Synthesis,Pharmacological Evaluation,and Docking Studies of Novel Pyridazinone‐Based Cannabinoid Receptor Type 2 Ligands

In recent years, cannabinoid type 2 receptors (CB₂R) have emerged as promising therapeutic targets in a wide variety of diseases. Selective ligands of CB₂R are devoid of the psychoactive effects typically observed for CB₁R ligands. Based on our recent studies on a class of pyridazinone 4‐carboxamides, further structural modifications of the pyridazinone core were made to better investigate the structure–activity relationships for this promising scaffold with the aim to develop potent CB₂R ligands. In binding assays, two of the new synthesized compounds [6‐(3,4‐dichlorophenyl)‐2‐(4‐fluorobenzyl)‐cis‐N‐(4‐methylcyclohexyl)‐3‐oxo‐2,3‐dihydropyridazine‐4‐carboxamide ( 2 ) and 6‐(4‐chloro‐3‐methylphenyl)‐cis‐N‐(4‐methylcyclohexyl)‐3‐oxo‐2‐pentyl‐2,3‐dihydropyridazine‐4‐carboxamide ( 22 )] showed high CB₂R affinity, with K_i values of 2.1 and 1.6 nm , respectively. In addition, functional assays of these compounds and other new active related derivatives revealed their pharmacological profiles as CB₂R inverse agonists. Compound 22 displayed the highest CB₂R selectivity and potency, presenting a favorable in silico pharmacokinetic profile. Furthermore, a molecular modeling study revealed how 22 produces inverse agonism through blocking the movement of the toggle‐switch residue, W6.48.     

Synthesis and Biological Evaluation of Papain‐Family Cathepsin L‐Like Cysteine Protease Inhibitors Containing a 1,4‐Benzodiazepine Scaffold as Antiprotozoal Agents

Novel papain‐family cathepsin L‐like cysteine protease inhibitors endowed with antitrypanosomal and antimalarial activity were developed, through an optimization study of previously developed inhibitors. In the present work, we studied the structure–activity relationships of these derivatives, with the aim to develop new analogues with a simplified and more synthetically accessible structure and with improved antiparasitic activity. The structure of the model compounds was significantly simplified by modifying or even eliminating the side chain appended at the C3 atom of the benzodiazepine scaffold. In addition, a simple methylene spacer of appropriate length was inserted between the benzodiazepine ring and the 3‐bromoisoxazoline moiety. Several rhodesain and falcipain‐2 inhibitors displaying single‐digit micromolar or sub‐micromolar antiparasitic activity against one or both parasites were identified, with activities that were one order of magnitude more potent than the model compounds.     

Diet effects in the asthma treatment: A systematic review

Introduction: Obesity in asthmatic patients has important relationships with asthma control, pulmonary function, and quality of life. The objective of this study was to conduct a systematic review of the literature on the effect of diet on asthma management in adults. Methods: We searched PubMed, Embase, and Scopus (January 1948–October 2014) for randomized clinical trials that evaluated the effects of diet in adults with asthma. Results: Of 12,215 studies identified, 21 were included. A reduction in weight of at least 7.5% from baseline as a result of caloric restriction can be beneficial for improving disease control, quality of life, and pulmonary function in obese patients with asthma. A dietary pattern rich in foods with potential antioxidant effect had an impact in improving asthma control, but with little clinical significance. Studies involving antioxidant supplementation showed improvements in asthma control with magnesium supplementation and less decline in lung function with vitamin C supplementation. Studies of fatty acid supplementation demonstrated effects on weight loss and improvement of asthma control and lung function. Studies of supplementation with propolis and caffeine reported significant increases in FEV1. Conversely, studies of high dietary salt intake reported greater declines in lung function. Conclusions: The evidence shows that, for obese adults with asthma, the best dietary intervention seems to be caloric restriction, regardless of specific dietary components.     

Semantical investigations into nonmonotonic and probabilistic logics

Different forms of semantics have been proposed for conditionals of the form “Usually, if A then B”, ranging from quantitative probability distributions to qualitative approaches using plausibility orderings, possibility distributions, or conditional objects. Atomic-bound systems, also called big-stepped probabilities, allow qualitative reasoning with probabilities, aiming at bridging the gap between qualitative and quantitative argumentation and providing a model for the nonmonotonic reasoning system P. By using Goguen and Burstall’s notion of institutions for the formalization of logical systems, we elaborate precisely which formal connections exist among big-stepped probabilities, standard probabilities, and qualitative logics. Based on our investigations, we also develop two variants of conditional objects, one of them having a simpler semantics while still providing a model for system P.     

Hyperazeotropic ethanol salted-out by extractive distillation. Theoretical evaluation and experimental check

A distillation process for the production of hyperazeotropic ethanol from a dilute wine obtained from the fermentation of biomass has been studied. This process utilizes the coupling of a soft preconcentration stage and of a dehydration stage based on the salting-out effect produced by calcium chloride on the ethanol in an aqueous solution, with the disappearance of the azeotrope. The salt is employed in a close cycle, due to the presence of a regeneration stage, therefore no consumption of calcium chloride is noticed.

The distillation process utilizes one column consisting of two sections operating at different pressures in order to reach an efficient heat recovery.

In this paper, a simplified flow-sheet of the process and the principal operating conditions of the distillation column are illustrated. When compared with other processes, conventional or under development, this one is characterized by the promising reduction of the specific energy requirement.

The operating conditions chosen for the distillation with salt have been experimentally checked using a laboratory column running continuously with calcium chloride as salting-out agent. Moreover, the experiments confirmed the reliability of the mathematical model of the process. Further experiments are in progress with the aim of utilizing a mixture of salts which can be fed from the bottom of the dehydration section back to the fermentor, so that the salt regeneration stage can be reduced.     

Activation of the glmS Ribozyme Confers Bacterial Growth Inhibition

The ever‐growing number of pathogenic bacteria resistant to treatment with antibiotics call for the development of novel compounds with as‐yet unexplored modes of action. Here, we demonstrate the in vivo antibacterial activity of carba‐α‐d ‐glucosamine (CGlcN). In this mode of action study, we provide evidence that CGlcN‐mediated growth inhibition is due to glmS ribozyme activation, and we demonstrate that CGlcN hijacks an endogenous activation pathway, hence utilizing a prodrug mechanism. This is the first report describing antibacterial activity mediated by activating the self‐cleaving properties of a ribozyme. Our results open the path towards a compound class with an entirely novel and distinct molecular mechanism.     

Bildung von Pyrrolinonreduktonen beim Erhitzen von Hexosen mit Aminosauren

Zusammenfassung Beim Erhitzen von Glucose mit primären Aminen oder Aminosäuren in wäßriger Lösung werden u.a. Pyrrolinonreduktone der Struktur(10) gebildet. Das Reaktionsverhalten dieser bisher nicht bekannten Aminoreduktone wird untersucht und der Nachweis in Glucose-Glycin-Umsetzungsgemischen and in Malz durchgeführt. Die beim Erhitzen von Hexosen mit sekunddren Aminen beobachtete Bildung der sog. Aminohexosereduktone(5a) wird in Gegenwart von primären Aminen fast völlig zugunsten der Pyrrolinone unterdrückt.

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Formation of pyrrolinone reductones by heating hexoses with amino acids

Summary When an aqueous solution of glucose and primary amines or amino acids is heated pyrrolinone reductones of structure(10) are formed. Reactions of these till now unknown amino reductones are studied. Detection in heated glucose glycine mixtures and in malt is performed. Formation of the so-called amino hexose reductones (5a), observed when secondary amines are heated with hexoses, is almost completely suppressed in the presence of primary amines in favour of pyrrolinones.

     

On the representation and management of medical records in a knowledge-based system

The need for adapting Hospital Information Systems (HISs) to new applications (aimed at clinical data management) and to the ever growing population requires an evolution from both the representation and the usability points of view. The goal of this paper is to discuss the interdependencies of the advanced data representation models necessary to the new HISs and the interaction requirements. In particular, we present the technical taken in the MILORD (Multimedia Interaction with Large Object-oriented Radiological and clinical Databases) project to implement a departmental environment which integrates different kinds of clinical data in a user-friendly and homogeneous way. The implementation platform of the MILORD system is based on results obtained in the KIWIS project, which produced an advanced knowledge-base environment for large database systems. The interaction with a HIS is analyzed identifying the HIS-specific interaction tasks, the typical phases of the interaction with an information system, and the necessary interaction paradigms. In particular we describe the approach adopted in KIWIS for overcoming the problem of querying object-oriented databases and we discuss the new requirements that multimediality poses on the interaction paradigms.     

Validation of Analytical Multiparameter Homogenization Models for Out-of-Plane Loaded Masonry Walls by Means of the Finite Element Method

The linear elastic analysis of in-plane and out-of-plane loaded masonry walls is still significant under service loads and is required by codes of practice, therefore the knowledge of the homogenized mechanical properties of masonry is of relevant interest. The aim of this paper is to discuss the problem of the out-of-plane loaded masonry walls in detail and to assess the accuracy and reliability of different homogenization approaches presented in the technical literature, with particular interest in recent explicit formulas obtained through an asymptotic model (as reported by Cecchi and Sab in 2002). Several meaningful comparisons are presented for different types of new and historical masonry structures currently employed in Italy. The validation of the analytical models is carried out by means of a three-dimensional (3D) finite-element (FE) out-of-plane homogenization. A final structural comparison among analytical models, FE out-of-plane homogenization, and a computationally expensive heterogeneous 3D FE model is discussed for a simply supported square panel laterally loaded.