningeal irritation was absent in 9 patients (60%). On admission headache and altered consciousness was present in 53%, while headache, fever, nuchal rigidity was present in only 33.3%. Diagnosis was culture and/or PCR confirmed in 46.7% of the cases. Two third of patients were followed-up at least for one year, and nine patients presented neurological sequel. Authors found that patients with central nervous system tuberculosis present with unspecific symptoms, but later progressive disorientation, cranial nerve palsies and convulsions may develop. Headache and altered consciousness proved to be the leading symptoms among these patients. Even today, diagnostic gold standard procedure is cultivating M. tuberculosis on solid and liquid medium. The polymerase chain reaction, which is known to have sensitivity between 27% and 86%, was positive in two of eight samples. Revealing predisposing factors (immunodeficiency, HIV infection, previous tuberculosis exposure) promotes setting up early diagnosis. Co-administration of four antituberculotic drugs for 12 months cured all patients, but authors note that even in cases with early diagnosis and optimal treatment various neurological impairment and seldom death can occur. CONCLUSIONS: Central nervous system tuberculosis is a rare but regularly emerging disease with unspecific signs and symptoms. The diagnosis may be difficult. It should be considered as a differential diagnostic issue in patients with uncharacteristic subacute conditions with headache, disorientation, elevated protein and low glucose in cerebrospinal fluid.

[Experience with multiplex nested PCR and fluorescent antibody tests in the diagnosis of acute central nervous system infections with herpes simplex virus type 1 and 2]. / Tapasztalatok a heveny központi idegrendszeri fertozések herpes simplex vírus-1/2 diagnosztikájában a multiplex nested PCR- és a fluoreszcens jelzésu antitestválasz-vizsgálat kombinációjával.

UNLABELLED: The specific diagnosis of herpes simplex virus type 1 and 2 infections has an extreme importance in acute infections of central nervous system due to both availability of specific antiviral therapy and the possible serious consequences of the disease. AIMS: Evaluation of the relevance and interpretation of the results of PCR and the specific antibody testing. METHODS: Home made multiplex nested herpes simplex virus PCR and immunofluorescent IgM, IgA, IgG antibody tests were carried out in a total of 474 cerebrospinal fluid and 555 serum samples of 396 patients with acute infection of the central nervous system between 1. January, 2003 and 31. December, 2009. RESULTS: The herpes simplex virus etiology was verified in 21% of 396 patients (82 patients, mean 12 cases per year): 26 were diagnosed by both methods (32%), 41 by PCR only (50%), 15 by the detection of intrathecal antibody production only (18%) (p<0.0001). HSV type1 or 2 DNA remained detectable in 35% of the samples drawn after the 30th day of the disease. These patients were all younger than two years of age. CONCLUSIONS: 1. PCR increased the ratio of verified herpes simplex virus etiology in acute central nervous infections. 2. Testing the specific antibody response cannot be ceased even in the availability of PCR. 3. Herpes simplex virus type 1 or 2 DNA might persist in central nervous system in spite of the specific antiviral therapy especially in the infants. 4. Herpes simplex virus PCR can be repeated if an early sample is negative or if it is suspected false positive. 5. There is a need for cooperation between clinicians and virologists in the appropriate interpretation of the results and in finding etiology.

Synthesis and HPLC-ECD Study of Cytostatic Condensed O,N-Heterocycles Obtained from 3-Aminoflavanones.

Racemic chiral O,N-heterocycles containing 2-arylchroman or 2-aryl-2H-chromene subunit condensed with morpholine, thiazole, or pyrrole moieties at the C-3-C-4 bond were synthesized with various substitution patterns of the aryl group by the cyclization of cis- or trans-3-aminoflavanone analogues. The 3-aminoflavanone precursors were obtained in a Neber rearrangement of oxime tosylates of flavanones, which provided the trans diastereomer as the major product and enabled the isolation of both the cis- and trans-diastereomers. The cis- and trans-aminoflavanones were utilized to prepare three diastereomers of 5-aryl-chromeno[4,3-b][1,4]oxazines. Antiproliferative activity of the condensed heterocycles and precursors was evaluated against A2780 and WM35 cancer cell lines. For a 3-(N-chloroacetylamino)-flavan-4-ol derivative, showing structural analogy with acyclic acid ceramidase inhibitors, 0.15 µM, 3.50 µM, and 6.06 µM IC50 values were measured against A2780, WM35, and HaCat cell lines, and apoptotic mechanism was confirmed. Low micromolar IC50 values down to 2.14 µM were identified for the thiazole- and pyrrole-condensed 2H-chromene derivatives. Enantiomers of the condensed heterocycles were separated by HPLC using chiral stationary phase, HPLC-ECD spectra were recorded and TDDFT-ECD calculations were performed to determine the absolute configuration and solution conformation. Characteristic ECD transitions of the separated enantiomers were correlated with the absolute configuration and effect of substitution pattern on the HPLC elution order was determined.

First description of a rifampicin-resistant Neisseria meningitidis serogroup Y strain causing recurrent invasive meningococcal disease in Hungary.

A Hungarian soldier previously immunized against Neisseria meningitidis by quadrivalent polysaccharide vaccine was twice infected with meningococci within six weeks. The patient was treated with ceftriaxone during both episodes and he successfully recovered. His close contacts received rifampicin prophylaxis. An investigation was performed to characterize the genetic background of the pathogens to ascertain if the recurrent invasive meningococcal disease was caused by the same strain and to find out the reason for reinfection. Both meningococci belonged to the fine type Y:P1.5-2,10-1:F4-1:ST-23. This is the first description of the Europe-wide prevalent N. meningitidis serogroup Y in Hungary. In the first episode, we found wild-type rpoB allele in the non-culturable sample implying the susceptibility to rifampicin. The culturable isolate from the second episode proved resistant to rifampicin and had a point mutation in the rpoB gene. The rifampicin resistance might have evolved during the prophylactic treatment of contacts. Previous immunization of the patient with polysaccharide vaccine was ineffective due to his immunodeficiency, thus immunization with conjugate vaccine was proposed. We have proposed the implementation of centralized rifampicin susceptibility testing of N. meningitidis strains within a defined time frame to intervene and administer appropriate prophylaxis to close contacts.

Severe tick-borne encephalitis in a patient previously infected by West Nile virus.

We describe severe tick-borne encephalitis (TBE) in a patient who had previously experienced West Nile fever, another flavivirus infection endemic in Hungary. Previous West Nile virus infection does not develop immunity either against TBE virus infection or the disease, and it does not mitigate its clinical course. The possibility of antibody-dependent enhancement is considered.