Non-coplanar helimagnetism in the layered van-der-Waals metal DyTe3.

Van-der-Waals magnetic materials can be exfoliated to realize ultrathin sheets or interfaces with highly controllable optical or spintronics responses. In majority, these are collinear ferro-, ferri-, or antiferromagnets, with a particular scarcity of lattice-incommensurate helimagnets of defined left- or right-handed rotation sense, or helicity. Here, we report polarized neutron scattering experiments on DyTe3, whose layered structure has highly metallic tellurium layers separated by double-slabs of dysprosium square nets. We reveal cycloidal (conical) magnetic textures, with coupled commensurate and incommensurate order parameters, and probe the evolution of this ground state in a magnetic field. The observations are well explained by a one-dimensional spin model, with an off-diagonal on-site term that is spatially modulated by DyTe3's unconventional charge density wave (CDW) order. The CDW-driven term couples to antiferromagnetism, or to the net magnetization in an applied magnetic field, and creates a complex magnetic phase diagram indicative of competing interactions in this easily cleavable van-der-Waals helimagnet.

Belgian patients of the European Registry for Hidradenitis Suppurativa (ERHS-Be): data, scores and phenotypes since 2015.

Introduction Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease, characterized by painful and recurrent lesions in apocrine gland-bearing skin areas. It is a heterogeneous disease, which makes assessment and data collection difficult. Questionnaires with detailed items, such as the Belgian European Registry for Hidradenitis Suppurativa (ERHS-Be), are useful to study HS and its associated comorbidities. The aim of this registry is to uncover new factors associated with HS, understand HS patients' clinical profiles and efficacy of treatments. Material and methods The ERHS-Be registry is based on questionnaires, with sections for socio-demographic data, medical and HS history, clinical examination and treatment plan. It allows identification of different clinical phenotypes and automatic calculation of severity scores. Results At present, 606 patients are included in the ERHS-Be (67% women, 33% men). Mean age at first visit is 38.5 years. Tobacco use is present in 72.6% of patients. A family history of HS is noted in 42% of patients. Comorbidities are documented in this cohort: depression is present in 43.8% of patients, arthritis in 27.8%, obesity in 31.5%, hypertension in 10.6%, diabetes mellitus in 6.4% and dyslipidemia in 12.4%. Moreover, 7.7% of patients suffer from IBD and 27.4% have a pilonidal sinus. History of severe acne is found in 32.1% of patients and psoriasis in 9.3%. Thirteen percent of women in our cohort suffer from polycystic ovarian syndrome. Severity of disease is quantified in 533 patients: for instance, Hurley I, II and III scores proportions are respectively 32.3%, 52.7% and 15%, while the mean IHS4 score is 5.2. This registry also enables determination of relative phenotype proportions in our cohort, according to different classifications. Conclusion The ERHS-Be questionnaires allow systematic and larger data collection, including detailed comorbidities, phenotypes and severity of disease. Analysis of this large database will contribute to a better understanding and management of HS, at a time where new therapeutic options are becoming available.

Chemical Repair of Radical Damage to the GC Base Pair by DNA-Bound Bisbenzimidazoles.

The migration of an electron-loss center (hole) in calf thymus DNA to bisbenzimidazole ligands bound in the minor groove is followed by pulse radiolysis combined with time-resolved spectrophotometry. The initially observed absorption spectrum upon oxidation of DNA by the selenite radical is consistent with spin on cytosine (C), as the GC• pair neutral radical, followed by the spectra of oxidized ligands. The rate of oxidation of bound ligands increased with an increase in the ratio (r) ligands per base pair from 0.005 to 0.04. Both the rate of ligand oxidation and the estimated range of hole transfer (up to 30 DNA base pairs) decrease with the decrease in one-electron reduction potential between the GC• pair neutral radical of ca. 1.54 V and that of the ligand radicals (E0', 0.90-0.99 V). Linear plots of log of the rate of hole transfer versus r give a common intercept at r = 0 and a free energy change of 12.2 ± 0.3 kcal mol-1, ascribed to the GC• pair neutral radical undergoing a structural change, which is in competition to the observed hole transfer along DNA. The rate of hole transfer to the ligands at distance, R, from the GC• pair radical, k2, is described by the relationship k2 = k0 exp(constant/R), where k0 includes the rate constant for surmounting a small barrier.

Fingerprints of Chalcogen Bonding Revealed Through 77Se-NMR.

77Se-NMR is used to characterise several chalcogen bonded complexes of derivatives of the organoselenium drug ebselen, exploring a range of electron demand. NMR titration experiments support the intuitive understanding that chalcogen bond donors bearing more electron withdrawing substituents give rise stronger chalcogen bonds. The chemical shift of the selenium nucleus is also shown to move upfield as it participates in a chalcogen bond. Solid-state NMR is used to explore chalcogen bonding in co-crystals. Due to the lack of molecular reorientation on the NMR timescale in the solid state, the shape of the chemical shift tensor can be determined using this technique. A range of co-crystals are shown to have extremely large chemical shift anisotropy, which suggests a strongly anisotropic electron density distribution around the selenium atom. A single crystal NMR experiment was conducted using one of the co-crystals, affording the absolute orientation of the chemical shift tensor within the crystal. This showed that the selenium nucleus is strongly shielded in the direction of the chalcogen bond (due to the approach of the lone pair of the Lewis base), and strongly deshielded in the perpendicular direction. The orientation of the deshielded axis is consistent with the presence of a second σ-hole which is not participating in a chalcogen bond, showing the profound effect of electron density anisotropy on the chemical shift.

Identifying the best cutoff value of the fecal occult blood immunochemical test in the detection of advanced and neoplastic colorectal lesions.

Objective: Screening is an effective tool for detecting colorectal lesions in asymptomatic subjects. There is a positive correlation between fecal immunochemical test (FIT) values and the size of tumors. Despite the efficacy of screening, the detection of colorectal cancer (CRC) remains low. The primary objective was to evaluate the best FIT cutoff value for detecting advanced adenomas and CRC among individuals at average risk in a country with a high incidence and morbidity from CRC. Methods: This observational and prospective study analyzed consecutive cases in 1461 asymptomatic subjects with a positive FIT (≥ 100 ng hemoglobin [Hb]/mL) referred for colonoscopy (2012-2015) at a tertiary center in Uruguay. Results: Colorectal lesions were detected in 35.3% (516/1461) of cases, with a mean age of 62.8 ± 8.3 years. About 53.2% were men and 65.1% of the tumors were located in the left side of the colon. The size of the lesion and FIT values (p = 0.001) were positively correlated. Laterally spreading tumors predominated in the right colon (586 ng Hb/mL; 95% Confidence interval [CI] 443.4-760). One hundred and thirty-five (26%) lesions were advanced adenomas (15 ± 6.7 mm); 694.6 ng/mL; 95% CI 632.4-756.9). The highest diagnostic yield (0.5112) for advanced adenomas was at a FIT level of 400 ng Hb/mL (accuracy 88.6%). There were significant differences in FIT values early and advanced CRC (927 ng/mL; [95% CI: 637-1082] vs. 1453 [95% CI: 1352-1594; p = 0.001]). Conclusion: A FIT value of 400 ng Hb/mL was the best diagnostic yield to detect advanced adenomas and CRC. This value is useful during the COVID-19 pandemic as it allows prioritization of colonoscopy to those most at risk of significant disease, thus reducing risks to both patients and healthcare workers.

Objetivo: El cribado es una herramienta eficaz para detectar lesiones colorrectales en sujetos asintomáticos. Existe una correlación positiva entre los valores de la prueba inmunoquímica fecal (FIT) y el tamaño de los tumores. A pesar de la eficacia del cribado, la detección del cáncer colorrectal (CCR) sigue siendo baja. El objetivo principal fue evaluar el mejor valor de corte FIT para detectar adenomas avanzados y CCR entre personas con riesgo promedio en un país con alta incidencia y morbilidad por CCR. Métodos: Este estudio observacional y prospectivo analizó 1461 sujetos asintomáticos con FIT positivo (≥ 100 ng de hemoglobina [Hb]/mL) remitidos para colonoscopia (2012-2015) en un centro terciario en Uruguay. Resultados: Se detectaron lesiones colorrectales en el 35,3% (516/1461) de los casos, con una edad media de 62,8 ± 8,3 años. Alrededor del 53,2% eran hombres y el 65,1% de los tumores estaban ubicados en el lado izquierdo del colon. El tamaño de la lesión y los valores FIT (p = 0,001) se correlacionaron positivamente. Los tumores con extensión lateral predominaron en el colon derecho (586 ng Hb/mL; intervalo de confianza [IC] del 95%: 443,4-760). Ciento treinta y cinco (26%) lesiones fueron adenomas avanzados (15 ± 6,7 mm); 694,6 ng/ml; IC 95% 632,4-756,9). El rendimiento diagnóstico más alto (0,5112) para los adenomas avanzados se obtuvo con un nivel FIT de 400 ng Hb/ml (precisión del 88,6%). Hubo diferencias significativas en los valores de FIT de CCR temprano y avanzado (927 ng/mL; [IC 95%: 637-1082] vs. 1453 [IC 95%: 1352-1594; p = 0,001]). Conclusión: Un valor FIT de 400 ng Hb/mL fue el mejor rendimiento diagnóstico para detectar adenomas avanzados y CCR. Este valor es útil durante la pandemia de COVID-19, ya que permite priorizar la colonoscopia a aquellos con mayor riesgo de padecer una enfermedad importante, reduciendo así los riesgos tanto para los pacientes como para los trabajadores de la salud.

Observation by SANS and PNR of pure Néel-type domain wall profiles and skyrmion suppression below room temperature in magnetic [Pt/CoFeB/Ru]10 multilayers.

We report investigations of the magnetic textures in periodic multilayers [Pt(1 nm)/(CoFeB(0.8 nm)/Ru(1.4 nm)]10 using polarised neutron reflectometry (PNR) and small-angle neutron scattering (SANS). The multilayers are known to host skyrmions stabilized by Dzyaloshinskii-Moriya interactions induced by broken inversion symmetry and spin-orbit coupling at the asymmetric interfaces. From depth-dependent PNR measurements, we observed well-defined structural features and obtained the layer-resolved magnetization profiles. The in-plane magnetization of the CoFeB layers calculated from fitting of the PNR profiles is found to be in excellent agreement with magnetometry data. Using SANS as a bulk probe of the entire multilayer, we observe long-period magnetic stripe domains and skyrmion ensembles with full orientational disorder at room temperature. No sign of skyrmions is found below 250 K, which we suggest is due to an increase of an effective magnetic anisotropy in the CoFeB layer on cooling that suppresses skyrmion stability. Using polarised SANS at room temperature, we prove the existence of pure Néel-type windings in both stripe domain and skyrmion regimes. No Bloch-type winding admixture, i.e. an indication for hybrid windings, is detected within the measurement sensitivity, in good agreement with expectations according to our micromagnetic modelling of the multilayers. Our findings using neutron techniques provide valuable microscopic insights into the rich magnetic behavior of skyrmion-hosting multilayers, which are essential for the advancement of future skyrmion-based spintronic devices.

The study presents a unique investigation of [Pt/CoFeB/Ru]₁₀ multilayers, revealing suppressed skyrmion phases, intricate magnetic domain structures, and Néel-type domain walls, providing crucial insights for spintronic applications.

Chemical and Antiplasmodial Investigations on Eremophila-Derived Alkaloids and Semisynthetic Ether Analogues.

Microthecaline A (1), the known antiplasmodial quinoline serrulatane alkaloid from the roots of Eremophila microtheca F. Muell. ex Benth. (Scrophulariaceae), was targeted for isolation and subsequent use in the generation of a semisynthetic ether library. A large-scale extraction and isolation yielded the previously undescribed quinoline serrulatane microthecaline B (2), along with crystalline 1 that enabled the first X-ray crystallographic analysis to be undertaken on this rare alkaloid structure class. The X-ray diffraction analysis of 1 supported the absolute configuration assignment of microthecaline A, which was originally assigned by ECD data analysis. Microthecaline A (1) was converted into 10 new semisynthetic ether derivatives (3-12) using a diverse series of commercially available alkyl halides. Chemical structures of the new serrulatane alkaloid and semisynthetic ether analogues were assigned by spectroscopic and spectrometric analyses. Antiplasmodial evaluations of 1-12 showed that the semisynthetic derivative 5 elicited the most potent activity with an IC50 value of 7.2 µM against Plasmodium falciparum 3D7 (drug-sensitive) strain.

Semisynthesis and Cytotoxic Evaluation of an Ether Analogue Library Based on a Polyhalogenated Diphenyl Ether Scaffold Isolated from a Lamellodysidea Sponge.

The known oxygenated polyhalogenated diphenyl ether, 2-(2',4'-dibromophenoxy)-3,5-dibromophenol (1), with previously reported activity in multiple cytotoxicity assays was isolated from the sponge Lamellodysidea sp. and proved to be an amenable scaffold for semisynthetic library generation. The phenol group of 1 was targeted to generate 12 ether analogues in low-to-excellent yields, and the new library was fully characterized by NMR, UV, and MS analyses. The chemical structures for 2, 8, and 9 were additionally determined via single-crystal X-ray diffraction analysis. All natural and semisynthetic compounds were evaluated for their ability to inhibit the growth of DU145, LNCaP, MCF-7, and MDA-MB-231 cancer cell lines. Compound 3 was shown to have near-equivalent activity compared to scaffold 1 in two in vitro assays, and the activity of the compounds with an additional benzyl ring appeared to be reliant on the presence and position of additional halogens.

Up against the wall - emergency double myocardial rupture repair.

BACKGROUND: Left ventricular free wall rupture (LVFWR) and interventricular septal rupture (VSR) are potentially catastrophic mechanical complications after acute myocardial infarction (AMI). When they occur together, "double myocardial rupture" (DMR), survival is unlikely. DMR is seen in only 0.3% of all AMIs. With or without surgical intervention, the odds are against the patient. CASE PRESENTATION: A 57-year-old male self-referred to the emergency department of a remote hospital 5 days after first experiencing chest pain. Investigations in ED confirmed an inferior ST-segment elevation myocardial infarction (STEMI) complicated by DMR. Coronary angiography revealed a mid-course total occlusion of the right coronary artery (RCA). He was rapidly transferred to our regional cardiac surgical unit, arriving straight into the operating theatre, in cardiogenic shock. He was briefly conscious, before arresting prior to intubation and being massaged onto bypass. Not only did he survive the all-night operation, requiring a mitral valve replacement in the process, but he survived multiple postoperative complications to be eventually transferred on postoperative day 66, neurologically intact, to a peripheral unit to complete his rehabilitation. He was subsequently discharged home 88 days after the operation and was able to ambulate with a walking frame into his first postoperative follow-up clinic appointment. CONCLUSIONS: Our patient, against all odds, has survived DMR and multiple postoperative complications. We present the details of his case and the literature surrounding the condition. The patient's mental fortitude and his supportive family played a significant role, along with excellent multidisciplinary team work, in assuring his survival.

Total Synthesis of Icumazole A Using a Modified Cadiot-Chodkiewicz Coupling.

The first total synthesis of myxobacteria metabolite icumazole A (1) is reported. Key steps in the route include an organocatalyzed asymmetric self-aldol reaction followed by an acetate aldol reaction to form the stereotriad present in the oxazole moiety, an intramolecular Diels-Alder reaction to form the isochromanone, and an acetylide addition and selective methylation. The final steps involved a high-yielding modified Cadiot-Chodkiewicz coupling and stereoselective reduction to secure the Z,Z-diene and afford 1.

Belgian atopic dermatitis guidelines.

Atopic dermatitis (AD) is one of the most common, bothersome and difficult to treat skin disorders. Recent introduction of new systemic treatments has revolutionized the management of AD. The goal of this guideline is to provide evidence-based recommendations for the management of patients suffering from atopic dermatitis that easily can be implemented in clinical practice. These recommendations were developed by 11 Belgian AD experts. Comments of all experts on the proposed statements were gathered, followed by an online voting session. The most relevant strategies for the management and treatment of AD in the context of the Belgian health care landscape are discussed. General measures, patient education and adequate topical treatment remain the cornerstones of AD management. For moderate to severe AD, the introduction of biologics and JAK inhibitors show unprecedented efficacy, although currently access is limited to a subgroup of patients meeting the reimbursement criteria.

Solvent-Directed Construction of a Nanoporous Metal-Organic Framework with Potential in Selective Adsorption and Separation of Gas Mixtures Studied by Grand Canonical Monte Carlo Simulations.

In this report, a microporous metal-organic framework of [Ca(TDC)(DMA)]n (1) and a two-dimensional coordination polymer of [Ca(TDC)(DMF)2 ]n (2), (TDC2- =Thiophene-2,5-dicarboxylate, DMA=N, N'-dimethylacetamide and DMF=N, N'-dimethylformamide) based on Ca(II) were designed by the effect of solvent, and X-ray analysis was performed for the single crystals of 1 and 2. Then, compound 1 was synthesized in three different methods and identified with a set of analyses. Compared to other adsorbents, MOFs are widely used in the field of adsorption and separation of various gases due to a series of distinctive features such as diverse and adjustable structures pores with different dimensions, high porosity and surface area with regular distribution of active sites. Therefore, the ability of 1 to uptake single gases (CH4 , CO2 , C2 H2 , H2, and N2 ) and separation of several binary mixtures of gases (CO2 /CH4 , CO2 /N2 , CO2 /H2 and CO2 /C2 H2 ), were investigated using Grand Canonical Monte Carlo simulations. Volumetric and gravimetric adsorption isotherms in various operating conditions, the isosteric heat of adsorption (qst ), the chemical potential for each thermodynamic state, and snapshots during the simulation process were reported in all cases. The results obtained from the adsorption simulation indicate that compound 1 has a high capacity for uptake of H2 (16 mmol g-1 ) and N2 (12.5 mmol g-1 ), CO2 (6.6 mmol g-1 ), C2 H2 (5 mmol g-1 ) and CH4 (1.5 mmol g-1 ) gases at 1 bar. It also performs well in separating CO2 in binary mixtures, which can be attributed to the presence of open metal sites in nodes of 1 and their electrostatic tendency to interact with CO2 containing the higher quadrupole dipole moment compared to other components of the mixture.

Western outcomes of circumferential endoscopic submucosal dissection for early esophageal squamous cell carcinoma.

BACKGROUND AND AIMS: Circumferential endoscopic submucosal dissection (cESD) in the esophagus has been reported to be feasible in small Eastern case series. We assessed the outcomes of cESD in the treatment of early esophageal squamous cell carcinoma (ESCC) in Western countries. METHODS: We conducted an international study at 25 referral centers in Europe and Australia using prospective databases. We included all patients with ESCC treated with cESD before November 2022. Our main outcomes were curative resection according to European guidelines and adverse events. RESULTS: A total of 171 cESDs were performed on 165 patients. En bloc and R0 resections rates were 98.2% (95% confidence interval [CI], 95.0-99.4) and 69.6% (95% CI, 62.3-76.0), respectively. Curative resection was achieved in 49.1% (95% CI, 41.7-56.6) of the lesions. The most common reason for noncurative resection was deep submucosal invasion (21.6%). The risk of stricture requiring 6 or more dilations or additional techniques (incisional therapy/stent) was high (71%), despite the use of prophylactic measures in 93% of the procedures. The rates of intraprocedural perforation, delayed bleeding, and adverse cardiorespiratory events were 4.1%, 0.6%, and 4.7%, respectively. Two patients died (1.2%) of a cESD-related adverse event. Overall and disease-free survival rates at 2 years were 91% and 79%. CONCLUSIONS: In Western referral centers, cESD for ESCC is curative in approximately half of the lesions. It can be considered a feasible treatment in selected patients. Our results suggest the need to improve patient selection and to develop more effective therapies to prevent esophageal strictures.

Transition between distinct hybrid skyrmion textures through their hexagonal-to-square crystal transformation in a polar magnet.

Magnetic skyrmions, topological vortex-like spin textures, garner significant interest due to their unique properties and potential applications in nanotechnology. While they typically form a hexagonal crystal with distinct internal magnetisation textures known as Bloch- or Néel-type, recent theories suggest the possibility for direct transitions between skyrmion crystals of different lattice structures and internal textures. To date however, experimental evidence for these potentially useful phenomena have remained scarce. Here, we discover the polar tetragonal magnet EuNiGe3 to host two hybrid skyrmion phases, each with distinct internal textures characterised by anisotropic combinations of Bloch- and Néel-type windings. Variation of the magnetic field drives a direct transition between the two phases, with the modification of the hybrid texture concomitant with a hexagonal-to-square skyrmion crystal transformation. We explain these observations with a theory that includes the key ingredients of momentum-resolved Ruderman-Kittel-Kasuya-Yosida and Dzyaloshinskii-Moriya interactions that compete at the observed low symmetry magnetic skyrmion crystal wavevectors. Our findings underscore the potential of polar magnets with rich interaction schemes as promising for discovering new topological magnetic phases.

A fucoidan plant drink reduces Helicobacter pylori load in the stomach: a real-world study.

Background: Helicobacter pylori (Hp) infection is highly prevalent globally and is predominantly managed by antibiotics. Recently, the anti-adhesive, antioxidant, antitoxin, immunomodulatory, anti-coagulant, and anti-infective activities of fucoidan, a polysaccharide extracted from brown seaweeds, have been widely studied, and the results showed promise. Fucoidan has the potential to be utilized in Hp eradication therapy. Our present clinical study was designed to evaluate the efficiency of Lewuyou®, a fucoidan plant drink (FPD) in eradicating Hp in humans. Methods: This multi-center, clinical study was conducted between October 2020 and July 2021. Hp infection was confirmed by urea breath test (UBT). A total of 122 patients with confirmed Hp infection were enrolled; after exclusion of incomplete data, 85 eligible patients (37 males and 48 females aged 20-81 years) were included in the final analysis. FPD (50 mL per vial) was orally administered twice daily for a 4-week cycle, and 41 patients completed an 8-week cycle. Results: No adverse event (AE) was reported in all 122 participants who had consumed FPD. The Hp eradication rate and clearance rate were 77.6% (66/85) and 20.0% (17/85), respectively, after 4 weeks of FPD consumption and 80.5% (33/41) and 26.8 (11/41) , respectively, after 8 weeks of consumption. Conclusions: The 4- and 8-week protocols of FPD consumption were safe and effective at reducing Hp load on the gastric mucosa, with Hp eradicated in the majority of participants.

High incidence of antibiotic resistance amongst isolates of Helicobacter pylori collected in Nottingham, UK, between 2001 and 2018.

Introduction. Helicobacter pylori is the leading cause of peptic ulcers and gastric cancer. The most common treatment regimens use combinations of two or three antibiotics and a proton pump inhibitor (PPI) to suppress stomach acid. The World Health Organization designated clarithromycin-resistant H. pylori as a high priority pathogen for drug development, due to increasing antibiotic resistance globally.Hypothesis/Gap Statement. There is no routine surveillance of H. pylori primary antimicrobial sensitivities in the UK, and published data are lacking.Aim. This study aimed to characterize antimicrobial sensitivities of isolates collected in Nottingham, UK, between 2001 and 2018.Methodology. Gastric biopsy samples were collected, with informed written consent and ethics approval, from 162 patients attending the Queen's Medical Centre in Nottingham for an upper GI tract endoscopy. Antibiotic sensitivity was assessed using E-Tests and a more cost-effective disc diffusion test.Results. The clarithromycin, amoxicillin and levofloxacin disc diffusion tests provided identical results to E-Tests on a subset of 30 isolates. Disparities were observed in the metronidazole test results, however. In total, 241 isolates from 162 patients were tested using at least one method. Of all isolates, 28 % were resistant to clarithromycin, 62 % to metronidazole and 3 % to amoxicillin, which are used in first-line therapies. For those antibiotics used in second- and third-line therapies, 4 % were resistant to levofloxacin and none of the isolates were resistant to tetracycline. Resistance to more than one antibiotic was found in 27 % of isolates. The frequency of patients with a clarithromycin-resistant strain increased dramatically over time: from 16 % between 2001 and 2005 to 40 % between 2011 and 2018 (P=0.011). For the same time periods, there was also an increase in those with a metronidazole-resistant strain (from 58 to 78 %; P=0.05). The frequencies of clarithromycin and metronidazole resistance were higher in isolates from patients who had previously received eradication therapy, compared to those who had not (40 % versus 77 %, and 80 % versus 92 %, respectively). Of 79 pairs of isolates from the antrum and corpus regions of the same patient's stomach, only six had differences in their antimicrobial susceptibility profiles.Conclusion. Although there was high and increasing resistance to clarithromycin and metronidazole, there was no resistance to tetracycline and the frequencies of amoxicillin and levofloxacin resistance were very low.

Synthesis of More Highly Oxidized Alkyl Citrates via Direct Regio- and Stereoselective Oxidation.

An approach to more highly oxidized alkyl citrates by direct regio- and stereoselective oxidations is reported. The total synthesis and structural assignment of alkyl citrate L-731-128 are described, and the synthesis of its C4 oxidized congener L-731,127 utilized a regio- and stereoselective enolate oxidation with oxygen gas. A highly stereoselective Rubottom oxidation of a cyclic silylketene acetal then enabled oxidation at C2 to afford the cinatrins C1 and C3.

Pyrimidine-morpholine hybrids as potent druggable therapeutics for Alzheimer's disease: Synthesis, biochemical and in silico analyses.

The identification of effective and druggable cholinesterase inhibitors to treat progressive neurodegenerative Alzheimer's disorder remains a continuous drug discovery hunt. In this perspective, the present study investigates the design and discovery of pyrimidine-morpholine hybrids (5a-l) as potent cholinesterase inhibitors. Palladium-catalyzed Suzuki-Miyaura cross-coupling reaction was employed to introduce the structural diversity on the pyrimidine heterocyclic core. A range of commercially available boronic acids was successfully coupled showing a high functional group tolerance. In vitro cholinesterase inhibitory potential using Ellman's method revealed significantly strong potency. Compound 5h bearing a meta-tolyl substituent at 2-position of pyrimidine ring emerged as a lead candidate against AChE with an inhibitory potency of 0.43 ± 0.42 µM, ∼38-fold stronger value than neostigmine (IC50 = 16.3 ± 1.12 µM). Compound 5h also showed the lead inhibition against BuChE with an IC50 value of 2.5 ± 0.04 µM. The kinetics analysis of 5h revealed the non-competitive mode of inhibition against AChE whereas computational modelling results of potent leads depicted diverse contacts with the binding site amino acid residues. Molecular dynamics simulations revealed the stability of biomolecular system, while, ADME analysis demonstrated druglikeness behaviour of potent compounds. Overall, the investigated pyrimidine-morpholine scaffold presented a remarkable potential to be developed as efficacious anti-Alzheimer's drugs.