Norbert Haider

Extended Functional Groups (EFG): An Efficient Set for Chemical Characterization and Structure-Activity Relationship Studies of Chemical Compounds

The article describes a classification system termed “extended functional groups” (EFG), which are an extension of a set previously used by the CheckMol software, that covers in addition heterocyclic compound classes and periodic table groups. The functional groups are defined as SMARTS patterns and are available as part of the ToxAlerts tool (http://ochem.eu/alerts) of the On-line CHEmical database and Modeling (OCHEM) environment platform. The article describes the motivation and the main ideas behind this extension and demonstrates that EFG can be efficiently used to develop and interpret structure-activity relationship models.

Semicarbazide-Sensitive Amine Oxidase: Current Status and Perspectives

Semicarbazide-sensitive amine-oxidase (SSAO) is present in various human tissues and in plasma. Oxidative deamination of short-chain aliphatic amines is catalyzed by this enzyme to afford the corresponding aldehydes, ammonia and hydrogen peroxide. Methylamine and aminoacetone have been recognized to be physiological substrates for SSAO. There are several pathological states where increased serum SSAO activity have been found, such as diabetes mellitus, congestive heart failure, multiple types of cerebral infarction, uraemia, and hepatic cirrhosis. The role of SSAO in pathophysiology of diabetes has been most extensively investigated. The elevated formation of the potentially cytotoxic products of the enzyme may contribute to the endothelial injury of blood vessels, resulting in the early development of severe atherosclerosis; it may also contribute to the pathogenesis of diabetic angiopathy. It is now suggested that SSAO inhibitors may prevent the development of atherosclerosis and diabetic complications as well. Inhibitors can be conveniently subdivided into the main groups of hydrazine derivatives, arylalkylamines, propenyl- and propargylamines, oxazolidinones, and haloalkylamines. Of them, aryl(alkyl)hydrazines, and 3-halo-2-phenylallylamines are generally very strong SSAO inhibitors. Most of these inhibitors of SSAO have been originally developed for other purposes, or they are simple chemical reagents with highly reactive structural element(s); these compounds have not been able to fulfil all criteria of high potency, selectivity, and acceptable toxicity. New potent compounds with selectivity and low toxicity are needed, which may prove useful tools for understanding the roles and function of SSAO, or they may even be valuable substances for treatment of various diseases.

CO : A chemical ontology for identification of functional groups and semantic comparison of small molecules

A novel chemical ontology based on chemical functional groups automatically, objectively assigned by a computer program, was developed to categorize small molecules. It has been applied to PubChem and the small molecule interaction database to demonstrate its utility as a basic pharmacophore search system. Molecules can be compared using a semantic similarity score based on functional group assignments rather than 3D shape, which succeeds in identifying small molecules known to bind a common binding site. This ontology will serve as a powerful tool for searching chemical databases and identifying key functional groups responsible for biological activities.

Semicarbazide-Sensitive Amine Oxidase/Vascular Adhesion Protein 1: Recent Developments Concerning Substrates and Inhibitors of a Promising Therapeutic Target

SSAO/VAP-1 is not only involved in the metabolism of biogenic and xenobiotic primary amines and in the production of metabolites with cytotoxic effects or certain physiological actions, but also plays a role, for example, as an adhesion molecule, in leukocyte trafficking, in regulating glucose uptake and in adipocyte homeostasis. Interest in the enzyme has been stimulated by the findings that the activities of the SSAOs are altered (mostly increased) in various human disorders, including diabetes, congestive heart failure, liver cirrhosis, Alzheimers disease and several inflammatory diseases, although the underlying causes are often unknown. On the basis of their insulin-mimicking effect, SSAO substrates are possibly capable of ameliorating metabolic changes in diabetes, while SSAO inhibitors (somewhat of a contradiction) are of potential benefit in preventing diabetes complications, atherosclerosis and oxidative stress contributing to several disorders or modulating inflammation, and hence may be of substantial therapeutic value. Great efforts have been made to develop novel compounds which may lead to future drugs useful in therapy, based on their effects on SSAO/VAP-1, and some of the results relating to novel substrates and inhibitors are surveyed in the present review.

Fingerprint-based in silico models for the prediction of P-glycoprotein substrates and inhibitors

Graphical abstract

Functionality Pattern Matching as an Efficient Complementary Structure/Reaction Search Tool: an Open-Source Approach

An open-source software package for creating and operating web-based structure and/or reaction databases is presented. Besides standard search capabilities (text, structure/substructure/similarity), the system offers a fast additional search option, entirely based on binary pattern matching, which uses automatically assigned functional group descriptors.

Inverse-electron-demand diels-alder reactions of condensed pyridazines, part 1. Synthesis of phthalazine derivatives from pyridazino[4,5-d]pyridazines.

Abstract The 1,4-diarylpyridazino[4,5-d]pyridazine derivatives 1a,b were found to undergo [4+2] cycloaddition reactions with a variety of electron-rich dienophiles like enamines and ketene acetals to afford phthalazine derivatives in good to high yields.

Intramolecular diels-alder reactions of pyrazines with alkynylphenyl moieties as side-chain dienophiles

Abstract Intramolecular Diels-Alder reactions of (2-alkynylphenyl-X)-pyrazines (X = O, NAc, S) under neutral and acidic conditions are described. The isomer distribution of the resulting tricyclic b - and c -annelated pyridines is discussed.

Synthesis and in-vitro antitumor activity of 1-[3-(indol-1-yl)prop-1-yn-1-yl]phthalazines and related compounds.

A series of novel 3-(indol-1-yl)prop-1-yn-1-yl-substituted phthalazines and related azines was prepared via a concise pathway by palladium-catalyzed cross-coupling of appropriate halo-azines and N-propargylindoles. Some of the compounds exhibited significant antitumor activity in an in-vitro assay.

Inverse-electron-demand Diels-Alder reactions of condensed pyridazines, 5.1 1,4-bis(trifluoromethyl)-pyridazino[4,5-b]indole as an azadiene

The pyridazino[4,5-b]indole (3), which is conveniently available from 3-methylthioindole and the tetrazine (2), undergoes thermally induced inverse-electron-demand Diels-Alder reactions with enamines to afford the cycloalkeneannelated carbazoles (7,8) or the 2-substituted carbazole (9), respectively