Computational and Synthetic Target-based Approaches to the Discovery of Novel Anticonvulsant Compounds.

Background: During the past decades, an important number of anticonvulsant drugs have been incorporated into the collection of drugs to treat epilepsy. However, two main difficulties remain unsolved in therapy: the development of drug-resistant epilepsy and the occurrence of severe toxic effects caused by the medication in responsive patients. The retrospective analysis of the strategies for discovering known anticonvulsant drugs showed that screening campaigns on animal models of epilepsy have been almost the exclusive strategy for identifying the marketed compounds.

Purification and characterization of Saccharomyces eubayanus killer toxin: Biocontrol effectiveness against wine spoilage yeasts.

Microbiological contamination by spoilage yeasts species are frequent during winemaking, and biological control using antagonistic yeasts is considered a more beneficial alternative to conventional synthetic antimicrobials. Saccharomyces eubayanus killer toxin (SeKT) was produced and purified in a synthetic optimized medium. Purification procedure allowed the identification of SeKT as protein with an apparent molecular mass of 70 kDa and activity at physicochemical conditions suitable for winemaking process.

A structure-based approach towards the identification of novel antichagasic compounds: carbonic anhydrase inhibitors.

carbonic anhydrase (CA) has recently emerged as an interesting target for the design of new compounds to treat Chagas disease. In this study we report the results of a structure-based virtual screening campaign to identify novel and selective CA inhibitors. The combination of properly validated computational methodologies such as comparative modelling, molecular dynamics and docking simulations allowed us to find high potency hits, with K values in the nanomolar range.

Stereoselective Synthesis of Highly Substituted Tetrahydropyrans through an Evans Aldol-Prins Strategy.

A direct and general method for the synthesis of naturally occurring 2,3,4,5,6-pentasubstituted tetrahydropyrans has been developed, employing β,γ-unsaturated N-acyl oxazolidin-2-ones as key starting materials. The combination of the Evans aldol addition and the Prins cyclization allowed the diastereoselective and efficient generation of the desired oxacycles in two fashions: a one-pot Evans aldol-Prins protocol, in which five new σ bonds and five contiguous stereocenters were straightforwardly generated, and a two-step version, which additionally permitted the isolation of β,γ-unsaturated alcohol precursors bearing an N-acyl oxazolidin-2-one in the α position. From these alcohols were also obtained halogenated pentasubstituted tetrahydropyrans as well as 2,3,4,5-tetrasubstituted tetrahydrofurans, shedding light on the mechanism of the process.

Searching for New Leads To Treat Epilepsy: Target-Based Virtual Screening for the Discovery of Anticonvulsant Agents.

The purpose of this investigation is to contribute to the development of new anticonvulsant drugs to treat patients with refractory epilepsy. We applied a virtual screening protocol that involved the search into molecular databases of new compounds and known drugs to find small molecules that interact with the open conformation of the Nav1.2 pore.

Development and Validation of a Computational Model Ensemble for the Early Detection of BCRP/ABCG2 Substrates during the Drug Design Stage.

Breast Cancer Resistance Protein (BCRP) is an ATP-dependent efflux transporter linked to the multidrug resistance phenomenon in many diseases such as epilepsy and cancer and a potential source of drug interactions. For these reasons, the early identification of substrates and nonsubstrates of this transporter during the drug discovery stage is of great interest. We have developed a computational nonlinear model ensemble based on conformational independent molecular descriptors using a combined strategy of genetic algorithms, J48 decision tree classifiers, and data fusion.

Novel sulfamides and sulfamates derived from amino esters: Synthetic studies and anticonvulsant activity.

We report herein the design and optimization of a novel series of sulfamides and sulfamates derived from amino esters with anticonvulsant properties. The structures were designed based on the pharmacophoric pattern previously proposed, with the aim of improving the anticonvulsant action. The compounds were obtained by a new synthetic procedure with microwave assisted heating and the use of adsorbents in the isolation process.

Sulfamide derivatives with selective carbonic anhydrase VII inhibitory action.

A set of N,N'-disubstituted sulfamides and sodium cyclamate have been tested for their inhibitory action against six isoforms of carbonic anhydrase (CA, EC 4.2.1.

TdKT, a new killer toxin produced by Torulaspora delbrueckii effective against wine spoilage yeasts.

Microbiological spoilage is a major concern throughout the wine industry, and control tools are limited. This paper addresses the identification and partial characterization of a new killer toxin from Torulaspora delbrueckii with potential biocontrol activity of Brettanomyces bruxellensis, Pichia guilliermondii, Pichia manshurica and Pichia membranifaciens wine spoilage. A panel of 18 different wine strains of T.

N,N'-dicyclohexylsulfamide and N,N'-diphenethylsulfamide are anticonvulsant sulfamides with affinity for the benzodiazepine binding site of the GABA(A) receptor and anxiolytic activity in mice.

A set of sulfamides designed, synthesized and evaluated against maximal electroshock seizure (MES) and pentilenetetrazol (PTZ) tests with promising results, were tested for their affinity for the benzodiazepine binding site of the GABA(A) receptor. The most active compounds, N,N'-dicyclohexylsulfamide (7) and N,N'-diphenethylsulfamide (10), competitively inhibited the binding of [(3)H]-flunitrazepam to the benzodiazepine binding site with K(i)±SEM values of 27.7±4.

Validation of manual muscle testing and a subset of eight muscles for adult and juvenile idiopathic inflammatory myopathies.

Objective: To validate manual muscle testing (MMT) for strength assessment in juvenile and adult dermatomyositis (DM) and polymyositis (PM).

Methods: Patients with PM/DM (73 children and 45 adults) were assessed at baseline and reevaluated 6-9 months later. We compared Total MMT (a group of 24 proximal, distal, and axial muscles) and Proximal MMT (7 proximal muscle groups) tested bilaterally on a 0-10 scale with 144 subsets of 6 and 96 subsets of 8 muscle groups tested unilaterally.

Damage extent and predictors in adult and juvenile dermatomyositis and polymyositis as determined with the myositis damage index.

Objective: We undertook this study to validate the Myositis Damage Index (MDI) in juvenile and adult myositis, to describe the degree and types of damage and to develop predictors of damage.

Methods: Retrospective MDI evaluations and prospective assessment of disease activity and illness features were conducted. Patients with juvenile-onset disease (n = 143) were evaluated a median of 18 months after diagnosis; 135 patients were assessed 7-9 months later, and 121 were last assessed a median of 82 months after diagnosis.

Deaths associated with inappropriate intravenous colchicine administration.

Intravenous (IV) colchicine is occasionally prescribed for the treatment of acute gouty arthritis. The Food and Drug Administration (FDA) recently received a report of death in a patient that was associated with inappropriate IV dosing of colchicine. This report prompted further investigation of other deaths associated with IV colchicine use in the FDA Adverse Event Reporting System (AERS) and the medical literature.

Aseptic meningitis associated with rofecoxib.

Rofecoxib is a nonsteroidal anti-inflammatory drug that is reported to act by selectively inhibiting cyclooxygenase-2. A review and analysis of reports sent to the Spontaneous Reporting System of the Food and Drug Administration, Rockville, Md, suggest that aseptic meningitis is associated with rofecoxib use. To our knowledge, there have been no published reports of aseptic meningitis occurring in association with rofecoxib use to date.