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Adamantanamines 16, 18, 21, 24, 27, 28, 30, 32, 35, 36, 37, 40, 46 and 48 were synthesized and tested for anti-influenza A virus and trypanocidal activity. The stereoelectronic requirements for optimal antiviral and trypanocidal potency were investigated. The effect of introducing a hydroxyl group close to the amino group on this class of compounds was examined for the first time. Aminoalcohol 24 proved to be the most active of the compounds tested against influenza A virus, being 6-fold more active than amantadine, equipotent to rimantadine and 26-fold more potent than ribavirin. Aminoalcohols 36 and 37 were found to have considerable activity against bloodstream forms of the African trypanosome, Trypanosoma brucei, being almost 10 times more potent than rimantadine. © 2010 Elsevier Masson SAS. All rights reserved.

A synthesis scheme for 3'-C-methyl-2'-deoxynucleosides and 3'-C-methylidene-2',3'-dideoxy-5-methyluridine has been proposed with 2-deoxyribose as the starting material. Methyl 5-O-benzoyl-2-deoxyribofuranose was oxidized and the mixture of the 3'-keto derivatives was separated into the alpha- and beta-anomers. The beta-keto derivative was converted by reaction with MeMgBr, and after reaction with thymine and subsequent deprotection 1-(3'-C-methyl-2'-alpha-deoxy-alpha-D-threo-pentofuranosyl)thymine and its beta-anomer were obtained. The same reactions with the alpha-keto sugar gave 1-(3'-C-methyl-2'-deoxy-alpha-D-erythro-pentofuranosyl)thymine and its beta-anomer. 1-(5-O-Benzoyl-3'-C-methyl-2'-deoxy-alpha-D-threo-pentofuranosyl)thymine was converted to a mixture of 3'-C-methylidene-2',3'-dideoxy-5-methyluridine and 3'-C-methyl-2',3'-dideoxy-2',3'-didehydro-5-methyluridine, which were separated. The stereoselectivity of the Grignard reagent's attachment to 2-deoxyfuranose 3-ulosides has been ruled by the substitute configuration at Cl. Also, the effect of the hydroxyl or OBz group configuration at C3 on the condensation stereoselectivity of 3-C-methyl-2-deoxyfuranosides with silylated thymine has been studied. The structure of the obtained compounds was proved by 1H NMR UV, 13C NMR, and CD spectroscopy, as well as elemental (C, H, N) analysis. The C2'-endo-C1'-exo conformation, the anti conformation of thymine in relation to the glycosidic bond, and the gauche+conformation in relation to the C4'-C5' bond are characteristic for the 3'-C-methyl-2'-deoxythymidine structure in the crystals. 3'-C-Methyl-2'-deoxythymidine 5'-triphosphate was synthesized and proved to be a competitive inhibitor, with respect to dTTP, of a number of DNA polymerases, including the reverse transcriptases of human immunodeficiency virus type 1 (HIV-1) and avian myeloblastosis virus (AMV). None of the DNA polymerases examined were able to incorporate this compound into the growing DNA chain. In contrast, 3'-C-methylidene-2',3'-dideoxy-5-methyluridine 5'-triphosphate was found to be incorporated at the 3'-end of the DNA chain by HIV-1 reverse transcriptase, albeit with very low efficiency. 3'-C-Methyl-2'-deoxy-5-methyluridine did not suppress HIV-1 replication in MT-4 cells at 500 microM while its 5'-phosphite derivative exhibited modest anti-HIV-1 activity.

The in vitro antiviral and antitumor activities of (-)-debromoeudistomin K (1a) and 10 structural analogues (1b-1j and 11) were evaluated. The synthesis was accomplished with an intramolecular Pictet-Spengler condensation reaction as the key step. This examination revealed some structural and stereochemical features that are important for both the antiviral and antitumor activities. The most striking points for activity are the necessity to have the correct natural stereochemistry at both C(1) and C(13b) and the presence of the C(1)-NH2 substituent. As was revealed before with naturally isolated eudistomins a substituent in the indole ring greatly influences the biological activity. The 5-OMe derivative 1h shows high potency in both antiviral and antitumor models.

The new 2-alkyl-2-aminoadamantanes and analogues 4-10 were designed and synthesized by simplification of the structure of the potent anti-influenza virus A spiranic aminoadamantane heterocycles 2 and 3. The aim of the present work was to examine the effects of bulky and extended lipophilic moieties attached to amantadine 1 on binding to the M2 channel and the resulting antiviral potency. The binding affinities of the compounds to the M2 protein of influenza virus A/chicken/Germany/27 (Weybridge strain; H7N7) were measured for the first time using an assay based on quenching of Trp-41 fluorescence by His-37 protonation, and their antiviral potencies were evaluated against the replication of influenza virus A H2N2 and H3N2 subtypes and influenza virus B in MDCK cells. Of the various 2-alkyl-2-aminoadamantanes, and analogues, spiro[piperidine-2,2′-adamantane] 3 had the strongest M2 binding and antiviral potency, which were similar those of amantadine 1. The relative binding affinities suggested that the rigid carbon framework provided by the pyrrolidine or piperidine rings results in a more favorable orientation inside the M2 channel pore as compared to large, freely rotating alkyl groups. The aminoadamantane derivatives exhibited similar NMDA antagonistic activity to amantadine 1. A striking finding was the antiviral activity of the adamantanols 4, and 6, which lack any NMDA antagonist activity. © 2008 Elsevier Ltd. All rights reserved.

Adamantanopyrrolidines 8, 9 and 10, adamantanopyrrolidines 16 and 18, adamantanoxazolone 20, adamantanopyrazolone 23, adamantanopyrazolothione 24 and adamantanocyclopentanamine 32 were synthesized and tested for anti-influenza A virus and trypanocidal activity. The stereoelectronic requirements for optimal antiviral and trypanocidal potency were investigated. Pyrrolidine 16 proved to be the most active of the compounds tested against influenza A virus, being 4-fold more active than amantadine, equipotent to rimantadine and 19-fold more potent than ribavirin. Oxazolone 20 showed significant trypanocidal activity against bloodstream forms of the African trypanosome, Trypanosoma brucei, being approximately 3 times more potent than rimantadine and almost 50-fold more active than amantadine. © 2008 The Royal Society of Chemistry.

We examined whether the incorporation of a second amino group into the 1-aminoethyl pharmacophore of rimantadine 2 and into the piperidine pharmacophore of the heterocyclic rimantadine 4 was compatible with anti-influenza virus A activity. The new synthetic molecules are capable of forming two hydrogen bonds within the receptor. We identified molecules 8 and 16, bearing the adamantyl and 1,2-diaminoethyl groups, which are equipotent to rimantadine 2 bearing the adamantyl and 1-aminoethyl pharmacophore groups. Interestingly, diamino compound 16 is a 4-fold more potent inhibitor than its parent monoamino heterocyclic rimantadine 4 propably because of additional hydrogen bonding interactions with the M2 protein receptor. © 2006 Elsevier Ltd. All rights reserved.

Spiro[aziridine-2,2′-adamantanes] 1 and 2, spiro[azetidine-2,2′-adamantanes] 3 and 5, spiro[azetidine-3,2′-adamantane] 13, spiro[piperidine-4,2′-adamantanes] 25 and 27, and spiro barbituric analog 18 were synthesized and tested for their anti-influenza A virus properties and for trypanocidal activity. The effect of ring size on potency was investigated. Piperidine 25 showed significant anti-influenza A virus activity, being 12-fold more active than amantadine, about 2-fold more active than rimantadine, and 54-fold more potent than ribavirin. It also proved to be the most active of the compounds tested against bloodstream forms of the African trypanosome, Trypanosoma brucei, being 1.5 times more potent than rimantadine and at least 25 times more active than amantadine. © 2007 Elsevier Ltd. All rights reserved.

2-(1-Adamantyl)-2-methyl-pyrrolidines 3 and 4, 2-(1-adamantyl)-2-methyl-azetidines 5 and 6, and 2-(1-adamantyl)-2-methyl-aziridines 7 and 8 were synthesized and tested for their antiviral activity against influenza A. Parent molecules 3, 5, and 7 contain the α-methyl-1-adamantan-methanamine 2 pharmacophoric moiety (rimantadine). The ring size effect on anti-influenza A activity was investigated. Pyrrolidine 3 was the most potent anti-influenza virus A compound, 9-fold more potent than rimantadine 2, 27-fold more potent than amantadine 1, and 22-fold more potent than ribavirin. Azetidines 5 and 6 were both markedly active against influenza A H2N2 virus, 10- to 20-fold more potent than amantadine. Aziridine 7 was almost devoid of any activity against H2N2 virus but exhibited borderline activity against H3N2 influenza A strain. Thus, it appears that changing the five-, to four- to a three-membered ring results in a drop of activity against influenza A virus. © 2006 Elsevier Ltd. All rights reserved.

Various semisynthetic derivatives of glycopeptide antibiotics including vancomycin, eremomycin, teicoplanin, ristocetin A and DA-40926 have been evaluated for their inhibitory activity against feline infectious peritonitis virus (FIPV) and human (SARS-CoV, Frankfurt-1 strain) coronavirus in cell culture in comparison with their activity against human immunodeficiency virus (HIV). Several glycopeptide derivatives modified with hydrophobic substituents showed selective antiviral activity. For the most active compounds, the 50% effective concentrations (EC50) were in the lower micromolar range. In general, removal of the carbohydrate parts of the molecules did not affect the antiviral activity of the compounds. Some compounds showed inhibitory activity against both, whereas other compounds proved inhibitory to either, FIPV or SARS-CoV. There was no close correlation between the EC50 values of the glycopeptide derivatives for FIPV or SARS-CoV.

Decision-support systems in medicine should be equipped with a facility that provides patient-tailored information about which test had best be performed in which phase of the patient's management. A decision-support system with a good testselection facility may result in ordering fewer tests, decreasing financial costs, improving a patient's quality of life, and in an improvement of medical care in general. In close cooperation with two experts in oncology, we designed such a facility for a decision-support system for the staging of cancer of the oesophagus. The facility selects tests based upon a patient's health status and closely matches current routines. We feel that by extending our decision-support system with the facility, it provides further support for a patient's management and will be more interesting for use in daily medical practice. In this paper, we describe the test-selection facility that we designed for our decision-support system in oncology and present some initial results.

A series of aromatic polycationic molecules were synthesised and tested as potential non-classical antiherpes agents. Analogue (4) had a high potency in all four of the HSV cell lines used and is far more potent than ribavirin. The fact that none of the new compounds show any selectivity for HSV-2 over HSV-1 may imply that there is no intervention of a HSV-2 glycoprotein C (gC) dependent pathway. © 2005 Bentham Science Publishers Ltd.

Methanol and water extracts of the root of Epinetrum villosum (Exell) Troupin (Menispermaceae) were found to exhibit antimicrobial and antiplasmodial activities. Investigation of the active methanol fraction led to the isolation of four bisbenzylisoquinoline alkaloids, i.e., cycleanine, cycleanine N-oxide, isochondodendrine and cocsoline. Structures were established by spectroscopic methods. Cocsoline displayed antibacterial and antifungal activities (MIC values of 1000-15.62 and 31.25 microg/ml, respectively). Isochondodendrine was found to have the most potent antiplasmodial activity (IC50 = 0.10 microg/ml), whereas the IC50 on HCT-116 human colon carcinoma cells was 17.5 microg/ml (selectivity index 175). Cycleanine acted against HIV-2 (EC50=1.83 microg/ml) but was at least 10-fold less active against HIV-1. Cycleanine N-oxide showed no activity towards all tested microorganisms.

A couple of years ago, the Belgian Federal Ministry of Health decided to back the development of a basic conceptual model for Electronic Patient Record (EPR) in primary care. Using consensus and modeling relational techniques, a working group of experts and experienced practitioners identified 7 key structuring concepts: Health Care Element, Health Approach, Contact, Subcontact, Service, Health Agent, Period. This model could roughly be seen as a restrictive sub-model of the current CEN proposal (prENV 13940) or as a first step to assess this CEN pre-Norm in Belgium. The conceptual model is already used in teaching activities and in a Belgian software labeling process.

Silver(I) bromide reacts with 2-mercapto-3,4,5,6-tetrahydropyrimidine (StpmH(2), C4H8N2S) in DMSO with an excess of triethylamine to give a water-insoluble complex of formula [Ag-6(mu(2)-Br)(6)(mu(2)-StpmH(2))(4)(mu(3)-StpmH(2))(2)](n) (1), while the reaction of silver(I) nitrate with StpmH(2) under the same conditions gives a water-insoluble complex of formula [{Ag-4(mu(2)-StpmH(2))(6)}(NO3)(4)](n) (2). The products were characterized by elemental analyses, and FT-IR far-IR, UV/Vis, H-1 and C-13 NMR spectroscopy. Crystal structures of complexes 1 and 2 were determined by X-ray diffraction. Complex 1, C24H48Ag6N12S6, crystallizes in the triclinic system space group P (1) over bar, a = 8.041(1) Angstrom, b = 12.838(4) Angstrom, c = 13.281(2) Angstrom, alpha = 68.40(1)degrees, = 72.97(1)degrees, gamma = 87.80(2), Z = 2, forming a one-dimensional infinite ribbon structure by strong interatomic interactions of two mu(2)-Br bonds with Ag(1). Complex 2, C24H48Ag4N16O12S6, crystallizes in the orthorhombic system, space group Cmc2(1), and a = 32.148(3) Angstrom, b = 9.461(2) Angstrom, c = 7.234(1) Angstrom, alpha = beta = gamma = 90degrees, Z = 8, forming infinite Ag-S-Ag chains which are bridged to each other by a sulfur atom of mu(2)-StpmH(2) ligands. Complexes 1 and 2 were studied for their cytostatic activity against murine leukemia (L1210) and human T-lymphocyte (Molt4/C8 and CEM) cells and for their antiviral activity against a wide variety of viruses. They are markedly cytostatic at 50% inhibitory concentration (IC50) values ranging from 3 to 17 mug/mL. None of the compounds showed appreciable antiviral activity at subtoxic concentrations. (C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004. European Journal of Inorganic Chemistry