Publications

Abstract Because of the lack of significant disease-modifying drugs for neurodegenerative disorders, a pressing need for new chemical entities endowed with IMAO-B still exists. Within this framework, and for the first time, a study was performed to compare coumarin- and chomone-3-phenylcarboxamide scaffolds. Compounds 10a and 10b were the most potent, selective, and reversible noncompetitive IMAO-B. The benzopyrone sp(2) oxygen atom was found to be position independent and a productive contributor for the ligand-enzyme complex stability.

Abstract Monoamine oxidase (MAO) is an enzyme responsible for metabolism of monoamine neurotransmitters which play an important role in brain development and function. This enzyme exists in two isoforms, and it has been demonstrated that MAO-B activity, but not MAO-A activity, increases with aging. MAO inhibitors show clinical value because besides the monoamine level regulation they reduce the formation of byproducts of the MAO catalytic cycle, which are toxic to the brain. A series of 2-phenylbenzofuran derivatives was designed, synthesized and evaluated against hMAO-A and hMAO-B enzymes. A bromine substituent was introduced in the 2-phenyl ring, whereas position 5 or 7 of the benzofuran moiety was substituted with a methyl group. Most of the tested compounds inhibited preferentially MAO-B in a reversible manner, with IC50 values in the low micro or nanomolar range. The 2-( 2'-bromophenyl)-5-methylbenzofuran ( 5) was the most active compound identified (IC50 = 0.20 mu M). In addition, none of the studied compounds showed cytotoxic activity against the human neuroblastoma cell line SH-SY5Y. Molecular docking simulations were used to explain the observed hMAO-B structure-activity relationship for this type of compounds.

Abstract Chromone derivatives have been extensively studied recently because of to their promising biological activities. The new title chromone-thiazole hybrid presented here, C14H10N2O3S, is a candidate as a selective ligand for adenosine receptors. The compound has been synthesized and characterized by the usual spectroscopic means (NMR and EM/IE) and its structure elucidated by X-ray crystallography, which revealed the presence of packing polymorphism. The two polymorphs (one with space group P2(1)/n and one with P2(1)/c) show slightly different conformations and the major change induced by crystallization regards the intramolecular contacts defining the supramolecular structure. Those differences been highlighted by Hirshfeld surface analysis mapped over d(norm) and ESP.

Abstract The herbicide terbuthylazine (TBA) is widely used for preemergence or postemergence control of many grass and broadleaf weeds and has, besides other issues, a poor aqueous solubility profile that results in reduced bioavailability. Cyclodextrins and modified cyclodextrins were considered, among other substances, appropriate agents for improving pesticide water solubility. Therefore, the inclusion complex formation of terbuthylazine with beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was studied to attain its aqueous solubility enhancement. Their characterization was accomplished with different analytical techniques, namely, by UV-Vis, DSC, FTIR, and 1 HNMR. From the analysis of the complexation performance of the herbicide it was concluded that the interaction of terbuthylazine with CDs leads to the formation of inclusion complexes with a stoichiometry of 1 : 1. The association constants of the TBA/beta-CD and TBA/HP-beta-CD complexes were determined by UV. The mean values obtained for the stability constants are 460.4 +/- 26.5 and 532.1 +/- 27.6 to TBA/beta-CD and TBA/HP-beta-CD, respectively. H-1 NMR data corroborate the formation of the TBA/beta-CD and TBA/HP-beta-CD complexes synthesized by the kneading method. A formulation incorporating TBA cyclodextrin complexes might lead to an improvement in terbuthylazine bioavailability. The development of TBA-CD formulations may be interesting since it would enable, through their inclusion into the hydrophobic cavity of CDs, enhancement of solubility, bioavailability, and stability of the herbicide.

Abstract Coumarins represent an important family of naturally occurring and/or synthetic oxygen- containing heterocycles, bearing a characteristic benzopyrone framework. These compounds are widely distributed both in human diet and therapeutics. Among other characteristics, several coumarin derivatives proved to have an interesting antioxidant profile. In the current review, an overview of the role of natural coumarins as important antioxidants is presented and discussed. The benefits of antioxidants to prevent chronic diseases is also discussed in the current review. The most common assays performed to evaluate the antioxidant capacity described in this review are related to different reactive oxygen species involved in the oxidative process. Several reaction mechanisms were studied to investigate the antioxidant profile of coumarins. Among them, hydrogen atom transfer (HAT) and single electron transfer transfer (SET), were highly cited. To make the organization of this overview as clear as possible, coumarin derivatives were dived in: simple coumarins; aliphatic, terpenoid and aromaticcontaining coumarins; ring- fused coumarins and ellagic acid derivatives.

Abstract Melanogenesis is a physiological pathway for the formation of melanin. Tyrosinase catalyzes the first step of this process and down-regulation of its activity is responsible for the inhibition of melanogenesis. The search for molecules capable of controlling hyperpigmentation is a trend topic in health and cosmetics. A series of heteroarylcoumarins have been synthesized and evaluated. Compounds 4 and 8 exhibited higher tyrosinase inhibitory activities (IC50 = 0.15 and 0.38 mu M, respectively), than the reference compound, kojic acid (IC50 = 17.9 mu M). Compound 4 acts as competitive, while compound 8 as uncompetitive inhibitor of mushroom tyrosinase. Furthermore, compounds 2 and 8 inhibited tyrosinase activity and melanin production in B16F10 cells. In addition, compounds 2-4 and 8 proved to have an interesting antioxidant profile in both ABTS and DPPH radicals scavenging assays. Docking experiments were carried out in order to study the interactions between these heteroarylcoumarins and mushroom tyrosinase.

Abstract Background: Virtual methodologies have become essential components of the drug discovery pipeline. Specifically, structure-based drug design methodologies exploit the 3D structure of molecular targets to discover new drug candidates through molecular docking. Recently, dual target ligands of the Adenosine A2A Receptor and Monoamine Oxidase B enzyme have been proposed as effective therapies for the treatment of Parkinson's disease. Methods: In this paper we propose a structure-based methodology, which is extensively validated, for the discovery of dual Adenosine A2A Receptor/Monoamine Oxidase B ligands. This methodology involves molecular docking studies against both receptors and the evaluation of different scoring functions fusion strategies for maximizing the initial virtual screening enrichment of known dual ligands. Results: The developed methodology provides high values of enrichment of known ligands, which outperform that of the individual scoring functions. At the same time, the obtained ensemble can be translated in a sequence of steps that should be followed to maximize the enrichment of dual target Adenosine A2A Receptor antagonists and Monoamine Oxidase B inhibitors. Conclusion: Information relative to docking scores to both targets have to be combined for achieving high dual ligands enrichment. Combining the rankings derived from different scoring functions proved to be a valuable strategy for improving the enrichment relative to single scoring function in virtual screening experiments.

Abstract This work aims to calculate the carbon footprint of the ICB produced by a Portuguese company and to compare it with other insulation materials available in the market. A Life Cycle Thinking approach and the ISO/TS 14067 (2013) requirements were followed in this work to perform a "cradle-to-gate" life cycle analysis. The inventory analysis mainly uses primary data collected from a Portuguese ICB producing company, complemented with secondary data from commercial life cycle databases and literature concerning respectively, the external transportation of the cork raw-material and the emission factors of electricity and fuel production and use. Results of this study show that ICB has a carbon footprint of 116.229 kg CO2 equivalent per m(3) of ICB. It is the only insulation material present in the market with a negative carbon footprint, which is mainly due to the utilization of cork, a renewable raw material, the proximity of its source to the factory, and the use of biomass for generating the steam needed for its production process. To the authors' knowledge, this is the first study to report the carbon footprint of ICB and to compare it with other building insulation materials.

Abstract Background: Preeclampsia is a multifactorial disease with unknown pathogenesis. Even when recent studies explored this disease using several bioinformatics tools, the main objective was not directed to pathogenesis. Additionally, consensus prioritization was proved to be highly efficient in the recognition of genes-disease association. However, not information is available about the consensus ability to early recognize genes directly involved in pathogenesis. Therefore our aim in this study is to apply several theoretical approaches to explore preeclampsia; specifically those genes directly involved in the pathogenesis. Methods: We firstly evaluated the consensus between 12 prioritization strategies to early recognize pathogenic genes related to preeclampsia. A communality analysis in the protein-protein interaction network of previously selected genes was done including further enrichment analysis. The enrichment analysis includes metabolic pathways as well as gene ontology. Microarray data was also collected and used in order to confirm our results or as a strategy to weight the previously enriched pathways. Results: The consensus prioritized gene list was rationally filtered to 476 genes using several criteria. The communality analysis showed an enrichment of communities connected with VEGF-signaling pathway. This pathway is also enriched considering the microarray data. Our result point to VEGF, FLT1 and KDR as relevant pathogenic genes, as well as those connected with NO metabolism. Conclusion: Our results revealed that consensus strategy improve the detection and initial enrichment of pathogenic genes, at least in preeclampsia condition. Moreover the combination of the first percent of the prioritized genes with protein-protein interaction network followed by communality analysis reduces the gene space. This approach actually identifies well known genes related with pathogenesis. However, genes like HSP90, PAK2, CD247 and others included in the first 1% of the prioritized list need to be further explored in preeclampsia pathogenesis through experimental approaches.