Binding models of reversible inhibitors to type-B monoamine oxidase

Interest in the inhibitors of type-B monoamine oxidase has grown in recent years, due to the evidence for multiple roles of one such agent (selegiline) in the pharmacological management of neurodegenerative disorders. A set of 130 reversible and selective inhibitors of MAO-B (including tetrazole, oxadiazolone, and oxadiazinone derivatives) were taken from the literature and subjected to a three-dimensional quantitative structure–activity relationship (3D-QSAR) study, using CoMFA and GOLPE procedures. The steric and lipophilic fields, alone and in combination, provided us with informative models and satisfactory predictions (q²=0.73). The validity of these models was checked against the 3D X-ray structure of human MAO-B. Flexible docking calculations, performed by using a new approach which took advantage from QXP and GRID computational tools, showed the diverse inhibitors to interact with MAO-B in a similar binding mode, irrespective of the heterocycle characterizing them. A significant trend of correlation was observed between estimated energies of the complexes and the experimental inhibition data.     

Non-phase-matched enhancement of second-harmonic generation in multilayer nonlinear structures with internal reflections

Traditional notions of second-harmonic generation rely on phase matching or quasi phase matching to achieve good conversion efficiencies. We present an entirely new concept for efficient second-harmonic generation that is based on the interference of counterpropagating waves in multilayer structures. Conversion efficiencies are an order of magnitude larger than with phase-matched second-harmonic generation in similar multilayer structures.     

The Cardbox/Cardview Database for residues in live animals and their products

The growing interest of the public opinion in environmental problems has resulted in the establishment of national and international norms and regulations. Among others, the protection of human health requires the constant monitoring of several groups of potentially toxic substances as well as of their residues in live animals and their products. For this reason in recent years the European Commission decided to establish four Community Reference Laboratories (CRLs) for the analysis of residues in products of animal origin. The current mandate and operative conditions of the CRLs are described in the Council Directive 96/23/EC of 29 April 1996, which has the goal of promoting and supporting the harmonization of approaches among National Reference Laboratories (NRLs). In this context the CRL at the Istituto Superiore di Sanità of Rome is responsible for chemical elements, organochlorine compounds (including PCBs), carbamates, pyrethroids and organophosphorus compounds. The supply of updated information on the literature of relevance to the tasks of the NRLs is one of the duties of the Rome CRL. To this end, the so-called Cardbox Database has been set up, which for the time being is fully operative for chemical elements and organochlorine compounds.     

Crucigasterins A-E, antimicrobial amino alcohols from the Mediterranean colonial ascidian Pseudodistoma crucigaster

Five new unsaturated 2-amino-3-alcohols, crucigasterins A-E (2-6), were isolated together with known related compound 7 from the Mediterranean ascidian Pseudodistoma crucigaster and characterised as diacetyl derivatives (2a-6a) by spectroscopic methods. The threo-relative configuration of the amino alcohol portion was inferred by NOE analysis of the oxazolidinone derivative of crucigasterin A (2) as well as by ¹³C NMR comparison with synthetic threo and erythro model compounds. The co-occurring metabolites were assumed to have the same relative configuration as 2 by comparison of the diagnostic carbon value of C-1. The absolute stereochemistry of compound 7 that had not been previously reported was determined by applying the modified Mosher’s method on the corresponding N-acetyl derivative. The same absolute configuration was suggested for the other co-occurring crucigasterins by biogenetic considerations. Antibacterial and antifungal activities of selected crucigasterins were also evaluated.     

Modelling taxation and redistribution: A discrete active particle kinetic approach

In this paper a general framework is proposed, suitable for the modelling of the taxation and redistribution process in a closed society. This framework arises within a discrete kinetic approach for active particle systems, and is expressed by a system of nonlinear ordinary differential equations. It is intended to describe the evolution of the wealth distribution over the population, based on the interactions of single individuals. The framework is then employed towards the construction of a toy model, which is analytically and computationally investigated.     

Multitarget Drug Discovery for Alzheimer's Disease: Triazinones as BACE‐1 and GSK‐3β Inhibitors

Cumulative evidence strongly supports that the amyloid and tau hypotheses are not mutually exclusive, but concomitantly contribute to neurodegeneration in Alzheimer′s disease (AD). Thus, the development of multitarget drugs which are involved in both pathways might represent a promising therapeutic strategy. Accordingly, reported here in is the discovery of 6‐amino‐4‐phenyl‐3,4‐dihydro‐1,3,5‐triazin‐2(1H)‐ones as the first class of molecules able to simultaneously modulate BACE‐1 and GSK‐3β. Notably, one triazinone showed well‐balanced in vitro potencies against the two enzymes (IC₅₀ of (18.03±0.01) μM and (14.67±0.78) μM for BACE‐1 and GSK‐3β, respectively). In cell‐based assays, it displayed effective neuroprotective and neurogenic activities and no neurotoxicity. It also showed good brain permeability in a preliminary pharmacokinetic assessment in mice. Overall, triazinones might represent a promising starting point towards high quality lead compounds with an AD‐modifying potential.