Exploring the biological consequences of conformational changes in aspartame models containing constrained analogues of phenylalanine

<p>The dipeptide aspartame (Asp-Phe-OMe) is a sweetener widely used in replacement of sucrose by food industry. 2′,6′-Dimethyltyrosine (DMT) and 2′,6′-dimethylphenylalanine (DMP) are two synthetic phenylalanine-constrained analogues, with a limited freedom in χ-space due to the presence of methyl groups in position 2′,6′ of the aromatic ring. These residues have shown to increase the activity of opioid peptides, such as endomorphins improving the binding to the opioid receptors. In this work, DMT and DMP have been synthesized following a diketopiperazine-mediated route and the corresponding aspartame derivatives (Asp-DMT-OMe and Asp-DMP-OMe) have been evaluated <i>in vivo</i> and <i>in silico</i> for their activity as synthetic sweeteners.</p

Inhibition of Human Monoamine Oxidase: Biological and Molecular Modeling Studies on Selected Natural Flavonoids

Naturally occurring flavonoids display a plethora of different biological activities, but emerging evidence suggests that this class of compounds may also act as antidepressant agents endowed with multiple mechanisms of action in the central nervous system, increasing central neurotransmission, limiting the reabsorption of bioamines by synaptosomes, and modulating the neuroendocrine and GABA_A systems. Due to their presence in foods, food-derived products, and nutraceuticals, we established their role and structure–activity relationships as reversible and competitive human monoamine oxidase (MAO) inhibitors. In addition, molecular modeling studies, which evaluated their modes of MAO inhibition, are presented. These findings could provide pivotal implications in the quest of novel drug-like compounds and for the establishment of harmful drug–dietary supplement interactions commonly reported in the therapy with antidepressant agents

Identification of new anti-<i>Candida</i> compounds by ligand-based pharmacophore virtual screening

<p><i>Candida albicans</i> represents the most prevalent microbial population in mucosal and systemic infections, usually confined to severely immunocompromised people. Considering the increase of resistant strains and the demand for new antifungal drugs endowed with innovative mechanism of action, we performed a ligand-based virtual screening in order to identify new anti-<i>Candida</i> compounds. Starting from a large library of natural/semisynthetic products and several published synthesized compounds, three coumarin derivatives were discovered <i>in silico</i> as new hit compounds and submitted to the <i>in vitro</i> assay in order to confirm their predicted biological activity.</p

Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase‑B Efficiently Protect against Amyloid-β-Induced Neuronal Toxicity, Oxidative Stress, and Mitochondrial Dysfunction

We report here the first dual inhibitors of brain carbonic anhydrases (CAs) and monoamine oxidase-B (MAO-B) for the management of Alzheimer’s disease. Classical CA inhibitors (CAIs) such as methazolamide prevent amyloid-β-peptide (Aβ)-induced overproduction of reactive oxygen species (ROS) and mitochondrial dysfunction. MAO-B is also implicated in ROS production, cholinergic system disruption, and amyloid plaque formation. In this work, we combined a reversible MAO-B inhibitor of the coumarin and chromone type with benzenesulfonamide fragments as highly effective CAIs. A hit-to-lead optimization led to a significant set of derivatives showing potent low nanomolar inhibition of the target brain CAs (KIs in the range of 0.1–90.0 nM) and MAO-B (IC50 in the range of 6.7–32.6 nM). Computational studies were conducted to elucidate the structure–activity relationship and predict ADMET properties. The most effective multitarget compounds totally prevented Aβ-related toxicity, reverted ROS formation, and restored the mitochondrial functionality in an SH-SY5Y cell model surpassing the efficacy of single-target drugs

Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase‑B Efficiently Protect against Amyloid-β-Induced Neuronal Toxicity, Oxidative Stress, and Mitochondrial Dysfunction

We report here the first dual inhibitors of brain carbonic anhydrases (CAs) and monoamine oxidase-B (MAO-B) for the management of Alzheimer’s disease. Classical CA inhibitors (CAIs) such as methazolamide prevent amyloid-β-peptide (Aβ)-induced overproduction of reactive oxygen species (ROS) and mitochondrial dysfunction. MAO-B is also implicated in ROS production, cholinergic system disruption, and amyloid plaque formation. In this work, we combined a reversible MAO-B inhibitor of the coumarin and chromone type with benzenesulfonamide fragments as highly effective CAIs. A hit-to-lead optimization led to a significant set of derivatives showing potent low nanomolar inhibition of the target brain CAs (KIs in the range of 0.1–90.0 nM) and MAO-B (IC50 in the range of 6.7–32.6 nM). Computational studies were conducted to elucidate the structure–activity relationship and predict ADMET properties. The most effective multitarget compounds totally prevented Aβ-related toxicity, reverted ROS formation, and restored the mitochondrial functionality in an SH-SY5Y cell model surpassing the efficacy of single-target drugs

Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase‑B Efficiently Protect against Amyloid-β-Induced Neuronal Toxicity, Oxidative Stress, and Mitochondrial Dysfunction

We report here the first dual inhibitors of brain carbonic anhydrases (CAs) and monoamine oxidase-B (MAO-B) for the management of Alzheimer’s disease. Classical CA inhibitors (CAIs) such as methazolamide prevent amyloid-β-peptide (Aβ)-induced overproduction of reactive oxygen species (ROS) and mitochondrial dysfunction. MAO-B is also implicated in ROS production, cholinergic system disruption, and amyloid plaque formation. In this work, we combined a reversible MAO-B inhibitor of the coumarin and chromone type with benzenesulfonamide fragments as highly effective CAIs. A hit-to-lead optimization led to a significant set of derivatives showing potent low nanomolar inhibition of the target brain CAs (KIs in the range of 0.1–90.0 nM) and MAO-B (IC50 in the range of 6.7–32.6 nM). Computational studies were conducted to elucidate the structure–activity relationship and predict ADMET properties. The most effective multitarget compounds totally prevented Aβ-related toxicity, reverted ROS formation, and restored the mitochondrial functionality in an SH-SY5Y cell model surpassing the efficacy of single-target drugs

Analysis of imidazoles and triazoles in biological samples after MicroExtraction by packed sorbent

<p>This paper reports the MEPS-HPLC-DAD method for the simultaneous determination of 12 azole drugs (bifonazole, butoconazole, clotrimazole, econazole, itraconazole, ketoconazole, miconazole, posaconazole, ravuconazole, terconazole, tioconazole and voriconazole) administered to treat different systemic and topical fungal infections, in biological samples. Azole drugs separation was performed in 36 min. The analytical method was validated in the ranges as follows: 0.02–5 μg mL⁻¹ for ravuconazole; 0.2–5 μg mL⁻¹ for terconazole; 0.05–5 μg mL⁻¹ for the other compounds. Human plasma and urine were used as biological samples during the analysis, while benzyl-4-hydroxybenzoate was used as an internal standard. The precision (RSD%) and trueness (Bias%) values fulfill with International Guidelines requirements. To the best of our knowledge, this is the first HPLC-DAD procedure coupled to MEPS, which provides the simultaneous analysis of 12 azole drugs, available in the market, in human plasma and urine. Moreover, the method was successfully applied for the quantitative determination of two model drugs (itraconazole and miconazole) after oral administration in real samples.</p

Synthesis and biological evaluation of anti-<i>Toxoplasma gondii</i> activity of a novel scaffold of thiazolidinone derivatives

<p>We designed and synthesised novel <i>N</i>-substituted 1,3-thiazolidin-4-one derivatives for the evaluation of their anti-<i>Toxoplasma gondii</i> efficacy. This scaffold was functionalised both at the N1-hydrazine portion with three structurally different moieties and at the lactam nitrogen with substituted benzyl groups selected on the basis of our previous structure-activity relationships studies. Using three different assay methods, the compounds were assessed <i>in vitro</i> to determine both the levels of efficacy against the tachyzoites of <i>T. gondii</i> (IC₅₀ = 5–148 μM), as well as any evidence of cytotoxicity towards human host cells (TD₅₀ = 68 to ≥320 μM). Results revealed that ferrocene-based thiazolidinones can possess potent anti-tachyzoite activity (TI =2–64).</p

Kaempferol as Selective Human MAO‑A Inhibitor: Analytical Detection in Calabrian Red Wines, Biological and Molecular Modeling Studies

The purpose of this work was to determine the kaempferol content in three red wines of Calabria, a southern Italian region with a great number of certified food products. Considering that wine cultivar, climate, and soil influence the qualitative and quantitative composition in flavonoids of Vitis vinifera L. berries, the three analyzed samples were taken from the 2013 vintage. Moreover, the Gaglioppo samples, with assigned Controlled Origin Denomination (DOC), were also investigated in the production of years 2008, 2010, and 2011. In addition to the analysis of kaempferol, which is present in higher concentration than in other Italian wines, in vitro assays were performed to evaluate, for the first time, the inhibition of the human monoamine oxidases (hMAO-A and hMAO-B). Molecular recognition studies were also carried out to provide insight into the binding mode of kaempferol and selectivity of inhibition of the hMAO-A isoform

Microwave-assisted extraction, HPLC analysis, and inhibitory effects on carbonic anhydrase I, II, VA, and VII isoforms of 14 blueberry Italian cultivars

<p>The multi-component fingerprint and the biological evaluation of plant-derived material are indispensable for the pharmaceutical field, in food quality control procedures, and in all plant-based products. We investigated the quantitative content of biologically active compounds (anthocyanins and chlorogenic acid) of microwave-assisted blueberry extracts from 14 different Italian cultivars, using validated high-performance liquid chromatography-photodiode array detector (HPLC-PDA) method and routinely instrument configuration. The carbonic anhydrase (CA, EC 4.2.1.1) inhibition profiles against several pharmacologically relevant CA isoforms of blueberry extracts and some bioactive compounds were also investigated. The various cultivars showed a highly variable content in anthocyanins and chlorogenic acid, and their CA inhibitory effects were also highly variable. Overall these data prove that antioxidant natural products found in blueberries may be useful for designing pharmacological agents in which various CAs are involved, e.g., antiobesity, antitumor, or anticonvulsants agents.</p