Development of new thiazolidine-2,4-dione hybrids as aldose reductase inhibitors endowed with antihyperglycaemic activity: design, synthesis, biological investigations, and in silico insights

This research study describes the development of new small molecules based on 2,4-thiazolidinedione (2,4-TZD) and their aldose reductase (AR) inhibitory activities. The synthesis of 17 new derivatives of 2,4-TZDs hybrids was feasible by incorporating two known bioactive scaffolds, benzothiazole heterocycle, and nitro phenacyl moiety. The most active hybrid (8b) was found to inhibit AR in a non-competitive manner (0.16 µM), as confirmed by kinetic studies and molecular docking simulations. Furthermore, the in vivo experiments demonstrated that compound 8b had a significant hypoglycaemic effect in mice with hyperglycaemia induced by streptozotocin. Fifty milligrams per kilogram dose of 8b produced a marked decrease in blood glucose concentration, and a lower dose of 5 mg/kg demonstrated a noticeable antihyperglycaemic effect. These outcomes suggested that compound 8b may be used as a promising therapeutic agent for the treatment of diabetic complications

Chlorhexidine versus povidone–iodine skin antisepsis before upper limb surgery (CIPHUR) : an international multicentre prospective cohort study

Introduction Surgical site infection (SSI) is the most common and costly complication of surgery. International guidelines recommend topical alcoholic chlorhexidine (CHX) before surgery. However, upper limb surgeons continue to use other antiseptics, citing a lack of applicable evidence, and concerns related to open wounds and tourniquets. This study aimed to evaluate the safety and effectiveness of different topical antiseptics before upper limb surgery. Methods This international multicentre prospective cohort study recruited consecutive adults and children who underwent surgery distal to the shoulder joint. The intervention was use of CHX or povidone–iodine (PVI) antiseptics in either aqueous or alcoholic form. The primary outcome was SSI within 90 days. Mixed-effects time-to-event models were used to estimate the risk (hazard ratio (HR)) of SSI for patients undergoing elective and emergency upper limb surgery. Results A total of 2454 patients were included. The overall risk of SSI was 3.5 per cent. For elective upper limb surgery (1018 patients), alcoholic CHX appeared to be the most effective antiseptic, reducing the risk of SSI by 70 per cent (adjusted HR 0.30, 95 per cent c.i. 0.11 to 0.84), when compared with aqueous PVI. Concerning emergency upper limb surgery (1436 patients), aqueous PVI appeared to be the least effective antiseptic for preventing SSI; however, there was uncertainty in the estimates. No adverse events were reported. Conclusion The findings align with the global evidence base and international guidance, suggesting that alcoholic CHX should be used for skin antisepsis before clean (elective upper limb) surgery. For emergency (contaminated or dirty) upper limb surgery, the findings of this study were unclear and contradict the available evidence, concluding that further research is necessary

Synthèse asymétrique d’analogues tripeptidiques de l’asunaprévir basés sur une oxaproline et leur évaluation biologique

L’’ infection par le virus de l’ hépatite C (HCV) est considérée comme un des défis majeurs de santé publique en Egypte où la prévalence du virus de 10 % est la plus élevée au monde selon l’EHIS (Enquête sur les Problèmes de Santé en Egypte). Dans les récents développements thérapeutiques de nouveaux médicaments anti-HCV, une gamme d’inhibiteurs de protéase actifs a déjà été approuvée dans le traitement de l’HCV dans plusieurs pays (asunaprévir, paritaprévir, grazoprévir). Ces membres de la famille “prévir” ont en commun une structure tripeptidique équipée d’une unité 4-hétéroarylproline centrale. Notre travail de thèse s’est donné comme objectif de préparer deux nouvelles séries d’analogues potentiellement actifs comme anti-HCV. Ceux-ci impliquent le remplacement isostérique du cycle de la proline par un cycle isoxazolidine et l’introduction d’un groupe en position 4 de type heteroaryloxy- ou -CH2-. Les précurseurs des oxaprolines ont été synthétisés de novo avec une stratégie par cycloaddition 1,3-dipolaire (1,3-DC) impliquant une carboxynitrone et une vinyloxy/ allyl quinoline. L’unité oxaproline obtenue a été deprotégée séquentiellement (groupes N- et CO2H) et couplée jusqu’à l’obtention des tripeptides visés. Notre travail inclut deux domaines de la recherche méthodologique en chimie organique : (i) l’accès à des isoxazolidines très fonctionnelles par 1,3-DC avec la difficulté du diastéréocontrôle avec des aldonitrones et la sensibilité en milieu acide de ces composés et (ii) la synthèse et le couplage de dérivés d’acides aminés optiquement actifs non-naturels et difficile à faire. Des tests biochimiques et cellulaires ont été effectués sur les analogues formés.Hepatitis C virus (HCV) infection is considered the most challenging public health problem in Egypt where the prevalence is the highest in the world. Recent survey known as the Egyptian Health Issues Survey (EHIS) reported a prevalence of 10% HCV infection. In the recent therapeutical development of new anti-HCV drugs, a variety of active protease inhibitors have been already approved for treatment of HCV in some countries (asunaprevir, paritaprevir, grazoprevir). These members of the "previr" family display a common structure based on a tripeptide featuring a central 4-heteroarylproline unit. Our PhD work involves the attempts to prepare two new series of anti-protease analogues as novel anti-HCV agents. These analogues involve isosteric replacement of proline ring by isoxazolidine ring and introduction of either a heteroaryloxy or a heteroaryl-CH2- appendage at the C4 position. The oxaproline precursors have been de novo synthetized using an asymmetric 1,3-dipolar cycloaddition (1,3-DC) strategy, that involves the reaction between a vinyloxy / allyl quinoline and a carbalkoxynitrone. The obtained oxaproline unit have been subjected to sequential deprotection of N- and CO2H groups, and amide couplings to afford the target tripeptide analogues. Our work includes two domains of methodologic research in organic chemistry: (i) the access of highly functional isoxazolidines by 1,3-DC with the difficulty of diastereocontrol with aldonitrones and the acid sensitivity of these compounds (ii) the synthesis and the coupling of optically active non-natural and «difficult to make» amino acid derivatives. Both biochemical and cell-based assays have been done for the formed analogues

Estudio del espectro de infrarrojo y la relajación vibracional de péptidos en disolución acuosa= Study of the IR spectrum and the vibrational relaxation of peptides in water solution

En la presente tesis presentamos un estudio teórico del espectro infrarrojo y de la relajación vibracional de péptidos modelo disueltos en agua. Los péptidos son descritos utilizando campos de fuerza estándar de Mecánica Molecular y también Hamiltonianos electrónicos semiempíricos. El analisis de los ujos de energía vibracional intra e intermoleculares se realiza utilizando los Modos Normales Instantáneos. Así mismo se propone una nueva metodología para trazar su identidad durante la dinámica de relajación. Los tiempos de relajación obtenidos en nuestras simulaciones se encuentran en un acuerdo excelente con las medidas experimentales. También se describe la importancia relativa de los diferentes caminos de relajación, la velocidad de transferencia de energía hacia el disolvente y los cambios conformacionales de los péptidos. Palabras clave: Transferencia de energía, procesos de relajación, espectroscopía molecular, péptidos. Abstract In this thesis we present a theoretical study of the IR spectrum and the vibrational relaxation of model peptides solved in water. The peptides are described using standard Molecular Mechanics and Semiempirical Hamiltonian force elds. The analysis of the intra e intermolecular vibrational energy ows is carried out using the Instantaneous Normal Modes. A new methodology is proposed to track their identity during the relaxation dynamics. The relaxation lifetimes derived from our simulations are shown to be in excellent agreement with the experimental measurements. The relative importance of the di erent relaxation pathways, the rate of the energy transfer into the solvent and the conformational changes of the peptides are also described. Keywords: Energy transfer, relaxation processes, molecular spectroscopy, peptides

Understanding Chemistry and Unique NMR Characters of Novel Amide and Ester Leflunomide Analogues

A series of diverse substituted 5-methyl-isoxazole-4-carboxylic acid amides, imide and esters in which the benzene ring is mono or disubstituted was prepared. Spectroscopic and conformational examination was investigated and a new insight involving steric interference and interesting downfield deviation due to additional diamagnetic anisotropic effect of the amidic carbonyl group and the methine protons in 2,6-diisopropyl-aryl derivative (2) as conformationaly restricted analogues Leflunomide was discussed. Individual substituent electronic effects through π resonance of p-substituents and most stable conformation of compound (2) are discussed

On learning deep domain-invariant features from 2D synthetic images for industrial visual inspection

International audienceDeep learning resulted in a huge advancement in computer vision. However, deep models require a large amount of manually annotated data, which is not easy to obtain, especially in a context of sensitive industries. Rendering of Computer Aided Design (CAD) models to generate synthetic training data could be an attractive workaround. This paper focuses on using Deep Convolutional Neural Networks (DCNN) for automatic industrial inspection of mechanical assemblies, where training images are limited and hard to collect. The ultimate goal of this work is to obtain a DCNN classification model trained on synthetic renders, and deploy it to verify the presence of target objects in never-seen-before real images collected by RGB cameras. Two approaches are adopted to close the domain gap between synthetic and real images. First, Domain Randomization technique is applied to generate synthetic data for training. Second, a novel approach is proposed to learn better features representations by means of self-supervision: we used an Augmented Auto-Encoder (AAE) and achieved results competitive to our baseline model trained on real images. In addition, this approach outperformed baseline results when the problem was simplified to binary classification for each object individually

Design, synthesis, and biological investigation of oxadiazolyl, thiadiazolyl, and pyrimidinyl linked antipyrine derivatives as potential non-acidic anti-inflammatory agents

AbstractA novel series of 12 antipyrine derivatives containing 1,3,4-oxadiazoles (4a-d), 1,3,4-thiadiazoles (6a-d), and pyrimidines (8a-d), was preparedand assessed for its potential in vitro COX-2 inhibitors. Compared to Celecoxib, compounds 4b-d and 8d were the most potent derivatives c with a half-maximal inhibitory concentration range of 53–69 nM. Considering COX-2 selectivity index, compounds 4 b and 4c were chosen among these most potent derivatives for further investigation. The in vivo ability of compounds 4 b and 4c to counteract carrageenan-induced paw edoema has been assessed and their potential underlying mechanisms have been elucidated and the results have been further validated using molecular docking simulations