An Entry to Enantioenriched 3,3-Disubstituted Phthalides through Asymmetric Phase-Transfer-Catalyzed γ-Alkylation.

A novel asymmetric phase-transfer-catalyzed γ-alkylation of phthalide 3-carboxylic esters has been developed, giving access to 3,3-disubstituted phthalide derivatives, which present a chiral quaternary γ-carbon in good to excellent yields and good enantioselectivities (74-88% ee). The enantiomeric purity could be substantially enhanced to 94-95% ee by recrystallization. Both electron-withdrawing and electron-releasing substituents are well tolerated on the phthalide core as well as on the aromatic moiety of the alkylating agent. This methodology, enabling the introduction of an unfunctionalized group at the phthalide γ-position, fully complements previously reported organocatalytic strategies involving functionalized electrophiles, thus expanding the scope of accessible 3,3-disubstituted products. The high synthetic value of this asymmetric reaction has been proven by the formal synthesis of the naturally occurring alkaloid (+)-(9S,13R)-13-hydroxyisocyclocelabenzine.

Sulfoxonium ylides: simple compounds with chameleonic reactivity.

Sulfur ylides first disclosed in 1930 started to gain more attention in the 1960s, thanks mainly to the studies by Corey and Chaykovsky on their use for the preparation of strained rings. More recently, the chemistry of these compounds has experienced important growth, in part due to the similarity of their reactivities with diazo compounds. This short review provides an overview on the great assortment of reactions of sulfoxonium ylides, outlining a comparison between the chemistry of these ylides and their congeners: sulfonium ylides and diazo compounds. Insertion reactions, cyclisation reactions and ring-opening reactions are highlighted, giving particular attention to catalytic asymmetric methodologies.

Asymmetric trifluoromethylthiolation of azlactones under chiral phase transfer catalysis.

The first enantioselective method for the installation of the SCF3 group at the C-4 position of azlactones is described in the present communication under quinidinium phase transfer catalysis. The higher performance of substrates containing electron-rich 2-aryl groups at the azlactone was rationalized using DFT calculations.

Central-to-Axial Chirality Conversion Approach Designed on Organocatalytic Enantioselective Povarov Cycloadditions: First Access to Configurationally Stable Indole-Quinoline Atropisomers.

The first stereoselective synthesis of enantioenriched axially chiral indole-quinoline systems is presented. The strategy takes advantage of an organocatalytic enantioselective Povarov cycloaddition of 3-alkenylindoles and N-arylimines, followed by an oxidative central-to-axial chirality conversion process, allowing for access to previously unreported axially chiral indole-quinoline biaryls. The methodology is also implemented for the design and the preparation of challenging compounds exhibiting two stereogenic axes. DFT calculations shed light on the stereoselectivity of the central-to-axial chirality conversion, showing unconventional behavior.

A General Catalytic Enantioselective Transfer Hydrogenation Reaction of ß,ß-Disubstituted Nitroalkenes Promoted by a Simple Organocatalyst.

Given its synthetic relevance, the catalytic enantioselective reduction of ß,ß-disubstituted nitroalkenes has received a great deal of attention. Several bio-, metal-, and organo-catalytic methods have been developed, which however are usually applicable to single classes of nitroalkene substrates. In this paper, we present an account of our previous work on this transformation, which implemented with new disclosures and mechanistic insights results in a very general protocol for nitroalkene reductions. The proposed methodology is characterized by (i) a remarkably broad scope encompassing various nitroalkene classes; (ii) Hantzsch esters as convenient (on a preparative scale) hydrogen surrogates; (iii) a simple and commercially available thiourea as catalyst; (iv) user-friendly procedures. Overall, the proposed protocol gives a practical dimension to the catalytic enantioselective reduction of ß,ß-disubstituted nitroalkenes, offering a useful and general platform for the preparation of nitroalkanes bearing a stereogenic center at the ß-position in a highly enantioenriched form. A transition state model derived from control kinetic experiments combined with literature data is proposed and discussed. This model accounts and justifies the observed experimental results.

Catalytic Asymmetric Reactions of 4-Substituted Indoles with Nitroethene: A Direct Entry to Ergot Alkaloid Structures.

A domino Friedel-Crafts/nitro-Michael reaction between 4-substituted indoles and nitroethene is presented. The reaction is catalyzed by BINOL-derived phosphoric acid catalysts, and delivers the corresponding 3,4-ring-fused indoles with very good results in terms of yields and diastereo- and enantioselectivities. The tricyclic benzo[cd]indole products bear a nitro group at the right position to serve as precursors of ergot alkaloids, as demonstrated by the formal synthesis of 6,7-secoagroclavine from one of the adducts. DFT calculations suggest that the outcome of the reaction stems from the preferential evolution of a key nitronic acid intermediate through a nucleophilic addition pathway, rather than to the expected "quenching" through protonation.

Catalytic asymmetric addition of Meldrum's acid, malononitrile, and 1,3-dicarbonyls to ortho-quinone methides generated in situ under basic conditions.

A new approach to the utilization of highly reactive and unstable ortho-quinone methides (o-QMs) in catalytic asymmetric settings is presented. The enantioselective reactions are catalysed by bifunctional organocatalysts, and the o-QM intermediates are formed in situ from 2-sulfonylalkyl phenols through base-promoted elimination of sulfinic acid. The use of mild Brønsted basic conditions for transiently generating o-QMs in catalytic asymmetric processes is unprecedented, and allows engaging productively in the reactions nucleophiles such as Meldrum's acid, malononitrile and 1,3-dicarbonyls. The catalytic transformations give new and general entries to 3,4-dihydrocoumarins, 4H-chromenes and xanthenones. These frameworks are recurring structures in natural product and medicinal chemistry, as testified by the formal syntheses of (R)-tolterodine and (S)-4-methoxydalbergione from the catalytic adducts.

Organocatalytic Asymmetric Conjugate Additions to Cyclopent-1-enecarbaldehyde: A Critical Assessment of Organocatalytic Approaches towards the Telaprevir Bicyclic Core.

In the context of a programme directed at the manufacture of telaprevir, eight possible approaches to its bicyclic α-amino acid core, based on organocatalytic enantioselective conjugate additions to cyclopent-1-enecarbaldehyde, were identified and preliminarily explored. Four reactions, delivering advanced intermediates en route to the target amino acid, were selected for a thorough optimisation. Three of this reactions involved iminium ion catalysis with a prolinol catalyst (addition of nitromethane, nitroacetate and acetamidomalonate) and one was based on a Cinchona-derived phase-transfer catalyst (addition of glycine imines). A careful choice of additives allowed lowering of the catalyst loading to 0.5 mol% in some cases. The preparation of intermediates that would give access to the core of telaprevir in good yields and enantioselectivities by exploiting readily available substrates and catalysts, highlights the potential of organocatalytic technology for a cost-effective preparation of pharmaceuticals.

The Emergence of Quinone Methides in Asymmetric Organocatalysis.

Quinone methides (QMs) are highly reactive compounds that have been defined as "elusive" intermediates, or even as a "synthetic enigma" in organic chemistry. Indeed, there were just a handful of examples of their utilization in catalytic asymmetric settings until some years ago. This review collects organocatalytic asymmetric reactions that employ QMs as substrates and intermediates, from the early examples, mostly based on stabilized QMs bearing specific substitution patterns, to more recent contributions, which have dramatically expanded the scope of QM chemistry. In fact, it was only very recently that the generation of QMs in situ through strategies compatible with organocatalytic methodologies has been realized. This tactic has finally opened the gate to the full exploitation of these unstable intermediates, leading to a series of remarkable disclosures. Several types of synthetically powerful asymmetric addition and cycloaddition reactions, applicable to a broad range of QMs, are now available.

Biomarkers for Serious Bacterial Infections in Febrile Children.

Febrile infections in children are a common cause of presentation to the emergency department (ED). While viral infections are usually self-limiting, sometimes bacterial illnesses may lead to sepsis and severe complications. Inflammatory biomarkers such as C reactive protein (CRP) and procalcitonin are usually the first blood exams performed in the ED to differentiate bacterial and viral infections; nowadays, a better understanding of immunochemical pathways has led to the discovery of new and more specific biomarkers that could play a role in the emergency setting. The aim of this narrative review is to provide the most recent evidence on biomarkers and predictor models, combining them for serious bacterial infection (SBI) diagnosis in febrile children. Literature analysis shows that inflammatory response is a complex mechanism in which many biochemical and immunological factors contribute to the host response in SBI. CRP and procalcitonin still represent the most used biomarkers in the pediatric ED for the diagnosis of SBI. Their sensibility and sensitivity increase when combined, and for this reason, it is reasonable to take them both into consideration in the evaluation of febrile children. The potential of machine learning tools, which represent a real novelty in medical practice, in conjunction with routine clinical and biological information, may improve the accuracy of diagnosis and target therapeutic options in SBI. However, studies on this matter are not yet validated in younger populations, making their relevance in pediatric precision medicine still uncertain. More data from further research are needed to improve clinical practice and decision making using these new technologies.

Enantioselective organocatalytic strategies to access noncanonical α-amino acids.

Organocatalytic asymmetric synthesis has evolved over the years and continues to attract the interest of many researchers worldwide. Enantiopure noncanonical amino acids (ncAAs) are valuable building blocks in organic synthesis, medicinal chemistry, and chemical biology. They are employed in the elaboration of peptides and proteins with enhanced activities and/or improved properties compared to their natural counterparts, as chiral catalysts, in chiral ligand design, and as chiral building blocks for asymmetric syntheses of complex molecules, including natural products. The linkage of ncAA synthesis and enantioselective organocatalysis, the subject of this perspective, tries to imitate the natural biosynthetic process. Herein, we present contemporary and earlier developments in the field of organocatalytic activation of simple feedstock materials, providing potential ncAAs with diverse side chains, unique three-dimensional structures, and a high degree of functionality. These asymmetric organocatalytic strategies, useful for forging a wide range of C-C, C-H, and C-N bonds and/or combinations thereof, vary from classical name reactions, such as Ugi, Strecker, and Mannich reactions, to the most advanced concepts such as deracemisation, transamination, and carbene N-H insertion. Concurrently, we present some interesting mechanistic studies/models, providing information on the chirality transfer process. Finally, this perspective highlights, through the diversity of the amino acids (AAs) not selected by nature for protein incorporation, the most generic modes of activation, induction, and reactivity commonly used, such as chiral enamine, hydrogen bonding, Brønsted acids/bases, and phase-transfer organocatalysis, reflecting their increasingly important role in organic and applied chemistry.

Treatment options for children with multi-drug resistant tuberculosis.

INTRODUCTION: According to the latest report from the World Health Organization (WHO), approximately 10.0 million people fell ill with tuberculosis (TB) in 2020, 12% of which were children aged under 15 years. There is very few experience on treatment of multi-drug resistant (MDR)-TB in pediatrics. AREAS COVERED: The aim of this review is to analyze and summarize therapeutic options available for children experiencing MDR-TB. We also focused on management of MDR-TB prophylaxis. EXPERT OPINION: The therapeutic management of children with MDR-TB or MDR-TB contacts is complicated by a lack of knowledge, and the fact that many potentially useful drugs are not registered for pediatric use and there are no formulations suitable for children in the first years of life. Furthermore, most of the available drugs are burdened by major adverse events that need to be taken into account, particularly in the case of prolonged therapy. A close follow-up with a standardized timeline and a comprehensive assessment of clinical, laboratory, microbiologic and radiologic data is extremely important in these patients. Due to the complexity of their management, pediatric patients with confirmed or suspected MDR-TB should always be referred to a specialized center.

The Mycobacterium tuberculosis protein tyrosine phosphatase MptpA features a pH dependent activity overlapping the bacterium sensitivity to acidic conditions.

The Mycobacterium tuberculosis low-molecular weight protein tyrosine phosphatase (MptpA) is responsible for the inhibition of phagosome-lysosome fusion and is essential for the bacterium pathogenicity. This inhibition implies that M. tuberculosis is not exposed to a strongly acidic environment in vivo, enabling successful propagation in host cells. Remarkably, MptpA has been previously structurally and functionally investigated, with special emphasis devoted to the enzyme properties at pH 8.0. Considering that the virulence of M. tuberculosis is strictly dependent on the avoidance of acidic conditions in vivo, we analysed the pH-dependence of the structural and catalytic properties of MptpA. Here we show that this enzyme undergoes pronounced conformational rearrangements when exposed to acidic pH conditions, inducing a severe decrease of the enzymatic catalytic efficiency at the expense of phosphotyrosine (pTyr). In particular, a mild decrease of pH from 6.5 to 6.0 triggers a significant increase of K0.5 of MptpA for phosphotyrosine, the phosphate group of which we determined to feature a pKa2 equal to 5.7. Surface plasmon resonance experiments confirmed that MptpA binds poorly to pTyr at pH values < 6.5. Notably, the effectiveness of the MptpA competitive inhibitor L335-M34 at pH 6 does largely outperform the inhibition exerted at neutral or alkaline pH values. Overall, our observations indicate a pronounced sensitivity of MptpA to acidic pH conditions, and suggest the search for competitive inhibitors bearing a negatively charged group featuring pKa values lower than that of the substrate phosphate group.

Case Report: short stature, kidney anomalies, and cerebral aneurysms in a novel homozygous mutation in the PCNT gene associated with microcephalic osteodysplastic primordial dwarfism type II.

We report the case of a boy (aged 3 years and 7 months) with severe growth failure (length: -9.53 SDS; weight: -9.36 SDS), microcephaly, intellectual disability, distinctive craniofacial features, multiple skeletal anomalies, micropenis, cryptorchidism, generalized hypotonia, and tendon retraction. Abdominal US showed bilateral increased echogenicity of the kidneys, with poor corticomedullary differentiation, and a slightly enlarged liver with diffuse irregular echotexture. Initial MRI of the brain, performed at presentation, showed areas of gliosis with encephalomalacia and diffused hypo/delayed myelination, and a thinned appearance of the middle and anterior cerebral arteries. Genetic analysis evidenced a novel homozygous pathogenic variant of the pericentrin (PCNT) gene. PCNT is a structural protein expressed in the centrosome that plays a role in anchoring of protein complexes, regulation of the mitotic cycle, and cell proliferation. Loss-of-function variants of this gene are responsible for microcephalic osteodysplastic primordial dwarfism type II (MOPDII), a rare inherited autosomal recessive disorder. The boy died at 8 years of age as a result of an intracranial hemorrhage due to a cerebral aneurism associated with the Moyamoya malformation. In confirmation of previously published results, intracranial anomalies and kidney findings were evidenced very early in life. For this reason, we suggest including MRI of the brain with angiography as soon as possible after diagnosis in follow-up of MODPII, in order to identify and prevent complications related to vascular anomalies and multiorgan failure.

Antibiotic Prophylaxis for the Prevention of Urinary Tract Infections in Children: Guideline and Recommendations from the Emilia-Romagna Pediatric Urinary Tract Infections (UTI-Ped-ER) Study Group.

Background: Urinary tract infection (UTI) represents one of the most common infectious diseases and a major cause of antibiotic prescription in children. To prevent recurrent infections and long-term complications, low-dose continuous antibiotic prophylaxis (CAP) has been used. However, the efficacy of CAP is controversial. The aim of this document was to develop updated guidelines on the efficacy and safety of CAP to prevent pediatric UTIs. Methods: A panel of experts on pediatric infectious diseases, pediatric nephrology, pediatric urology, and primary care was asked clinical questions concerning the role of CAP in preventing UTIs in children. Overall, 15 clinical questions were addressed, and the search strategy included accessing electronic databases and a manual search of gray literature published in the last 25 years. After data extraction and narrative synthesis of results, recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology. Results: The use of CAP is not recommended in children with a previous UTI, with recurrent UTIs, with vesicoureteral reflux (VUR) of any grade, with isolated hydronephrosis, and with neurogenic bladder. CAP is suggested in children with significant obstructive uropathies until surgical correction. Close surveillance based on early diagnosis of UTI episodes and prompt antibiotic therapy is proposed for conditions in which CAP is not recommended. Conclusions: Our systematic review shows that CAP plays a limited role in preventing recurrences of UTI in children and has no effect on its complications. On the other hand, the emergence of new antimicrobial resistances is a proven risk.

Bioinspired organocatalytic asymmetric reactions.

Several small organic molecule catalysts are reminiscent of natural enzymes in their mode of action and substrate interaction/activation. This striking similarity has been a great source of inspiration for the development of new organocatalytic asymmetric processes. A few representative examples, mostly dealing with catalysts interacting through multiple hydrogen-bonds (synthetic oxyanion holes), are highlighted in this perspective.

Sulfoxonium Ylides in Aminocatalysis: An Enantioselective Entry to Cyclopropane-Fused Chromanol Structures.

The 1,1a,2,7b-tetrahydrocyclopropa[c]chromene, arising from fusion of chromane and cyclopropane rings is the core of medicinally relevant compounds. Engaging sulfoxonium ylides in enantioselective aminocatalytic reactions for the first time, a convenient entry to this scaffold is presented. Several ring-fused derivatives were obtained in moderate-to-good yields and enantioselectivities and with perfect diastereoselectivity at the cyclopropane, using an α,α-diphenylprolinol aminocatalyst. The versatility of the hemiacetal moiety in the products was leveraged to effect various synthetic manipulations.

Antibiotic Resistance in Paediatric Febrile Urinary Tract Infections.

Febrile urinary tract infection (UTI) is currently considered the most frequent cause of serious bacterial illness in children in the first 2 years of life. UTI in paediatrics can irreversibly damage the renal parenchyma and lead to chronic renal insufficiency and related problems. To avoid this risk, an early effective antibiotic treatment is essential. Moreover, prompt treatment is mandatory to improve the clinical condition of the patient, prevent bacteraemia, and avoid the risk of bacterial localization in other body sites. However, antibiotic resistance for UTI-related bacterial pathogens continuously increases, making recommendations rapidly outdated and the definition of the best empiric antibiotic therapy more difficult. Variation in pathogen susceptibility to antibiotics is essential for the choice of an effective therapy. Moreover, proper identification of cases at increased risk of difficult-to-treat UTIs can reduce the risk of ineffective therapy. In this review, the problem of emerging antibiotic resistance among pathogens associated with the development of paediatric febrile UTIs and the best potential solutions to ensure the most effective therapy are discussed. Literature analysis showed that the emergence of antibiotic resistance is an unavoidable phenomenon closely correlated with the use of antibiotics themselves. To limit the emergence of resistance, every effort to reduce and rationalise antibiotic consumption must be made. An increased use of antibiotic stewardship can be greatly effective in this regard.

Management of Pediatric Urinary Tract Infections: A Delphi Study.

Urinary tract infection (UTI) is one of the most common infectious diseases in the pediatric population and represents a major cause of antibiotic consumption and hospitalization in children. Considering the ongoing controversies on the management of pediatric UTI and the challenges due to increasing antimicrobial resistance, the aim of the present study was to evaluate the level of agreement on UTI management in pediatric age in Emilia-Romagna Region, Italy, and to assess on the basis of recent studies whether there is the need to change current recommendations used by primary care pediatricians, hospital pediatricians, and pediatric surgeons in everyday clinical practice to possibly improve outcomes. This consensus provides clear and shared indications on UTI management in pediatric age, based on the most updated literature. This work represents, in our opinion, the most complete and up-to-date collection of statements on procedures to follow for pediatric UTI, in order to guide physicians in the management of the patient, standardize approaches, and avoid abuse and misuse of antibiotics. Undoubtedly, more randomized and controlled trials are needed in the pediatric population to better define the best therapeutic management in cases with antimicrobial resistance and real usefulness of long-term antibiotic prophylaxis.

Effects of COVID-19-related life changes on mental health in Syrian refugees in Turkey.

BACKGROUND: Mental disorders are currently the greatest global health burden. The coronavirus diseases 2019 (COVID-19) pandemic is having an adverse impact on people's mental health, particularly in vulnerable populations, such as refugees. AIMS: The present study was designed to examine the association between COVID-19 and changes in mental health in Syrian refugees in Turkey. METHOD: We conducted a two-wave panel survey of a representative sample of 302 of the estimated 500 000 Syrian refugees (ages 18 and older) living under humanitarian support in Istanbul (first wave between 9 and 15 July 2020 and the follow-up between 11 and 14 September 2020). We administered seven items from the CoRonavIruS Health Impact Survey in addition to one-context specific item about life changes because of COVID-19, and measures of depression (10-item Center for Epidemiologic Study Depression Scale, CESD-10), anxiety (6-item State-Trait Anxiety Inventory, STAI-6) and perceived stress (Perceived Stress Scale, PSS-4). RESULTS: A factor analysis yielded three COVID-19 factors, labelled 'social relationships', 'stress' and 'hope.' We conducted a series of cross-lag panel analyses to test associations between the COVID-19 factors and mental health. We found associations between all COVID-19 factors and CESD-10, between COVID-19 'stress' and STAI-6, and between COVID-19 'stress' and COVID-19 'hope' and PSS-4. CONCLUSIONS: Our measures of life changes because of the COVID-19 pandemic are associated with changes in the mental health of Syrian refugees living in Istanbul. It is therefore important that they are provided with services to reduce what may be particularly debilitating consequences of COVID-19.