The vast majority of the world population is infected with at least one member of the human herpesvirus family. Herpes simplex virus (HSV) infections are the cause of cold sores and genital herpes as well as life-threatening or sight-impairing disease mainly in immunocompromized patients, pregnant women and newborns. Since the milestone development in the late 1970s of acyclovir (Zovirax), a nucleosidic inhibitor of the herpes DNA polymerase, no new non-nucleosidic anti-herpes drugs have been introduced. Here we report new inhibitors of the HSV helicase-primase with potent in vitro anti-herpes activity, a novel mechanism of action, a low resistance rate and superior efficacy against HSV in animal models. BAY 57-1293 (N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4- (2-pyridinyl)phenyl]acetamide), a well-tolerated member of this class of compounds, significantly reduces time to healing, prevents rebound of disease after cessation of treatment and, most importantly, reduces frequency and severity of recurrent disease. Thus, this class of drugs has significant potential for the treatment of HSV disease in humans, including those resistant to current medications.

Glycobiology opens a wide field for new therapeutic approaches. However, the complexity and unavailability of various carbohydrate test compounds has excluded this class of natural products from modern screening systems. Alternatively, glycomimetics are considered to be more drug-like candidates for development. By means of multicomponent condensations (MCCs) utilizing suitable carbohydrate synthons, rapid and effective access to glycoconjugate libraries can be obtained. The flexibility of MCCs allows the assembly of diverse carbohydrate containing libraries. It may be assumed that MCCs containing carbohydrate moieties will play an important role in glycomimetic chemistry and biology.

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ABSTRACT Amphiphilic 2-amino-2-deoxy-β-D-glucopyranosylamides were synthesized from N-protected glucosamine derivatives via N-glycosidation with fatty amines, subsequent N-acylation with fatty acid derivatives and deprotection. They could further be modified with amino acids to give peptido-glycopyranosyl amides, some of which exhibited strong immunostimulatory (BAY Q8939, 8) or immunoadjuvant (BAY R1005, 9) activities.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Four-component reactions: The Ugi reaction of four suitably functionalized carbohydrate derivatives (as a per-O-benzylated amine, an aldehyde, a carboxylic acid, and an isocyanide) allow the effective assembly of diverse compound libraries. The complex glycoconjugates formed can be deprotected (see the picture for an example), and the resulting glycomimetics are of high interest for screening purposes.

Vierfaches Verschmelzen: Über die Ugi-Reaktion aus vier entsprechend funktionalisierten Kohlenhydratbausteinen (als per-O-benzylierte Amine, Aldehyde, Carbonsäuren und Isonitrile) lassen sich diversifizierte Substanzbibliotheken effektiv aufbauen. Die komplexen Glycokonjugate sind nach Entschützung (siehe Abbildung für ein Beispiel) als Glycomimetika für Screening-Zwecke von Bedeutung.

In search of a simple synthetic access to analogs of naturally occurring glycolipids, glycosylamides have been synthesised in a two-step procedure from unprotected sugars, long-chain amines, and fatty acids. The N-glycosylation proceeded stereospecifically yielding crystalline β-glycopyranosylamines. 13C NMR spectroscopy of the glycosylamines in organic solvents revealed partial anomerisation, leading to α-glycosylamines and in part to corresponding N-furanosides. Selective N-acylation of either pure β-glycosylamines or anomeric mixtures thereof with activated fatty acid led to formation of β-glycosylamides exclusively. As evidenced by NMR spectroscopy, the glycosylamides exhibited rotameric isomerism. The glycosylamides were found to be strong stimulators of the specific immune response against antigens.

Optically pure 6-deoxy-inososes, 6-deoxy-inositols and 6-deoxy-inositol-1,4,5-trisphosphates were synthesized from D-galactose by the carbohydrate-inosose Ferrier rearrangement. 6-Deoxy-inositolphosphates exhibit a tight binding to the Ins-P3-receptor making such compounds an interesting tool for studying the intracellular signalling.

Although the most successful vaccines still consist of attenuated or killed pathogens, it is evident that genetic engineering will eventually provide pure antigens in sufficient quantities. To achieve a protective effect, however, the immune response to these structures, which are only weakly immunogenic, must be activated by adjuvants. The discovery of chemically defined, well-tolerated, synthetic adjuvants is therefore especially important in effective immunoprophylaxis. A very promising class of compounds in this respect are synthetic glycosylamides, with two long alkyl chains consisting of alkylamines and fatty acids. Unlike natural glycolipids, which exert an immunosuppressive effect, the new glycolipid analogues described here show marked immunostimulation. In vaccination experiments with various antigens they provide efficient protection. Their mode of action, which differs from that of known adjuvants, makes glycolipid analogues particularly interesting for immunization of patients with defective T lymphocyte function, for example AIDS patients.

Few steps and a very good yield are characteristics of the block synthesis of a heptasaccharide that is the smallest strongly elicitor-active unit binding to a receptor in the host-parasite system, soybean/Phytophthora megasperma. The intermediates central to the block synthesis are the thiotrisaccharide donor 1 and the glycosyl acceptor 2 (Ac = CH3CO, Bz = C6H5CO, Bzl = C6H5CH2).

A number of natural and synthetic sugar analogues have been tested for their antiviral activity, using an influenza virus strain as a model. Hemagglutinating titres (HA) and cytopathic effect (CPE) were surveyed to estimate the virus production. It was found that introduction of the benzyl group into these sugars generally causes them to become antivirally active. Substitution with methyl, acetyl, uridyl and thiocyanyl groups or derivatization with azido, isopropylidene and benzylidene groups were without effect. All sugars containing the 2-deoxy-2-acetamido group were inactive.