Publications

Abstract The use of privileged structures in drug discovery has proven to be an effective strategy, allowing the generation of innovative hits/leads and successful optimization processes. Chromone is recognized as a privileged structure and a useful template for the design of novel compounds with potential pharmacological interest, particularly in the field of neurodegenerative, inflammatory, and infectious diseases as well as diabetes and cancer. This perspective provides the reader with an update of an earlier article entitled "Chromone: A Valid Scaffold in Medicinal Chemistry" (Chem. Rev. 2014, 114, 4960-4992) and is mainly focused on chromones of biological interest, including those isolated from natural sources. Moreover, as drug repurposing is becoming an attractive drug discovery approach, recent repurposing studies of chromone-based drugs are also reported.

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.

Abstract Reactive species are continuously produced in vivo by all body tissues. However, when an imbalance between the reactive species production and the endogenous pool of antioxidants occurs, the resulting oxidative stress can somehow intensify the pathophysiological mechanisms of several diseases, such as neurodegenerative diseases. Although the aetiology of Parkinson's and Alzheimer's diseases is not yet completely understood, it is accepted by the scientific community that the oxidative stress can act as a trigger or can be involved in the course of both diseases. Therefore, the development of an antioxidant-based therapy could be a helpful approach to ameliorate the deleterious effects of oxidative stress in neurodegenerative diseases. Coumarins and chromones are natural or synthetic chemical entities described as privileged structures with diverse biological activities that have been used to design new drugs with potential anti-Alzheimer and anti-Parkinson profiles. Since some of these compounds also displayed potent antioxidant activity, the rationale approach to developing new drugs based on the benzopyran scaffold, as therapeutic alternatives for neurodegenerative diseases, is a valid and compelling topic. This review provides a medicinal chemistry overview on the discovery and development of benzopyran-based compounds endowed with antioxidant, neuroprotective and anti-Alzheimer or anti-Parkinson activities.

Abstract So far, no connection between coffee consumption and breast cancer development has been confirmed, although a positive association has been described for specific individuals. The general rule is that coffee consumption has no effect or actually decreases the incidence of breast cancer. Several coffee constituents such as caffeine, lignans, flavonoids, and hydroxycinnamic acids have been investigated in the context of breast cancer. Hydroxycinnamic acids, especially caffeic and ferulic acids, display a potent antioxidant and anti-radical activity in models of breast cancer, acting through different mechanisms. Although caffeic and ferulic acid have well-established properties, some derivatives of both molecules, possessing slight modifications in their structure, have improved chemotherapeutic activity toward breast cancer cells. Therefore, natural phytochemical molecules such as those present in coffee are a promising and pragmatic clinical approach, by presenting low toxicity to normal cells and high activity toward their malignant counterparts.

Abstract Methamphetamine (METH) is a highly addictive psychostimulant drug of abuse that negatively interferes with neurogenesis. In fact, we have previously shown that METH triggers stem/progenitor cell death and decreases neuronal differentiation in the dentate gyrus (DG). Still, little is known regarding its effect on DG stem cell properties. Herein, we investigate the impact of METH on mice DG stem/progenitor cell self-renewal functions. METH (10 nM) decreased DG stem cell self-renewal, while 1 nM delayed cell cycle in the G0/G1-to-S phase transition and increased the number of quiescent cells (G0 phase), which correlated with a decrease in cyclin E, pEGFR and pERK1/2 protein levels. Importantly, both drug concentrations (1 or 10 nM) did not induce cell death. In accordance with the impairment of self-renewal capacity, METH (10 nM) decreased Sox2(+)/Sox2(+) while increased Sox2(-)/Sox2(-) pairs of daughter cells. This effect relied on N-methyl-D-aspartate (NMDA) signaling, which was prevented by the NMDA receptor antagonist, MK-801 (10 mu M). Moreover, METH (10 nM) increased doublecortin (DCX) protein levels consistent with neuronal differentiation. In conclusion, METH alters DG stem cell properties by delaying cell cycle and decreasing self-renewal capacities, mechanisms that may contribute to DG neurogenesis impairment followed by cognitive deficits verified in METH consumers. (C) 2014 The Authors. Published by Elsevier B. V.

Abstract Testing impulsive behavior in rodents is challenging and labor-intensive. We developed a new behavioral paradigm-the Variable Delay-to-Signal (VDS) test-that provides rapid and simultaneous assessment of response and decision impulsivity in rodents. Presentation of a light at variable delays signals the permission for action (nose poke) contingent with a reward. 2 blocks of 25 trials at 3 s delay flank a block of 70 trials in which light is presented with randomly selected 6 or 12 s delays. Exposure to such large delays boosts the rate of premature responses when the delay drops to 3 s in the final block, an effect that is blunted by an acute methamphetamine challenge and that correlates with the delay-discounting (DD) paradigm (choice impulsivity). Finally, as expected, treatment with the NMDA antagonist MK-801 caused a generalized response increase in all VDS blocks. The pharmacological validation, particularly with methamphetamine which has a well established dual effect on response and decision impulsivity, and the correlations between the impulsive behavior in the DD and VDS paradigms, suggests that the later is able to provide, in a single session, a multi-dimensional assessment of impulsive behavior.

Abstract Parkinson's disease (PD) is a neurodegenerative disorder mainly characterized by a progressive neurodegeneration of the dopaminergic neurons. The available pharmacological therapy for PD aims to stop the progress of symptoms, reduce disability, slowing the neurodegenerative process and/or preventing long-term complications along the therapy. The main strategic developments that have led to progress in the medical management of PD have focused on improvements in dopaminergic therapies. Despite all the recent research, there are only a few classes of drugs approved for the treatment of motor related symptoms of PD which primarily act on the dopaminergic neurons system: L-dopa, dopamine agonists, monoamine oxidase-B (MAO-B) and catechol-O-methyl transferase (COMT) inhibitors. Anticholinergic drugs and glutamate antagonists are also available but are not commonly used in routine practice. As no effective therapeutic strategy has yet been attended, other solutions must be investigated. Privileged structures, such as indoles, arylpiperazines, biphenyls and benzopyranes are currently ascribed as helpful approaches. Different families of nitrogen and oxygen heterocycles, such as pyrazoles, hydrazinylthiazoles, xanthones, coumarins or chromones have also been extensively used as scaffolds in medicinal chemistry programs for searching novel MAO-B inhibitors. Nitrogen derivatives play a key role in this subject with several studies pointing out hydrazines, thiazoles or indoles as important scaffolds for the development of novel MAO-B inhibitors. This review comprises an overview of the state of the art on the actual pharmacological therapy for PD followed by a specific focus on the discovery and development of nitrogen-based heterocyclic compounds analogues as promising MAO-B inhibitors.

Abstract With the ultimate purpose of finding out the structural features that are relevant for MAO inhibitory activity and selectivity towards MAO-B isoform, a series of compounds encompassing a beta-nitrostyrene moiety was designed and the in vitro inhibitory activity was evaluated. In the present work, we report the synthesis and the pharmacological evaluation of a series of functionalized derivatives of beta-methyl-beta-nitrostyrene with distinct substitution patterns in the phenyl ring, namely hydroxyl, methoxy, benzyloxy and methylenedioxy. All the studied compounds were substituted in meta and para positions of the phenyl ring related to the nitrovinyl side chain. The synthesized compounds were evaluated towards both human MAO isoforms, displaying some of them activities in the low micromolar range. Particularly compound 6 (a methylenedioxy derivative) exhibits high potency and selectivity towards MAO-B.

Abstract 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-gamma-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 IC50 values at nanomolar range. (C) 2010 Published by Elsevier Ltd.