Giulio Ferino

8‐Substituted 3‐Arylcoumarins as Potent and Selective MAO‐B Inhibitors: Synthesis, Pharmacological Evaluation, and Docking Studies

Neurodegenerative disorders are becoming more prevalent given the increase in the aging population. This has inspired active research in the development of new drugs that could mark an important advance in the treatment of complex diseases such as Alzheimer′s and Parkinson′s. With the aim of finding new MAO‐B‐selective inhibitors, we report the synthesis, in vitro evaluation, and docking simulation of a new series of 3‐arylcoumarins variously substituted at the 8‐position. Most of the studied compounds show high affinity and selectivity for the hMAO‐B isoform, with IC50 values in the low micro‐ to nanomolar range. Some of them have greater hMAO‐B inhibitory activity and selectivity than the reference compound, selegiline. Compounds 7 and 8 are the most active of this series, with compound 8 being fivefold more potent against MAO‐B and severalfold more selective than selegiline. Docking experiments were carried out with hMAO‐B crystal structures, providing new information about the enzyme–inhibitor interaction and the potential therapeutic application of the new 8‐substituted 3‐arylcoumarins.

Hydroxycoumarins as selective MAO-B inhibitors.

A series of 3-aryl-4-hydroxycoumarin derivatives was synthesized with the aim to find out the structural features for the MAO inhibitory activity and selectivity. Methoxy and/or chloro substituents were introduced in the 3-phenyl ring, whereas the position 6 in the coumarin moiety was not substituted or substituted with a methyl group or a chloro atom due to their different electronic, steric and/or lipophilic properties. Most of the synthesized compounds presented MAO-B inhibitory activity. The presence of methoxy and chloro groups, respectively in the para and meta positions of the 3-phenyl ring, have an important influence on the inhibitory activity. Moreover, the presence of a chloro atom in the six position of the moiety (compound 7) improved the inhibitor activity as well as its selectivity against MAO-B compared with iproniazide, used as reference compound. Docking experiments were carried out to understand which are the most energetically preferred orientations adopted by compounds 5, 6 and 7 inside the MAO-B binding pocket.

Using spectral moments of spiral networks based on PSA/mass spectra outcomes to derive quantitative proteome-disease relationships (QPDRs) and predicting prostate cancer.

In prostate cancer (PCa), prognostic (predictive) factors are particularly important given the marked heterogeneity of this disease at clinical, morphologic, and biomolecular levels. Blood contains a treasure of previously unstudied biomarkers that could reflect the ongoing physiological state of all tissue. The serum prostate-specific antigen (PSA) measurement is a very good biomarker for PCa, but the percentage of bad classification is somewhat high. The blood proteome mass spectra (MS) represent a potential tool for detection of diseases; however the identification of a single biomarker from the complex output from MS is often difficult. In this paper, we propose a general strategy, based on computational chemistry techniques, which should improve the predictive power of PSA. Our group adapted the square-spiral graph to represent human serum-plasma-proteome MS for healthy and PCa patients. These graphs were previously applied to DNA and/or protein sequences. In this work, we calculated different classes of connectivity indices (CIs), and created various models based on the spectral moments. The best QPDRs model found showed accuracy values ranging from 71.7% to 97.2%, and 70.4% to 99.2% of specificity. This methodology might be useful for several applications in computational chemistry.

Monoamine Oxidase Inhibitors: Ten Years of Docking Studies

The number of papers dealing with the structure-based drug design is continuously growing, which demonstrates the importance of such tools in medicinal chemistry. In the current paper, the published literature concerning the use of the ligand-protein docking methodologies in the study of the monoamine oxidase (MAO) enzymes was reviewed. Ten years of studies aimed at developing new compounds active as MAO inhibitors (MAOIs) were covered. The literature regarding thiazole, caffeine, pyrazole, chromone, indeno-pyridazin, β-carboline, indole, coumarin, anilide and amphetamine derivatives, was discussed in some detail. It is apparent that, through this computational approach, more selective and potent molecules can be proposed as inhibitors by applying precise modifications on the basic scaffold.

MAO Inhibitory Activity of 2-Arylbenzofurans versus 3-Arylcoumarins: Synthesis, in vitro Study, and Docking Calculations

Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. Several 3‐arylcoumarin derivatives were previously described as interesting selective MAO‐B inhibitors. Preserving the trans‐stilbene structure, a series of 2‐arylbenzofuran and corresponding 3‐arylcoumarin derivatives were synthesized and evaluated as inhibitors of both MAO isoforms, MAO‐A and MAO‐B. In general, both types of derivatives were found to be selective MAO‐B inhibitors, with IC50 values in the nano‐ to micromolar range. 5‐Nitro‐2‐(4‐methoxyphenyl)benzofuran (8) is the most active compound of the benzofuran series, presenting MAO‐B selectivity and reversible inhibition (IC50=140 nM). 3‐(4′‐Methoxyphenyl)‐6‐nitrocoumarin (15), with the same substitution pattern as that of compound 8, was found to be the most active MAO‐B inhibitor of the coumarin series (IC50=3 nM). However, 3‐phenylcoumarin 14 showed activity in the same range (IC50=6 nM), is reversible, and also severalfold more selective than compound 15. Docking experiments for the most active compounds into the MAO‐B and MAO‐A binding pockets highlighted different interactions between the derivative classes (2‐arylbenzofurans and 3‐arylcoumarins), and provided new information about the enzyme–inhibitor interaction and the potential therapeutic application of these scaffolds.

Protein Graphs in Cancer Prediction

The consequences of breast, colon and prostate cancer create the necessity of new, simpler and faster theoretical models that may allow earlier cancer detection. The present work has built several Quantitative Protein (or Proteome) – Disease Relationships (QPDRs). QPDRs, similar to Quantitative Structure Activity Relationship (QSAR) models, are based on topological indices (TIs) and/or connectivity indices (CIs) of graphs. In particular, we used Star graphs and Lattice networks of protein sequence or MS outcomes of blood proteome in order to predict the proteins related to breast and colon cancer and to improve the diagnostic potential of the PSA biomarker for prostate cancer. The advantages of this method are the simplicity, fast calculations and few resources needed (free software programmes, such as MARCH-INSIDE and S2SNet). Thus, this ideal theoretical scheme can be easily extended to other types of diseases or even other fields, such as Genomics or Systems Biology.

Novel coumarins and related copper complexes with biological activity: DNA binding, molecular docking and in vitro antiproliferative activity

Coumarins show biological activity and are widely exploited for their therapeutic effects. Although a great number of coumarins substituted by heterocyclic moieties have been prepared, few studies have been carried out on coumarins containing pyridine heterocycle, which is known to modulate their physiological activities. We prepared and characterized three novel 3-(pyridin-2-yl)coumarins and their corresponding copper(II) complexes. We extended our investigations also to three known similar coumarins, since no data about their biochemical activity was previously been reported. The antiproliferative activity of the studied compounds was tested against human derived tumor cell lines and one human normal cell line. The DNA binding constants were determined and docking studies with DNA carried out. Selected Quantitative Structure-Activity Relationship (QSAR) descriptors were calculated in order to relate a set of structural and topological descriptors of the studied compounds to their DNA interaction and cytotoxic activity.

Rare disease: a focus on metabolomics

ABSTRACT Introduction: A disease or disorder is defined rare when it affects less than 1 in 2000 subjects. 400 million people worldwide are living with a rare disease; approximately 50% of these patients are children, and 30% of them die within the first 5 years of life. The wide aetiology diversity leads to high variability in symptomatology, and clinical manifestations and consequently to challenging diagnosis. New experimental approaches are therefore recommended to improve diagnosis, and for the development of new therapeutic strategies. In the last years, metabolomics have allowed to better understand the metabolic processes associated with several rare diseases. Areas covered: This review describes the use of metabolomics for the study of the metabolic alterations related to some of the most studied pediatric rare disorders. Metabolomics, by means of 1H NMR spectroscopy and MS spectrometry, allows the identification and the quantification of a large number of metabolites (biomarkers) in different biofluids. Expert opinion: Metabolomics proved to be a powerful tool for the clinical investigation of rare diseases. The power of discrimination seems to be reliable for all the considered biofluids (urine, blood, and amniotic fluid). Standardization of the analytical and statistical steps is still needed for further studies with larger populations and meta-analysis.

Metabolomics profiling reveals different patterns in an animal model of asphyxial and dysrhythmic cardiac arrest

Cardiac arrest (CA) is not a uniform condition and its pathophysiology strongly depends on its cause. In this work we have used a metabolomics approach to study the dynamic metabolic changes occurring in the plasma samples of a swine model following two different causes of CA, namely asphyxia (ACA) and ventricular fibrillation (VFCA). Plasma samples were collected at baseline and every minute during the experimental phases. In order to identify the metabolomics profiles characterizing the two pathological entities, all samples were analysed by 1H NMR spectroscopy and LC-MS/MS spectrometry.The metabolomics fingerprints of ACA and VFCA significantly differed during the peri-arrest period and the resuscitation phase. Major alterations were observed in plasma concentrations of metabolites related to tricarboxylic acid (TCA) cycle, urea cycle, and anaplerotic replenishing of TCA. ACA animals showed significant metabolic disturbances during the asphyxial and CA phases, while for VFCA animals this phenomenon resulted shifted at the resuscitation phase. Interestingly, starting from the asphyxial phase, the ACA animals were stratified in two groups based on their metabolomics profiles that resulted to be correlated with the clinical outcome. Succinate overproduction was observed in the animals with the worse outcome, suggesting a potential prognostic role for this metabolite.

Halogen and Hydrogen Bonding Benzothiophene Diol Derivatives: A Study Using ab initio Calculations and X‐Ray Crystal Structure Measurements

The aim of this study is to describe and compare the supramolecular interactions, in the solid state, of chloro-, bromo-, and iodobenzothiophene diols. The compounds were obtained through organo-catalyzed reactions starting from 3-substituted halobenzothiophene carbaldehydes. Energies of the noncovalent interactions were obtained by density functional theory calculations. Bond distances and angles were found to be in accordance with those determined by X-ray structure analysis. anti-Bromobenzothiophene derivatives showed strong halogen⋅⋅⋅π interactions between bromine and the heterocyclic phenyl ring, corresponding to an energy of 7.5 kcal mol−1. syn-Bromo and syn-iodo derivatives appeared to be isostructural, showing X⋅⋅⋅O (carbonyl) interactions, π stacking, and formation of extended hydrogen bonding networks. In contrast, the chloro derivatives displayed no halogen bonding interactions.