Discovery of thiazolo [5,4-c] isoquinoline based compounds as acetylcholinesterase inhibitors through computational target prediction, molecular docking and bioassay

We thank Nathalie Reichmann and Leendert Hamoen (University of Amsterdam) for critical reading of the manuscript, Ana Velic (Proteome Center Tübingen) for help with proteome analysis and Mike VanNieuwenhze (Indiana University) for the generous gift of HADA. This study was funded by the European Research Council through grant ERC‐2017‐CoG‐771709 (to MGP), by national funds through FCT– Fundação para a Ciência e a Tecnologia, PTDC/BIA‐MIC/6982/2020 (to HV); PTDC/BIA‐PLA/3432/2012 (to SRF); FCT through MOSTMICRO‐ITQB R&D Unit (UIDB/04612/2020, UIDP/04612/2020) and LS4FUTURE Associated Laboratory (LA/P/0087/2020) and FCT fellowship SFRH/BD/147052/2019 (to BMS); by the Swiss National National Foundation through P300P3_155346 (to AJ); by the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska‐Curie grant agreement No 839596 (to SS) and by the European Molecular Biology Organization through award ALTF 673‐2018 (to SS). Figure 6D and Appendix Fig S7 were created with Biorender.com .A computer-aided drug design (CADD) approach was developed for a focused chemical library comprising a series of sixteen thiazolo[5,4-c]isoquinoline derivatives. Little is known about this group of heteroaromatic compounds, both from the point of view of their synthesis and their biological properties. First, our CADD approach included target prediction by Mondrian conformal prediction with the ChEMBL database. The acetylcholinesterase (AChE) was identified as having a high probability of thiazolo[5,4-c]isoquinolines being active against it. Secondly, the molecular docking predictions revealed four promising thiazoloisoquinolines (2, 7, 13 and 14) according to their prominent ligand-protein energy scores and relevant binding affinities with the AChE pocket residues. The subsequent in vitro evaluation of promising hits and related ones revealed a set of novel AChE inhibitors. Therefore, the findings reported herein may provide a new strategy for discovering novel AChE inhibitors.publishersversionpublishe

Phenology and Seasonal Ecosystem Productivity in an Amazonian Floodplain Forest

everal studies have explored the linkages between phenology and ecosystem productivity across the Amazon basin. However, few studies have focused on flooded forests, which correspond to c.a. 14% of the basin. In this study, we assessed the seasonality of ecosystem productivity (gross primary productivity, GPP) from eddy covariance measurements, environmental drivers and phenological patterns obtained from the field (leaf litter mass) and satellite measurements (enhanced vegetation index (EVI) from the Moderate Resolution Imaging Spectroradiometer/multi-angle implementation correction (MODIS/MAIAC)) in an Amazonian floodplain forest. We found that ecosystem productivity is limited by soil moisture in two different ways. During the flooded period, the excess of water limits GPP (Spearman’s correlation; rho = −0.22), while during non-flooded months, GPP is positively associated with soil moisture (rho = 0.34). However, GPP is maximized when cumulative water deficit (CWD) increases (rho = 0.81), indicating that GPP is dependent on the amount of water available. EVI was positively associated with leaf litter mass (Pearson’s correlation; r = 0.55) and with GPP (r = 0.50), suggesting a coupling between new leaf production and the phenology of photosynthetic capacity, decreasing both at the peak of the flooded period and at the end of the dry season. EVI was able to describe the inter-annual variations on forest responses to environmental drivers, which have changed during an observed El Niño-Southern Oscillation (ENSO) year (2015/2016)

Accurate Atmospheric Parameters at Moderate Resolution Using Spectral Indices: Preliminary Application to the MARVELS Survey

Studies of Galactic chemical and dynamical evolution in the solar neighborhood depend on the availability of precise atmospheric parameters (Teff, [Fe/H] and log g) for solar-type stars. Many large-scale spectroscopic surveys operate at low to moderate spectral resolution for efficiency in observing large samples, which makes the stellar characterization difficult due to the high degree of blending of spectral features. While most surveys use spectral synthesis, in this work we employ an alternative method based on spectral indices to determine the atmospheric parameters of a sample of nearby FGK dwarfs and subgiants observed by the MARVELS survey at moderate resolving power (R~12,000). We have developed three codes to automatically normalize the observed spectra, measure the equivalent widths of the indices and, through the comparison of those with values calculated with pre-determined calibrations, derive the atmospheric parameters of the stars. The calibrations were built using a sample of 309 stars with precise stellar parameters obtained from the analysis of high-resolution FEROS spectra. A validation test of the method was conducted with a sample of 30 MARVELS targets that also have reliable atmospheric parameters from high-resolution spectroscopic analysis. Our approach was able to recover the parameters within 80 K for Teff, 0.05 dex for [Fe/H] and 0.15 dex for log g, values that are lower or equal to the typical external uncertainties found between different high-resolution analyzes. An additional test was performed with a subsample of 138 stars from the ELODIE stellar library and the literature atmospheric parameters were recovered within 125 K for Teff, 0.10 dex for [Fe/H] and 0.29 dex for log g. These results show that the spectral indices are a competitive tool to characterize stars with the intermediate resolution spectra.Comment: Accepted for publication in AJ. Abstract edited to comply with arXiv standards regarding the number of character

Negative correlation between Placental Growth Factor and Endocan-1 in women with preeclampsia

Objective: To analyse Endocan-1, a biomarker of vascular endothelial related pathologies, and Placental growth factor (PlGF), an angiogenic factor and a placental dysfunction marker in patients with pre-eclampsia (PE). Methods: Case-control study conducted at São Lucas Hospital. Endocan-1 and PlGF levels were quantified in maternal plasma using MagPlexTH-C microspheres system and analysed by ANCOVA adjusted by BMI, gestational age and maternal age. To estimate the difference between groups, mean ratio (MR) and 95% confidence interval (CI) were calculated. Pearson correlation test was used to establish any association between Endocan-1 and PlGF levels. The null hypothesis was rejected when

Novel 2-(R-phenyl)amino-3-(2-methylpropenyl)-[1,4]-naphthoquinones: synthesis, characterization, electrochemical behavior and antitumor activity

Novel 2-(R-phenyl)amino-3-(2-methyl-propenyl)-[1,4]-naphthoquinones (R = H, 4-OMe, 4-Ferrocenyl, 4-Me, 3-Me, 4-I, 3-I, 4-CN, 3-CN, 4-NO2 and 3-NO2) derived from nor-lapachol [2-hydroxy-3-(2-methylpropenyl)-1,4-naphthoquinone] were obtained in good yields. Their structures were proposed on the basis of a single crystal X-ray diffraction study (R = OMe, 2b), ¹H and 13C NMR studies and calculations using the B3LYP functional and the 6-311+G(2d,p) basis set. The half-wave potentials of the aminonaphthoquinones and ¹H NMR chemical shifts of the 3-propenyl hydrogen in 2a-k show good correlation with the substituent Hammett constants on the phenylamino ring. The antitumor assays showed promising activity for substrate methoxy-nor-lapachol 1 and the 4-ferrocenyl derivative 2c.Novas 2-(R-fenil)amino-3-(2-metilpropenil)-[1,4]-naftoquinonas (R = H, 4-OMe, 4-Ferrocenil, 4-Me, 3-Me, 4-I, 3-I, 4-CN, 3-CN, 4-NO2 e 3-NO2) derivadas do nor-lapachol [2-hidroxi-3-(2-metilpropenil)-1,4-naftoquinona] foram obtidas em bons rendimentos. A estrutura dos compostos foi proposta com base em estudos de difração de raios-X (R = OMe, 2b), dados de RMN de ¹H e 13C e cálculos teóricos utilizando o funcional B3LYP e a base 6-311+G(2d,p). Os potenciais de meia-onda das aminonaftoquinonas e o deslocamento químico do hidrogênio da cadeia 3-propenil dos compostos 2a-k mostraram boa correlação com as constantes de Hammett dos substituintes presentes no anel fenileno. A avaliação da citotoxicidade evidenciou atividade antitumoral promissora para o substrato metóxi-nor-lapachol 1 e o derivado 4-ferrocenil 2c.169178Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Exploring the brown dwarf desert : new substellar companions from the SDSS-III MARVELS survey

Planet searches using the radial velocity technique show a paucity of companions to solar-type stars within ∼5 au in the mass range of ∼10–80 MJup. This deficit, known as the brown dwarf desert, currently has no conclusive explanation. New substellar companions in this region help assess the reality of the desert and provide insight to the formation and evolution of these objects. Here, we present 10 new brown dwarf and 2 low-mass stellar companion candidates around solar-type stars from the Multi-object APO Radial Velocity Exoplanet Large-Area Survey (MARVELS) of the Sloan Digital Sky Survey III. These companions were selected from processed MARVELS data using the latest University of Florida Two Dimensional pipeline, which shows significant improvement and reduction of systematic errors over previous pipelines. The 10 brown dwarf companions range in mass from ∼13 to 76 MJup and have orbital radii of less than 1 au. The two stellar companions have minimum masses of ∼98 and 100 MJup. The host stars of the MARVELS brown dwarf sample have a mean metallicity of [Fe/H] = 0.03 ± 0.08 dex. Given our stellar sample we estimate the brown dwarf occurrence rate around solar-type stars with periods less than ∼300 d to be ∼0.56 per cent

Bronquiolite viral: aspectos epidemiológicos, fisiopatológicos e manejo terapêutico

A Bronquiolite Viral (BV) é uma condição aguda que afeta o trato respiratório inferior. Especialmente comum durante os meses mais frios do outono e inverno, a BV é uma das principais causas de hospitalização em crianças. O Vírus Sincicial Respiratório (VSR) é frequentemente associado à BV e pode levar a complicações graves em bebês, incluindo letargia, febre, inapetência, otite média, entre outras. Na maioria dos casos, em lactentes, a doença se apresenta de forma leve e pode ser resolvida em algumas semanas. O diagnóstico da BV pode ser realizado clinicamente, com exames adicionais usados ​​para avaliar possíveis complicações. Os critérios de internação incluem baixos níveis de saturação de oxigênio, sinais de desconforto respiratório moderado a grave, apneia e desidratação. O tratamento geralmente envolve medidas de suporte, garantindo uma oxigenação adequada, uma melhora da respiração e também atendendo as necessidades de fluidos e nutrição das crianças. Todavia, ainda existe uma grande necessidade de novos estudos a respeito da BV, objetivando-se sanar as lacunas do conhecimento evidenciadas no presente artigo