The glycoconjugates have an enormous potential in drug design¹. Between them, glycopeptides are particularly important as they combine the structural features of amino acids and carbohydrates in the same molecule. Glycoconjugates containing the 1,2,3-triazole unit find application in medicinal chemistry, particularly in those cases where this unit acts as a bridge between an amino acid/peptide and the sugar moiety. In this work the synthesis of several glycoconjugates containing the 1,2,3-triazole unit as a bridge between a sugar (D-glucose) moiety and an amino acid or heteroaromatic unit is described. The starting alkynyl esters were prepared by reaction between N-protected glycine, tyrosine and phenylalanine, 7-hydroxycoumarin and 7-hydroxy-4-methylcoumarin and propargyl bromide with high yields. The 1,2,3-triazole unit was formed by an azide-alkyne 1,3-dipolar cycloaddition, catalysed by a Cu(I) species, a chemical process usually known as click chemistry.^2,3The azido component was prepared in situ from a-acetobromoglucose. The precursors and the final compounds were characterized by usual methods. Thanks to FCT, Portugal for financial support to the NMR portuguese network (PTNMR, Bruker Avance III 400-Univ. Minho) and to FCT and FEDER -COMPETE-QREN-EU for financial support to the Research Centre, CQ/UM [PEst-C/QUI/UI0686/2011 (FCOMP-01-0124-FEDER-022716)] References 1. C. Böttcher, J. Spengler , S.A. Essawy, K. Burger, Monastshefte für Chemie, 2004, 135, 853-863. 2. F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noodleman, K. B. Sharpless, V. V. Fokin, J. Am. Chem. Soc., 2005, 127, 210-216. 3. R. Kumar, P.R. Maulik, A.K. Misra, Glycoconj. J., 2008, 6, 1898-1901.

The importance of non-covalent interactions have been demonstrated in many cases. Significant examples within the scope of biomolecular systems are widely known, such as ligand-receptor interactions, protein folding or molecular recognition. Among non-covalent interactions, those between cations and aromatic units are commonly observed between aromatic side chains such as those of Phe, Tyr, His or Trp and amino acids with side chains susceptible of protonation as Arg or Lys. In this work, a computational study has been carried out in systems formed by indole and imidazolium cation, in an attempt to model the interactions between the side chains of Trp and protonated His. Specific solvent effects have been considered by including up to three water molecules in the imidazolium···indole complex. The target of this study is to get insight on the geometric and energetic characteristics of this cation···π interaction, as well as quantifying the effect produced by a small number of water molecules in this system.

As it was shawn previously, in a series of monosubstituted benzenes the halogen atoms as substituents worsen correlation dependence of para-protons chemical shifts δ_p^Н on Brown\'s para-constants σ⁺_p. Point of halogens atoms are remoted at a fairly large distance from the straight line, built for 22 substituent\'s points (including halogens atoms), which has correlation coefficient R = 0.966. If we consider the halogen atoms as a separate group of substituents, the R value for diagram for remaining 18 compounds increases to 0.989. We have introduced for halogen substituents the conception of virtual "spectral Brown\'s para-constants", marked σ⁺_p,sp.. With the aim to calculate σ⁺_p,sp. up to 0.05, the point of halide atoms in diagram are moved horizontally to their intersection with a line built for the remaining 18 compounds. Dropping perpendiculars to the x-axis, we obtain the virtual value σ⁺_p,sp.. σ⁺_p,sp values of all 18 considered substitutes (except Ph and COOH), up to 0.10 coincide with the values ​​of the experimental Brown\'s para-constants σ⁺_p. The difference (σ⁺_p,sp.- σ⁺_p) for halogen substituents is from -0.20 (for iodine) to -0.50 (for fluorine). It is suggested that the "spectral Brown\'s para-constants" σ⁺_p,sp. show the maximum capacity of substituents to conjugate with the reaction center. We tried to justify the decision to consider halogen atoms as a separate group of substituents. The δ_i^Н dependences on the number of chemical bonds between the substituent and considered proton are presented graphically. It was found that the substances with electron-donating substituents (other than bromo- and iodobenzene) give graphics in the form of "mountain", which is located below the straight line of benzene ("benzene\'s line"), and the electron-withdrawing substituents give the graphics in the form of "pit", which is located above the "benzene\'s line". Graphics of bromobenzene and iodobenzene instead of the expected form of "low mountain" which located below the "benzene\'s line" and in its vicinity, due to unexplained upfield shift of δ_m^Н values ​​have anomalous "very deep pit" form, which is located above and below the "benzene\'s line", "punching" it. Also we discuss some other unexplained properties of halogen elements.

Many phenolic acids are plant metabolites widely distributed throughout the vegetal kingdom. Recent interest in phenolic acids stems from their potential as bioactive constituents and their potential protective role, through ingestion of fruits and vegetables, against oxidative damage diseases like neurodegenerative diseases and cancer. This communication aims to identify structural alerts associated with clastogenic activity that may present the phenolic acids. It was performed a QSAR study (Quantitative structure-activity relationships) that allowed to use a structure vs clastogenic activity relationship model, which encodes topological information to a substructural level, according to the TOPS-MODE approach (Topological substructural molecular design). The predictions were made using the technique of linear discriminant analysis. The used software was STATISTIC and MODESLAB. The model has presented an adequate probability of good classification for the external prediction set. It has been identified the relevant structural features to the activity under study, such as: amount and position of hydroxyl and/or methoxy groups. These structural modifications represented an indicator of the toxicity of these compounds and provide a strategy for the design of new derivatives devoid of this activity. This study can be of interest to better understand the properties of natural substances in food, and also in the development of functional foods or nutraceuticals and drug design.

With the aim of exploring the antibacterial interest of the 3-arylcoumarinic skeleton, a new series of amino/nitro substituted 3-arylcoumarins was synthesized and evaluated for their antibacterial activity against clinical isolates Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative). This series was selected thinking on finding out the structural features for their antibacterial activity and selectivity. Therefore, in the present manuscript different positions of nitro, methyl, methoxy, amino and bromo substituents, under the 3-arylcoumarin scaffold, were reported. Some of these molecules exhibited antibacterial activity against S. aureus comparable to the standards – oxolinic acid and ampicillin. The best derivative of the studied series is compound 6, active and selective against S. aureus, with a MIC = 8 µg/mL. The preliminary structure-activity relationship (SAR) study showed that the antibacterial activity against S. aureus depends on the position of the substitution pattern on the 3-arylcoumarin moiety. Compound 6 will be the inspiration for the search of new active and selective antibacterial compounds.

Trypanosoma cruzi, the causative agent of Chagas\' disease, which is widely disseminated in Central and South America, represents an endemic neglected disease located in this geographic region. Therefore, there is an urgent need for the discovery of new, more effective, and safer drugs for human use. Natural products have played a major role in the chemotherapy of parasitic diseases. Based on the observed biological activities of two kind of natural compunds, coumarins and chalcones, we have synthesized coumarin-chalcone hybrids with the aim of evaluating their activity against Trypanosoma cruzi, and their antioxidant properties. All derivates have shown moderate trypanocidal activity in the epimastigote stage (clone Dm28c) being compound 3 the one with the highest activity. These preliminary findings encourage us to future structural optimization of this compound. In spite of the moderate trypanocidal activity of coumarin-chalcone hybrids, they have been proved to be very good antioxidants. Based on these results, we can conclude that compounds 3 and 4 are potential candidates for in vitro studies of their antioxidant activity.

Glycosylated peptides have a fundamental role in biological systems: in fact, more than half of all proteins carry carbohydrate moieties, generating different glycoforms whose exact composition often controls protein function and distribution in biological systems [1]. The details of glycan regulation of protein activity and stability are still under intense scrutiny and the synthesis of welldefined glycopeptides is therefore an important target [2], which still presents many challenges to organic chemistry. One of the processes that is currently been elucidated is adenosine diphosphate ribosylation (ADP-ribosylation), a wide-occurring post-translational modification effected by enzymes that transfer ADP-ribose from NAD + to Asn, Glu, Asp, Arg or Cys residues of proteins, so altering their function [3]. Elucidation of ADP-ribosylation events would benefit greatly from the availability of well-defined ADP-ribosylated peptides and analogues thereof. In this paper we present a novel approach to the chemical synthesis of ribosylated amino acid building blocks using traceless Staudinger ligation. We describe an efficient and stereoselective synthesis of -N-ribosyl-asparagine (-N-ribosyl-Asn)and -N-ribosyl-glutamine (-N-ribosyl-Gln) building blocks starting from 5-tertbutyldiphenylsilyl-β-D-ribofuranosyl azide. The N-glycosyl aminoacids are produced in good yields as pure -anomers, suitably protected for peptide synthesis. 1. a) Varki, A. Glycobiology 1993, 3, 97-130. b) Dwek, R. A. Chem. Rev. 1996, 96, 683-720. c) Reuter, G.; Gabius, H.J. Cell. Mol. Life Sci. 1999, 55, 368-422. d) Gamblin, D. P.; Scanlan, E. M.; David, B. G. Chem. Rev. 2009, 109, 131-163. 2. a) Marcaurelle, L. A.; Bertozzi, C. R. Glycobiology 2002, 12 (6), 69R-77R. b) Warren, J. D.; Miller, J. S., Keding, S. J.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 6576. 3. Corda, D.; Di Girolamo, M. EMBO J. 2003, 22, 1953-1958.

Compounds having indoline-thiosemicarbazone moiety within their structure display biological activity against a wide range of biological targets, being used in clinical practice as anticancer and antiviral agents. The generation of low-energy conformers is extremely important for various computational chemistry applications, such as 3D QSAR, pharmacophore searches, ligand-receptor docking, and 3D database searching. This paper presents the study of the conformational space of 1-{[5-fluoro-2-oxo-1-(piperidin-1-ylmethyl)-2,3-dihydro-1H-indol-3-ylidene]amino}-3-(prop-2-en-1-yl)thiourea by molecular mechanics and ab initio calculations using the Omega (OMEGA (version 2.4.6), OpenEye Science Software, Santa Fe, USA, 2010), respectively the Gaussian 2009 (http://www.gaussian.com/) software. 219 Z and E isomers were generated by the MMFF94s force field included in the Omega program. They were further energy minimized by Restricted Hartree-Fock (RHF/3-21G) calculations. All optimized structures were characterized as true minima by frequency calculations (Nimag = 0 for each compound). The generated conformers have been compared by the root-mean-square-deviation (RMSD) overlay procedure with the X-ray structure of the compound. In both cases (molecular mechanics and ab initio calculations) the Z conformer with the lowest RMSD fit value was different from the lowest energy conformer. Also, a chair shape for the piperidine ring and a planar indole–thiosemicarbazone moiety was found by both methods. The formation of one intramolecular hydrogen bond has been noticed in both cases. The RMSD fit values were lower in case of Omega conformers and the difference between the highest and lowest energy conformer was smaller in case of ab initio calculations.

Developed countries\' society face, with the increase of the population life expectancy, a major problem related with neurodegenerative diseases (ND), such as Parkinson\'s and Alzheimer\'s diseases. Therefore, a need for new drugs targeting these diseases emerges. Some of the few accessible treatments use monoamine oxidases inhibitors (MAOI-A and MAOI-B) and acetylcholinesterase inhibitors (AChEI). Coumarins are a large family of compounds of natural and/or synthetic origin that proved to have numerous pharmacological properties. In this study, we developed new synthetic methodologies to create novel multi-target inhibitors focused on the coumarin scaffold. Following this work, docking studies of the previously prepared compounds are currently in progress. Some preliminary results are presented in this communication.

The synthesis of neo-glycoconjugates has been gaining much attention in recent years due to the relevance of glycopeptides and glycoproteins in many biological processes.[i] Our group has been actively dedicating its efforts to the synthesis of α-N-linked glycosylamides and glycopeptides.[ii] α-N-linked glycopeptides are unnatural molecules, since they display an α linkage between the peptide side chain and the sugar moiety, unlike natural glycopeptides which connect the peptide to the glycan through a β-N-glycosidic bond. This novel type of glycosylation of peptides could introduce modifications that can mimic and/or interfere with molecular recognition events.[iii] Direct glycosylation of peptide chains is not viable for the synthesis of molecules with α-N-linked configuration, since the corresponding α-glycosyl amines isomerise to the β-anomers. Only very recently Nα-Fmoc-protected glycosyl amino acids have been efficiently and stereoselectively synthesized and linearly incorporated into a peptide sequence.[iii] In the present paper these novel building blocks have been employed for the synthesis of complex structures that resemble antifreeze glycopeptides (Figure 1).[iv] These sequences were prepared using solid phase synthesis with Fmoc protocol, experimenting with different conditions and also using microwave assisted solid phase synthesis, in an effort to enhance the reactivity of our unnatural building block. The α-N-linked glycopeptides were obtained with modest yields, their secondary structure was assessed by circular dichroism and their antifreeze properties were evaluated in the group of Prof. Robert N. Ben. Despite the fact that our compounds do not show significant antifreeze activity, this work constitutes the first attempt towards the synthesis of complex α-N-linked glycopeptides and has been useful to understand the behaviour, sometimes unexpected, of these molecules, in terms of reactivity and stability. [i] D. P. Gamblin, E. M. Scanlan, B. G. Davis, Chem. Rev. 2009, 109, 131-163. [ii] a) F. Nisic, A. Bernardi, Carbohydr. Res. 2011,346, 465-71. b) C. Colombo, A. Bernardi,Eur. J. Org. Chem. 2011, 3911–3919. [iii] F. Marcelo, F. J. Cañada, S. André, C. Colombo, F. Doro, H. J. Gabius, A. Bernardi, J. Jiménez-Barbero. Organic & Biomolecular Chemistry 2012, DOI: 10.1039/C2OB07135E. [iv] a) Garner, J.; Harding, M. M. ChemBioChem 2010, 11 2489-2498. b) Leclere, M; Kwok, K. B.; Luke K. W.; Allan, D. S.; Ben, R. N. Bioconjugate Chem. 2011, 22, 1804-1810.