Publications

Abstract The number of people affected by neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease is rapidly increasing owing to the global increase in life expectancy. Small molecules with neurotrophic effects have great potential for management of these neurological disorders. In this study, different (C1-C12) alkyl ester derivatives of hydroxycinnamic acids (HCAs) were synthesized (a total of 30 compounds). The neurotrophic capacity of the test compounds was examined by measuring promotion of survival in serum-deprived conditions and enhancement of nerve growth factor (NGF)-induced neurite outgrowth in PC12 neuronal cells. p-Coumaric, ferulic, and sinapic acids and their esters did not alter cell survival, while caffeic acid and all its alkyl esters, especially decyl and dodecyl caffeate, significantly promoted neuronal survival at 25m. Methyl, ethyl, propyl, and butyl caffeate esters also significantly enhanced NGF-induced neurite outgrowth, among which the most effective ones were propyl and butyl esters, which at 5m led to 25- and 22-fold increases in the number of neurites, respectively. The findings of the docking study suggested phosphatidylinositol 3-kinase (PI3K) as the potential molecular target. In conclusion, our findings demonstrate that alkyl esters of caffeic acid can be useful as scaffolds for the discovery of therapeutic agents for neurodegenerative diseases.

Abstract Detection and quantification of cocaine is a key tool in fields such as police apprehensions and the fight against drug trafficking. Thus, a simple, fast and inexpensive electroanalytical methodology for the determination of cocaine in seized street samples has been developed, employing linear sweep voltammetry. The method is based on the use of a glassy carbon (GC) electrode modified by a combination of multi-walled carbon nanotubes (MWCNT) with beta-cyclodextrin (beta-CD) incorporated in a polyaniline film. The proposed method shows high reproducibility, repeatability and specificity. Under optimal conditions, the beta-CD/MWCNT-modified GC electrode gives a detection limit of 1.02 mu M cocaine. The results obtained are in good agreement with those obtained by the high-performance liquid chromatography reference method. The new methodology proposed has excellent potential as the basis of a portable analytical sensor for on-site screening of cocaine in seized street samples.

Abstract The title coumarin derivative, C20H14N2O3, displays 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 molecule [dihedral angle between the coumarin and quinoline ring systems = 6.08 (6)degrees]. 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 The development of computational methods to discover novel drug-target interactions on a large scale is of great interest. We propose a new method for virtual screening based on protein interaction profile similarity to discover new targets for molecules, including existing drugs. We calculated Target Interaction Profile Fingerprints (TIPFs) based on ChEMBL database to evaluate drug similarity and generated new putative compound-target candidates from the non-intersecting targets in each pair of compounds. A set of drugs was further studied in monoamine oxidase B (MAO-B) and cyclooxygenase-1 (COX-1) enzyme through molecular docking and experimental assays. The drug ethoxzolamide and the natural compound piperlongumine, present in Piper longum L, showed hMAO-B activity with IC50 values of 25 and 65 mu M respectively. Five candidates, including lapatinib, SB-202190, RO-316233, GW786460X and indirubin-3'-monoxime were tested against human COX-1. Compounds SB-202190 and RO-316233 showed a IC50 in hCOX-1 of 24 and 25 mu M respectively (similar range as potent inhibitors such as diclofenac and indomethacin in the same experimental conditions). Lapatinib and indirubin-3'- monoxime showed moderate hCOX-1 activity (19.5% and 28% of enzyme inhibition at 25 mu M respectively). Our modeling constitutes a multi-target predictor for large scale virtual screening with potential in lead discovery, repositioning and drug safety.

Abstract We present herein the synthesis, and the structural and spectroscopic analysis of a non-planar tripod-shaped p-(N,N′-dimethylamino)benzyliden-1,3-indandione (DMABI) chromophore. This novel molecule is composed of a Si core with three incorporated arms, each of them contains a 1,3-indandione derivative with an electron donating (-NMe2) group, thus providing fluorescence capabilities. We prepared a DMABI arm by coupling a p-(N,N′-dimethylamino)benzaldehyde (DMAB) tripod substituted molecule with 1,3-indandione via aldol condensation. The structures of DMAB-tripods were confirmed by spectroscopic data and studied by quantum chemical calculations. Fluorescence spectroscopy was used for optical characterization. Quantum yields and the corresponding lifetimes reveal typical characteristics of conjugated derivatives. Finally, we monitored the enhancement in fluorescence intensity of compound 1 in the presence of 4-chloro-2,6-dinitroaniline (4CDNA) in the range between 0 and 20 mg L-1. We justify this enhancement by calculated energies and the distribution of the HOMO and the LUMO for DMABI-tripod and 4CDNA. © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2016.

Abstract In this work we report the first attempt to study the effect of activity cliffs over the generalization ability of machine learning (ML) based QSAR classifiers, using as study case a previously reported diverse and noisy dataset focused on drug induced liver injury (DILI) and more than 40 ML classification algorithms. Here, the hypothesis of structure-activity relationship (SAR) continuity restoration by activity cliffs removal is tested as a potential solution to overcome such limitation. Previously, a parallelism was established between activity cliffs generators (ACGs) and instances that should be misclassified (ISMs), a related concept from the field of machine learning. Based on this concept we comparatively studied the classification performance of multiple machine learning classifiers as well as the consensus classifier derived from predictive classifiers obtained from training sets including or excluding ACGs. The influence of the removal of ACGs from the training set over the virtual screening performance was also studied for the respective consensus classifiers algorithms. In general terms, the removal of the ACGs from the training process slightly decreased the overall accuracy of the ML classifiers and multi-classifiers, improving their sensitivity (the weakest feature of ML classifiers trained with ACGs) but decreasing their specificity. Although these results do not support a positive effect of the removal of ACGs over the classification performance of ML classifiers, the "balancing effect" of ACG removal demonstrated to positively influence the virtual screening performance of multi-classifiers based on valid base ML classifiers. Specially, the early recognition ability was significantly favored after ACGs removal. The results presented and discussed in this work represent the first step towards the application of a remedial solution to the activity cliffs problem in QSAR studies.

Abstract Cationic lipid nanoparticles (LNs) have been tested for sustained release and site-specific targeting of epigallocatechin gallate (EGCG), a potential polyphenol with improved pharmacological profile for the treatment of ocular pathologies, such as age-related macular edema, diabetic retinopathy, and inflammatory disorders. Cationic EGCG-LNs were produced by double-emulsion technique; the in vitro release study was performed in a dialysis bag, followed by the drug assay using a previously validated RP-HPLC method. In vitro HET-CAM study was carried out using chicken embryos to determine the potential risk of irritation of the developed formulations. Ex vivo permeation profile was assessed using rabbit cornea and sclera isolated and mounted in Franz diffusion cells. The results show that the use of cationic LNs provides a prolonged EGCG release, following a Boltzmann sigmoidal profile. In addition, EGCG was successfully quantified in both tested ocular tissues, demonstrating the ability of these formulations to reach both anterior and posterior segment of the eye. The pharmacokinetic study of the corneal permeation showed a first order kinetics for both cationic formulations, while EGCG-cetyltrimethylammonium bromide (CTAB) LNs followed a Boltzmann sigmoidal profile and EGCG-dimethyldioctadecy-lammonium bromide (DDAB) LNs a first order profile. Our studies also proved the safety and non-irritant nature of the developed LNs. Thus, loading EGCG in cationic LNs is recognised as a promising strategy for the treatment of ocular diseases related to anti-oxidant and anti-inflammatory pathways.

Abstract Methamphetamine (METH) is a psychostimulant, affecting hippocampal function with disparate cognitive effects, which depends on the dose and time of administration, ranging from improvement to impairment of memory. Importantly, in the United States, METH is approved for the treatment of attention deficit hyperactivity disorder. Modifications of long-term plasticity of synapses originating from the entorhinal cortex onto dentate granule cells (DGCs) have been proposed to underlie cognitive alterations similar to those seen in METH users. However, the effects of METH on synaptic plasticity of the dentate gyrus are unknown. Here, we investigated the impact of long-term administration of METH (2 mg/kg/d) on neurogenesis and synaptic plasticity of immature and mature DGCs of juvenile mice. We used a mouse model of neurogenesis (the G42 line of GAD67-GFP), in which GFP is expressed by differentiating young DGCs. METH treatment enhanced the differentiation of GFP(+) cells, as it increased the fraction of GFP(+) cells expressing the neuronal marker NeuN, and decreased the amount of immature DGCs coexpressing doublecortin. Interestingly, METH did not change the magnitude of long-term potentiation (LTP) in more immature neurons, but facilitated LTP induction in more differentiated GFP(-) and strengthened plasticity in mature GFP(-) DGCs. The METH-induced facilitation of LTP in GFP(+) neurons was accompanied with spine enlargement. Our results reveal a specific action of long-term use of METH in the long-term plasticity of excitatory synapses onto differentiating DGCs and might have important implications toward the understanding of the synaptic basis of METH-induced cognitive alterations.