Publications

Abstract Adenosine regulates tissue function by activating four G-protein-coupled adenosine receptors (ARs). Selective agonists and antagonists for ARs have been investigated for the treatment of a variety of immune disorders, cancer, brain, and heart ischemic conditions. We herein present a QSAR study based on a Topological sub-structural molecular design (TOPS-MODE) approach, intended to predict the ARs of a diverse dataset of 124 (94 training set/ 30 prediction set) adenosine derivatives. The final model showed good fit and predictive capability, displaying 85.1 % of the experimental variance. The TOPS-MODE approach afforded a better understanding and interpretation of the developed model based on the useful information extracted from the analysis of the contribution of different molecular fragments to the affinity.

Abstract Prostate Specific Antigen (PSA) is widely used as a biomarker for prostate cancer. Recently, an electrochemical biosensor for PSA detection by means of molecularly imprinted polymers (MIPs) was developed. This work evaluated the performance and the effectiveness of that PSA biosensor in screening the biomarker PSA in biological media with complex composition, collected from different human prostate cell line cultures. For that, the prostate cancer LNCaP and PC3 cells, and the non-cancerous prostate cell line PNT2 were cultured for 2, 7 and 14 days in either alpha-MEM or RPMI in the presence of 10% or 30% fetal bovine serum. Human gingival fibroblasts were used as a non-cancerous non-prostatic control. The different culture conditions modulated cellular proliferation and the expression of several prostate markers, including PSA. The electrochemical biosensor was able to specifically detect PSA in the culture media and values obtained were similar to those achieved by a commercial Enzyme-Linked Immunosorbent Assay (ELISA) kit, the most commonly used method for PSA quantification in prostate cancer diagnosis. Thus, the tested biosensor may represent a useful alternative as a diagnostic tool for PSA determination in biological samples.

Abstract Recent efforts have been focused on the development of centrally active COMT inhibitors, which can be valuable assets for neurological disorders such as Parkinson's disease, due to the severe hepatotoxicity risk associated with tolcapone. New nitrocatechol COMT inhibitors based on naturally occurring caffeic acid and caffeic acid phenethyl ester were developed. All nitrocatechol derivatives displayed potent inhibition of peripheral and cerebral COMT within the nanomolar range. Druglike derivatives 13, 15, and 16 were predicted to cross the blood brain barrier in vitro and were significantly less toxic than tolcapone and entacapone when incubated at 50 mu M with rat primary hepatocytes. Moreover, their unique acidity and electrochemical properties decreased the chances of formation of reactive quinone-imines and, as such, the potential for hepatotoxicity. The binding mode of 16 confirmed that the major interactions with COMT were established via the nitrocatechol ring, allowing derivatization of the side chain for future lead optimization efforts.

Abstract Novel 6-methyl-3-carboxamidocoumarins (compounds 4-15) were synthesized by an effective three step synthetic strategy and screened towards MAO, AChE and BuChE enzymes. In general, the compounds act as selective MAO-B inhibitors. Compound 11 is highlighted as a potent (IC50 hMAO-B = 4.66 nM), reversible and non-competitive MAO-B inhibitor.

Abstract The crystal structures of five 6-mercaptopurine derivatives, viz. 2-[(9-acetyl-9H-purin-6-yl) sulfanyl]-1-(3-methoxyphenyl) ethan-1-one (1), C16H14N4O3S, 2-[(9-acetyl-9H-purin-6-yl)sulfanyl]-1-(4-methoxyphenyl) ethan-1-one (2), C16H14N4O3S, 2-[(9-acetyl-9H-purin-6-yl)sulfanyl]-1-(4-chlorophenyl)ethan-1-one (3), C15H11ClN4O2S, 2-[(9-acetyl-9H-purin-6-yl)sulfanyl]-1-(4-bromophenyl)ethan-1-one (4), C15H11BrN4O2S, and 1-(3-methoxyphenyl)-2-[(9H-purin-6-yl)sulfanyl] ethan-1-one (5), C14H12N4O2S. Compounds (2), (3) and (4) are isomorphous and accordingly their molecular and supramolecular structures are similar. An analysis of the dihedral angles between the purine and exocyclic phenyl rings show that the molecules of (1) and (5) are essentially planar but that in the case of the three isomorphous compounds (2), (3) and (4), these rings are twisted by a dihedral angle of approximately 38 degrees. With the exception of (1) all molecules are linked by weak C-H center dot center dot center dot O hydrogen bonds in their crystals. There is pi-pi stacking in all compounds. A Cambridge Structural Database search revealed the existence of 11 deposited compounds containing the 1-phenyl-2-sulfanylethanone scaffold; of these, only eight have a cyclic ring as substituent, the majority of these being heterocycles.

Abstract The crystal structures of three benzamide derivatives, viz. N-(6-hydroxyhexyl)-3,4,5-trimethoxybenzamide, C16H25NO5, (1), N-(6-anilinohexyl)-3,4,5-trimethoxybenzamide, C22H30N2O4, (2), and N-(6,6-diethoxyhexyl)-3,4,5-trimethoxybenzamide, C20H33NO6, (3), are described. These compounds differ only in the substituent at the end of the hexyl chain and the nature of these substituents determines the differences in hydrogen bonding between the molecules. In each molecule, the m-methoxy substituents are virtually coplanar with the benzyl ring, while the p-methoxy substituent is almost perpendicular. The carbonyl O atom of the amide rotamer is trans related with the amidic H atom. In each structure, the benzamide N-H donor group and O acceptor atoms link the molecules into C(4) chains. In 1, a terminal -OH group links the molecules into a C(3) chain and the combined effect of the C(4) and C(3) chains is a ribbon made up of screw related R-2(2) (17) rings in which the center dot center dot center dot O-H center dot center dot center dot chain lies in the centre of the ribbon and the trimethoxybenzyl groups forms the edges. In 2, the combination of the benzamide C(4) chain and the hydrogen bond formed by the terminal N-H group to an O atom of the 4-methoxy group link the molecules into a chain of R-2(2) (17) rings. In 3, the molecules are linked only by C(4) chains.

Abstract Three coumarin derivatives, viz. 6-methyl-N-(3-methylphenyl)-2-oxo-2H-chromene-3-carboxamide, C18H15NO3 (1), N-(3-methoxyphenyl)-6-methyl-2-oxo-2H-chromene-3-carboxamide, C18H15NO4 (2), and 6-methoxy-N-(3-methoxyphenyl)-2-oxo-2H-chromene-3-carboxamide, C18H15NO5 (3), were synthesized and structurally characterized. The molecules display intramolecular N-H center dot center dot center dot O and weak C-H center dot center dot center dot O hydrogen bonds, which probably contribute to the approximate planarity of the molecules. The supramolecular structures feature C-H center dot center dot center dot O hydrogen bonds and pi-pi interactions, as confirmed by Hirshfeld surface analyses.

Abstract Due to the generalization of electronically supported activities, we anticipate that, in the near future, the letter "e" in "e-learning," indicating the use of electronic media and information and communication technologies in education, will be dropped and that "e-learning" will be referred to as simply "learning." This paper presents an attempt at understanding the causes of the name shift and at predicting its consequences. We offer a constructive reflection on how e-learning has been looked upon and on what we foresee will happen in the future, drawing briefly on several areas of knowledge and on the experience of the authors as educators at university, teacher training and high school levels. Our effort has also resulted in greater awareness of the importance of social tools and of the relevance of the human factor in the learning process.

Abstract The majority of current infectious diseases are almost untreatable by conventional antibiotic therapy given the advent of multidrug-resistant bacteria. The degree of severity and the persistence of infections are worsened when microorganisms form biofilms. Therefore, efforts are being applied to develop new drugs not as vulnerable as the current ones to bacterial resistance mechanisms, and also able to target bacteria in biofilms. Natural products, especially those obtained from plants, have proven to be outstanding compounds with unique properties, making them perfect candidates for these much-needed therapeutics. This review presents the current knowledge on the potentialities of plant products as antibiotic adjuvants to restore the therapeutic activity of drugs. Further, the difficulties associated with the use of the existing antibiotics in the treatment of biofilm-related infections are described. To counteract the biofilm resistance problems, innovative strategies are suggested based on literature data. Among the proposed strategies, the use of phytochemicals to inhibit or eradicate biofilms is highlighted. An overview on the use of phytochemicals to interfere with bacterial quorum sensing (QS) signaling pathways and underlying phenotypes is provided. The use of phytochemicals as chelating agents and efflux pump inhibitors is also reviewed.

Abstract Background: The systemic information enclosed in microarray data encodes relevant clues to overcome the poorly understood combination of genetic and environmental factors in Parkinson's disease (PD), which represents the major obstacle to understand its pathogenesis and to develop disease-modifying therapeutics. While several gene prioritization approaches have been proposed, none dominate over the rest. Instead, hybrid approaches seem to outperform individual approaches. Methods: A consensus strategy is proposed for PD related gene prioritization from mRNA microarray data based on the combination of three independent prioritization approaches: Limma, machine learning, and weighted gene co-expression networks. Results: The consensus strategy outperformed the individual approaches in terms of statistical significance, overall enrichment and early recognition ability. In addition to a significant biological relevance, the set of 50 genes prioritized exhibited an excellent early recognition ability (6 of the top 10 genes are directly associated with PD). 40 % of the prioritized genes were previously associated with PD including well-known PD related genes such as SLC18A2, TH or DRD2. Eight genes (CCNH, DLK1, PCDH8, SLIT1, DLD, PBX1, INSM1, and BMI1) were found to be significantly associated to biological process affected in PD, representing potentially novel PD biomarkers or therapeutic targets. Additionally, several metrics of standard use in chemoinformatics are proposed to evaluate the early recognition ability of gene prioritization tools. Conclusions: The proposed consensus strategy represents an efficient and biologically relevant approach for gene prioritization tasks providing a valuable decision-making tool for the study of PD pathogenesis and the development of disease-modifying PD therapeutics.