André Fonseca

Chromone 3-phenylcarboxamides as potent and selective MAO-B inhibitors.

Monoamine oxidase (MAO) is an enzyme, present in mammals in two isoforms MAO-A and MAO-B. These isoforms have a crucial role in neurotransmitters metabolism, representing an attractive drug target in the therapy of neurodegenerative diseases (MAO-B) and depression (MAO-A). In this context, our work has been focused on the discovery of new chemical entities (NCEs) for MAO inhibition, based on the development of chromone carboxamides. Chromone derivatives with a carboxamide function located in position 2- and 3- of the benzo-γ-pyrone core, (compounds 2-6 and 8-12) were synthesized, with moderate/good yields, by a one-pot condensation reaction using phosphonium salts as coupling reagents. The synthetic compounds were screened towards human MAO isoforms (hMAO) to evaluate their potency and selectivity. The chromone-3-carboxamides show high selectivity to hMAO-B, with compounds 9 and 12 displaying IC(50) values at nanomolar range.

What is the effect of LiDAR-derived DEM resolution on large-scale watershed model results? ☆

This paper examines the effect of raster cell size on hydrographic feature extraction and hydrological modeling using LiDAR derived DEMs. LiDAR datasets for three experimental watersheds were converted to DEMs at various cell sizes. Watershed boundaries and stream networks were delineated from each DEM and were compared to reference data. Hydrological simulations were conducted and the outputs were compared. Smaller cell size DEMs consistently resulted in less difference between DEM-delineated features and reference data. However, minor differences been found between streamflow simulations resulted for a lumped watershed model run at daily simulations aggregated at an annual average. These findings indicate that while higher resolution DEM grids may result in more accurate representation of terrain characteristics, such variations do not necessarily improve watershed scale simulation modeling. Hence the additional expense of generating high resolution DEMs for the purpose of watershed modeling at daily or longer time steps may not be warranted.

Watershed model parameter estimation and uncertainty in data-limited environments

Parameter uncertainty and sensitivity for a watershed-scale simulation model in Portugal were explored to identify the most critical model parameters in terms of model calibration and prediction. The research is intended to help provide guidance regarding allocation of limited data collection and model parameterization resources for modelers working in any data and resource limited environment. The watershed-scale hydrology and water quality simulation model, Hydrologic Simulation Program - FORTRAN (HSPF), was used to predict the hydrology of Lis River basin in Portugal. The model was calibrated for a 5-year period 1985-1989 and validated for a 4-year period 2003-2006. Agreement between simulated and observed streamflow data was satisfactory considering the performance measures such as Nash-Sutcliffe efficiency (E), deviation runoff (Dv) and coefficient of determination (R2). The Generalized Likelihood Uncertainty Estimation (GLUE) method was used to establish uncertainty bounds for the simulated flow using the Nash-Sutcliffe coefficient as a performance likelihood measure. Sensitivity analysis results indicate that runoff estimations are most sensitive to parameters related to climate conditions, soil and land use. These results state that even though climate conditions are generally most significant in water balance modeling, attention should also focus on land use characteristics as well. Specifically with respect to HSPF, the two most sensitive parameters, INFILT and LZSN, are both directly dependent on soil and land use characteristics. HSPF calibration/validation study on data limited watersheds.HSPF water balance parameters sensitivity analysis reported similar results for different watershed studies.The effect of model uncertainty is determined by the threshold value established to obtain the confidence interval.Accuracy of climate and land use data is very important for model performance.

Crystal structures of three 6-substituted coumarin-3-carboxamide derivatives

Three coumarin derivatives display intramolecular N—H⋯O and weak C—H⋯O hydrogen bonds, which probably contribute to the approximate planarity of the molecules. The supramolecular structures feature C—H⋯O hydrogen bonds and π–π interactions, as confirmed by Hirshfeld surface analyses.

Exploring coumarin potentialities: development of new enzymatic inhibitors based on the 6-methyl-3-carboxamidocoumarin scaffold

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.

Insight into the Interactions between Novel Coumarin Derivatives and Human A3 Adenosine Receptors

A study focused on the discovery of new chemical entities based on the 3‐arylcoumarin scaffold was performed with the aim of finding new adenosine receptor (AR) ligands. Thirteen synthesized compounds were evaluated by radioligand binding (A1, A2A, and A3) and adenylyl cyclase activity (A2B) assays in order to study their affinity for the four human AR (hAR) subtypes. Seven of the studied compounds proved to be selective A3AR ligands, with 3‐(4′‐methylphenyl)‐8‐(2‐oxopropoxy)coumarin (12) being the most potent (Ki=634 nM). None of the compounds showed affinity for the A2B receptor, while four compounds were found to be nonselective AR ligands for the other three subtypes. Docking simulations were carried out to identify the hypothetical binding mode and to rationalize the interaction of these types of coumarin derivatives with the binding site of the three ARs to which binding was observed. The results allowed us to conclude that the 3‐arylcoumarin scaffold composes a novel and promising class of A3AR ligands. ADME properties were also calculated, with the results suggesting that these compounds are promising leads for the identification of new drug candidates.

Integrating water quality responses to best management practices in Portugal

Nutrient nonpoint pollution has a significant impact on water resources worldwide. The main challenge of this work was to assess the application of best management practices in agricultural land to comply with water quality legislation for surface waters. The Hydrological Simulation Program—FORTRAN was used to evaluate water quality of Ave River in Portugal. Best management practices (infiltration basin) (BMP) were applied to agricultural land (for 3, 6, 9, 12, and 15% area) with removal efficiencies of 50% for fecal coliforms and 30% for nitrogen, phosphorus, and biochemical oxygen demand. The inflow of water quality constituents was reduced for all scenarios, with fecal coliforms achieving the highest reduction between 5.8 and 28.9% and nutrients and biochemical oxygen demand between 2 and 13%. Biochemical oxygen demand and orthophosphates concentrations achieved a good water quality status according to the European Legislation for scenarios of BMP applied to 3 and 12% agricultural area, respectively. Fecal coliform levels in Ave River basin require further treatment to fall below the established value in the abovementioned legislation. This study shows that agricultural watersheds such as Ave basins demand special attention in regard to nonpoint pollution sources effects on water quality and nutrient loads.

Coumarin versus Chromone Monoamine Oxidase B Inhibitors: Quo Vadis?

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 sp2 oxygen atom was found to be position independent and a productive contributor for the ligand-enzyme complex stability.

Photodamage and photoprotection: toward safety and sustainability through nanotechnology solutions

Abstract Nanotechnology offers substantial prospects for the development of innovative products and it is expected that the number of nanotechnology-based products will increase in the future. A number of promising applications are emerging, such as, smart packaging, nanosensors for pathogen detection, agrochemical nanoformulations, and nanoencapsulation of food ingredients for chemical preservation and shelf life extension. In this chapter, a special attention is given on how nanotechnology can mitigate the chemical changes of bioactive compounds, mainly those with nutritional value, occurring in food industry chain. Within this framework, an overview of the main external (oxygen, temperature, and light) factors that cause chemical degradation of some bioactive compounds present in food and affect food quality, and consequently contribute to food spoilage, and safety is also presented.

Coumarins and adenosine receptors: New perceptions in structure–affinity relationships

Adenosine receptor (AR) subtypes are involved in several physiological and pharmacological processes. Ligands that are able to selectively modulate one receptor subtype can delay or slow down the progression of diverse diseases. In this context, our research group focused its investigation into the discovery and development of novel, potent and selective AR ligands based on coumarin scaffold. Therefore, a series of 3‐phenylcarboxamidocoumarins were synthesized and their affinity for the human AR subtypes was screened by radioligand binding assays for A1, A2A and A3 receptors and for A2B by adenylyl cyclase assay. Compound 26 was found to be the most remarkable, with a hA1/hA3 and hA2A/hA3 selectivity of 42, for the A3 AR (Ki = 2.4 μm). Receptor‐driven molecular modelling studies have provided valuable information on the binding/selectivity data of compound 26 and for the following optimization process. Moreover, compound 26 presents drug‐like properties according to the general guidelines linked to the concept.