Accelerated Synthesis of Bicyclo[1.1.1]pentylamines: A High-Throughput Approach.

Strained bicyclic substructures such as bicyclo[1.1.1]pentylamines (BCPAs) are increasingly targeted in medicinal chemistry as arylamine bioisosteres. Here, we leverage high-throughput automated synthesis to rapidly develop library-amenable reaction conditions and maximize design space to expand access to BCPAs. This new protocol relies on a copper-mediated C-N coupling approach and uses accessible and bench-stable iodo-BCP building blocks. Its applicability has been exemplified by incorporating BCPs in drug-like compounds, providing straightforward access to a library of valuable aniline-like isosteres.

Factores de Riesgo de Hospitalización en Camas Básicas y Críticas asociados a Síndrome Inflamatorio Multisistémico Pediátrico (SIM) relacionado a COVID-19 de Niños, Niñas y Adolescentes: Revisión Sistemática Exploratoria / Risk Factors of Hospitalization in Basic and Critical Cases associated with Pediatric Multisystemic Inflammatory Syndrome (SIM) related to COVID-19 in Boys, Girls and Adolescents: Exploratory Systematic Review

Introducción. Introducción. La pandemia por SARS-CoV-2 en pediatría ha tenido un bajo impacto en niños y niñas adolescentes (NNA) debido a que un gran porcentaje son asintomáticos o desarrollan síntomas leves. No obstante, se han reportado casos de síndrome inflamatorio multisistémico pediátrico (SIM) por este virus, el cual afecta a múltiples órganos y sus manifestaciones se asemejan a la enfermedad de Kawasaki. La mayoría ha requerido hospitalización en unidades críticas (UCI). A pesar de la vigilancia epidemiológica de esta enfermedad, no se han reportado factores de riesgo (FR) para hospitalización. Objetivo. Explorar en la literatura los FR asociados a hospitalización en camas básicas y críticas de NNA con SIM relacionado a COVID-19. Métodos. Revisión sistemática exploratoria de bases de datos Pubmed, Epistemonikos, Lilacs y Scielo desde el año 2020, con un rango etario de 0 a 19 años, con estrategia de búsqueda sensible para FR de hospitalización en camas básicas y críticas por SIM. Resultados. De 84 artículos se seleccionaron 7. Las manifestaciones clínicas incluyeron fiebre persistente, síntomas gastrointestinales y parámetros inflamatorios severos. También se reporta asociación a comorbilidades y estrato socioeconómico bajo. El ingreso mediano a UCI fue de un 60%, y la mortalidad por SIM fue menor a un 2%, pero de mayor magnitud comparado con los ingresos por COVID-19 en este grupo etario. Los FR de ingreso a UCI fueron asociados a dolor abdominal [OR 1,7 (IC95% 1,2; 2,7)] y a mayor edad, con OR ajustado de 1,9 [IC95%1,4; 6] para edad de 6 a 12 años, OR ajustado de 2,6 [IC95% 1,8; 3,8] para edad de 13 a 20 años. La elevación de proteína C reactiva, troponina, ferritina, dímero D, péptido natriurético cerebral (BNP), BNP N-terminal pro tipo B o interleucina-6, y/o recuentos reducidos de plaquetas, linfocitos o albúmina se asociaron a ingreso a UCI. La etnia afroamericana se asoció a mayor ingreso a UCI con OR de 1,6 [IC95% 1,0; 2,4]. Conclusión. Los FR para hospitalización de NNA con SIM, reportados y seleccionados en la literatura, son edad sobre los 6 años, etnia afroamericana, presencia de comorbilidades y nivel socioeconómico bajo. Para el ingreso a UCI, se suma a esto, compromiso clínico respiratorio y/o gastrointestinal, y presencia de parámetros inflamatorios elevados. La mortalidad fue inferior al 2%, pero significativamente mayor que la mortalidad por infección COVID-19 exclusiva.

Background. SARS-CoV-2 pandemic in pediatrics population (children and adolescents) has low impact in due to large percent of asymptomatic or mild symptoms. However, since March 2020, cases of pediatric multisystemic inflammatory syndrome (PMIS) have been reported, which affects multiple organs and its main manifestations resemble Kawasaki disease. This group frequently required hospitalization in critical care units (ICU), and despite epidemiological surveillance of this disease, no risk factors (RF) for hospitalization of these children has been reported. Objetive. To explore RF in literature associated with pediatric hospitalization in basic and critical care beds from children and adolescents with PMIS related to COVID-19. Methodology. exploratory systematic review of Pubmed, Epistemonikos, Lilacs and Scielo databases, with limits: publication date from 2020 until now, and age range from 0 to 19 years. We made a sensitive search strategy for RF of pediatric hospitalization in basic and critical beds by PMIS. Results. clinical manifestations of hospitalized patients included persistent fever (3 to 5 days), gastrointestinal symptoms (vomiting, nausea, diarrhea and abdominal pain), and inflammatory laboratory parameters in highly ranges. It is also reported an association with presence of comorbidities and low socioeconomic status. The median admission to ICU was 60%, and mortality less than 2%, but greater magnitude compared to COVID-19 mortality. RF for ICU admission were associated with older age, with adjusted OR of 1.9 [CI95% 1.4; 6] for age 6 to 12 years, adjusted OR of 2.6 [CI95% 1.8; 3.8] for age 13 to 20 years, and abdominal pain [OR 1.7 (CI95% 1.2; 2.7)]. Among laboratory tests, elevated C-reactive protein, troponin, ferritin, D-dimer, brain natriuretic peptide (BNP), N-terminal pro-B-type BNP or interleukin-6, and/or reduced platelet, lymphocyte or albumin counts were associated with ICU admission. African-American ethnicity was also associated with higher ICU admission with OR of 1.6 [CI95% 1.0; 2.4]. Conclusion. RFs for hospitalization of children with PMIS reported and selected in the literature were: age over 6 years, Afro-American ethnicity, presence of comorbidities and low socioeconomic level. In addition to this, for ICU admission, it is reported respiratory and/or gastrointestinal clinical involvement, and elevated inflammatory parameters presence. Mortality was less than 2%, but significantly higher than mortality due to exclusive COVID-19 infection.

Diazaspirononane Nonsaccharide Inhibitors of O-GlcNAcase (OGA) for the Treatment of Neurodegenerative Disorders.

O-GlcNAcylation is a post-translational modification of tau understood to lower the speed and yield of its aggregation, a pathological hallmark of Alzheimer's disease (AD). O-GlcNAcase (OGA) is the only enzyme that removes O-linked N-acetyl-d-glucosamine (O-GlcNAc) from target proteins. Therefore, inhibition of OGA represents a potential approach for the treatment of AD by preserving the O-GlcNAcylated tau protein. Herein, we report the multifactorial optimization of high-throughput screening hit 8 to a potent, metabolically stable, and orally bioavailable diazaspirononane OGA inhibitor (+)-56. The human OGA X-ray crystal structure has been recently solved, but bacterial hydrolases are still widely used as structural homologues. For the first time, we reveal how a nonsaccharide series of inhibitors binds bacterial OGA and discuss the suitability of two different bacterial orthologues as surrogates for human OGA. These breakthroughs enabled structure-activity relationships to be understood and provided context and boundaries for the optimization of druglike properties.

Continuous Flow α-Arylation of N,N-Dialkylhydrazones under Visible-Light Photoredox Catalysis.

The first direct α-arylation of aldehyde-derived N,N-dialkylhydrazones with electron deficient aryl and heteroaryl cyanides under visible-light photoredox catalysis has been developed. Structurally complex α,α'-diaryl-N,N-cycloalkylhydrazones were obtained in moderate yields by repetition of the direct arylation protocol. A continuous-flow procedure for the preparation of α-aryl-N,N-dialkylhydrazones on a multigram scale has also been established.

Acylguanidine Beta Secretase 1 Inhibitors: A Combined Experimental and Free Energy Perturbation Study.

A series of acylguanidine beta secretase 1 (BACE1) inhibitors with modified scaffold and P3 pocket substituent was synthesized and studied with free energy perturbation (FEP) calculations. The resulting molecules showed potencies in enzymatic BACE1 inhibition assays up to 1 nM. The correlation between the predicted activity from the FEP calculations and the experimental activity was good for the P3 pocket substituents. The average mean unsigned error (MUE) between prediction and experiment was 0.68 ± 0.17 kcal/mol for the default 5 ns lambda window simulation time improving to 0.35 ± 0.13 kcal/mol for 40 ns. FEP calculations for the P2' pocket substituents on the same acylguanidine scaffold also showed good agreement with experiment and the results remained stable with repeated simulations and increased simulation time. It proved more difficult to use FEP calculations to study the scaffold modification from increasing 5 to 6 and 7 membered-rings. Although prediction and experiment were in agreement for short 2 ns simulations, as the simulation time increased the results diverged. This was improved by the use of a newly developed "Core Hopping FEP+" approach, which also showed improved stability in repeat calculations. The origins of these differences along with the value of repeat and longer simulation times are discussed. This work provides a further example of the use of FEP as a computational tool for molecular design.

Application of Free Energy Perturbation for the Design of BACE1 Inhibitors.

Novel spiroaminodihydropyrroles probing for optimized interactions at the P3 pocket of ß-secretase 1 (BACE1) were designed with the use of free energy perturbation (FEP) calculations. The resulting molecules showed pIC50 potencies in enzymatic BACE1 inhibition assays ranging from approximately 5 to 7. Good correlation was observed between the predicted activity from the FEP calculations and experimental activity. Simulations run with a default 5 ns approach delivered a mean unsigned error (MUE) between prediction and experiment of 0.58 and 0.91 kcal/mol for retrospective and prospective applications, respectively. With longer simulations of 10 and 20 ns, the MUE was in both cases 0.57 kcal/mol for the retrospective application, and 0.69 and 0.59 kcal/mol for the prospective application. Other considerations that impact the quality of the calculations are discussed. This work provides an example of the value of FEP as a computational tool for drug discovery.

Identification of a novel orally bioavailable phosphodiesterase 10A (PDE10A) inhibitor with efficacy in animal models of schizophrenia.

We report the continuation of a focused medicinal chemistry program aimed to further optimize a series of imidazo[1,2-a]pyrazines as a novel class of potent and selective phosphodiesterase 10A (PDE10A) inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic evaluation allowed the selection of compound 25a for its assessment in preclinical models of psychosis. The evolution of our medicinal chemistry program, structure-activity relationship (SAR) analysis, as well as a detailed pharmacological profile for optimized lead 25a are described.

N-Bridged 5,6-bicyclic pyridines: Recent applications in central nervous system disorders.

The search for novel heterobicyclic compounds within the drug-like chemical space continues to be an area of interest in medicinal chemistry. Unsaturated N-bridgehead heterocycles are well represented in marketed drugs for a variety of therapeutic areas, and continue to play an important role in central nervous system (CNS) drug discovery programs. Examples of medicinal chemistry strategies that make use of N-bridged 5,6-bicyclic pyridines are discussed here in this Minireview, which covers the literature from 2010 up to 2014. B1-class imidazopyridines and B3-class pyrazolopyridines have proven to be at the forefront of molecular prototypes that are capable of interacting with disease relevant targets in neurodegeneration and neuropsychiatry.

Practical preparation of challenging amides from non-nucleophilic amines and esters under flow conditions.

A fast and efficient protocol for the formation of amides from low nucleophilic amines and esters in flow is described. Products were obtained in good to excellent yields and with the advantage of simultaneous mixing of all reagents at once, avoiding steps for intermediate formation. The protocol is also suitable to be combined with ester synthesis, resulting in the preparation of amides in-line from haloarenes.

Muerte súbita por embolismo pulmonar metastásico de un tumor renal no diagnosticado en una niña de 11 años / Sudden death due to a metastatic pulmonary embolism due to an undiagnosed renal tumor in an 11 years old female

El tumor neuroectodérmico primitivo (PNET) es un tumor de células pequeñas, redondas y azules de rara presentación renal. La embolia pulmonar es excepcional en la edad pediátrica, no obstante, su presentación como embolismo masivo tiene como primera causa una neoplasia subyacente. Presentamos un caso de muerte súbita por embolismo pulmonar debido a un tumor no diagnosticado en una niña de 11 años. El estudio autópsico demostró la presencia de un tumor renal, que tras el estudio histopatológico, inmunohistoquímico y citogenético se diagnosticó como PNET (AU)

A primitive neuroectodermal tumor (PNET) is a small, round, blue cell, rare primary tumor in the kidney. Pulmonary embolism in children is uncommon, although an underlying malignancy is the leading cause of massive embolism. We present a case of sudden death due from metastatic pulmonary embolism due to an undiagnosed tumor in an 11-year-old female. The autopsy showed presence of a kidney tumor, which after histopathological, immunohistochemistry, and cytogenetic analyses, was diagnosed as a PNET (AU)

Discovery of a potent, selective, and orally active phosphodiesterase 10A inhibitor for the potential treatment of schizophrenia.

We report the discovery of a series of imidazo[1,2-a]pyrazine derivatives as novel inhibitors of phosphodiesterase 10A (PDE10A). In a high-throughput screening campaign we identified the imidazopyrazine derivative 1, a PDE10A inhibitor with limited selectivity versus the other phosphodiesterases (PDEs). Subsequent investigation of 1 and replacement of the trimethoxyphenyl group by a (methoxyethyl)pyrazole moiety maintained PDE10A inhibition but enhanced selectivity against the other PDEs. Systematic examination and analysis of structure-activity and structure-property relationships resulted in the discovery of 2, an in vitro potent and selective inhibitor of PDE10A with high striatal occupancy of PDE10A, promising in vivo efficacy in different rodent behavioral models of schizophrenia, and a good pharmacokinetic profile in rats.

Dihydrothiazolopyridone derivatives as a novel family of positive allosteric modulators of the metabotropic glutamate 5 (mGlu5) receptor.

Starting from a singleton chromanone high throughput screening (HTS) hit, we describe a focused medicinal chemistry optimization effort leading to the identification of a novel series of phenoxymethyl-dihydrothiazolopyridone derivatives as selective positive allosteric modulators (PAMs) of the metabotropic glutamate 5 (mGlu5) receptor. These dihydrothiazolopyridones potentiate receptor responses in recombinant systems. In vitro and in vivo drug metabolism and pharmacokinetic (DMPK) evaluation allowed us to select compound 16a for its assessment in a preclinical animal screen of possible antipsychotic activity. 16a was able to reverse amphetamine-induced hyperlocomotion in rats in a dose-dependent manner without showing any significant motor impairment or overt neurological side effects at comparable doses. Evolution of our medicinal chemistry program, structure activity, and properties relationships (SAR and SPR) analysis as well as a detailed profile for optimized mGlu5 receptor PAM 16a are described.

Rational design and synthesis of aminopiperazinones as ß-secretase (BACE) inhibitors.

Aminopiperazinone inhibitors of BACE were identified by rational design. Structure based design guided idea prioritization and initial racemic hit 18a showed good activity. Modification in decoration and chiral separation resulted in the 40 nM inhibitor, (-)-37, which showed in vivo reduction of amyloid beta peptides. The crystal structure of 18a showed a binding mode driven by interaction with the catalytic aspartate dyad and distribution of the biaryl amide decoration towards S1 and S3 pockets.

Light and electron microscopical data on the spores of Thelohanellus rhabdalestus n. sp. (Myxozoa: Myxosporea), a parasite of a freshwater fish from the Kwanza River, Angola.

The myxosporean Thelohanellus rhabdalestus n. sp. (Myxozoa: Bivalvulida), a parasite of the freshwater fish Rhabdalestes maunensis (Fower) collected from the Kwanza River, Angola, is described based on light and electron microscopical studies. The parasite occurs in irregular, milky-whitish, cyst-like plasmodia (up to 0.8 mm in diameter) in close contact with the liver and heart. The spores are pyriform, with slight tapering anterior and round posterior ends, and measure 16.8 ± 0.5 µm (n = 50) long, 10.2 ± 0.6 µm (n = 50) wide and 5.6 ± 0.8 µm (n = 25) thick. The spore wall is partly surrounded by a discontinuous, closely adhered, external coat of electron-dense material of variable thickness (up to c.35 nm). A single flask-shaped polar capsule [7.2 ± 0.3 µm (n = 50) long and 4.0 ± 0.4 µm (n = 50) in diameter] lies close to the apex of the spores and contains a polar filament with six or seven (rarely eight) coils oblique to its longitudinal axis. Based on morphological and ultrastructural differences, compared with other members of Thelohanellus Kudo, 1933, and judging from the host-specificity of previously described species, we consider this species new to science. This is the first reported myxosporean from the Angolan fauna.

Westphal reaction in solid-phase.

[reaction: see text]. A library of cycloimonium salts has been prepared through Westphal reaction in solid-phase. By reaction of solid-support-bound azolium or azinium acetates 2, 1,2-diketones 4, and base, cycloimonium salts 5 were synthesized in good to high yield and purities.

The enantioselective synthesis of alpha-amino acid derivatives via organoboranes.

Optically active (S)-alpha-amino acids are prepared in 54-95% ee (12 cases) by reaction of the Schiff base acetate of glycine tert-butyl ester with B-alkyl-9-BBN derivatives in the presence of the Cinchona alkaloid, cinchonidine, and base. The enantiomeric (R)-alpha-amino acids are available in 59-92% ee (3 cases) by using cinchonine as the chiral control element.

A solid-phase synthetic route to unnatural amino acids with diverse side-chain substitutions.

Reacting imine derivatives of resin-bound amino acids with alpha,omega-dihaloalkanes provides highly versatile intermediates to racemic alpha,alpha-disubstituted amino acids with a wide variety of side-chain functionality. Two strategies were developed to convert the intermediate omega-chloro or omega-bromo derivatives to the desired products. Together, they allow the creation of amino acids with diverse functionalities (omega-chlorides, nitriles, azides, acetates, thioacetates, thioethers, secondary and tertiary aliphatic amines, and anilines) placed at varying chain lengths (2-5) from the alpha-center of the amino acid.