3-Nitroatenolol: First Synthesis, Chiral Resolution and Enantiomers' Absolute Configuration.

4-Nitro and 7-nitro propranolol have been recently synthesized and characterized by us. (±)-4-NO2-propranolol has been shown to act as a selective antagonist of 6-nitrodopamine (6-ND) receptors in the right atrium of rats. As part of our follow-up to this study, herein, we describe the first synthesis of (±)-3-nitroatenolol as a probe to evaluate the potential nitration of atenolol by endothelium. Chiral chromatography was used to produce pure enantiomers. By using Riguera's method, which is based on the sign distribution of ΔδH, the absolute configuration of the secondary alcohol was determined.

Prednisone-hydrogen sulfide releasing hybrid shows improved therapeutic profile in asthma.

Introduction: Hydrogen sulfide (H2S) is emerging as an important potential therapeutic option for respiratory inflammatory diseases. In this study, we investigated the effectiveness of a novel corticosteroid derivative, that is chemically linked to an H2S donor, in managing asthma features. Methods: The effects of prednisone (PS), H2S donor (4-hydroxybenzamide; TBZ), and their combination (PS-TBZ) have been evaluated in vitro and in vivo. The in vitro experiments were conducted using lipopolysaccharidestimulated J774 macrophages, while the in vivo experiments utilizing an experimental asthma model. Results: In the in vitro study we found that PS-TBZ exhibited an increased effect compared to the individual parent compounds in modulating the production of inflammatory mediators. TBZ also significantly reduced bronchial contractility and enhanced bronchial relaxation. In the in vivo experiments, where we administered PS, TBZ, or PS-TBZ to ovalbumin-sensitized BALB/c mice, we confirmed that PS-TBZ had a significantly better action in controlling airway hyperreactivity as compared to TBZ or PS alone. Moreover, PS-TBZ was more effective in restoring salbutamol-induced relaxation. The immunohistochemistry analysis demonstrated a significant reduction in the production of α-SMA and procollagen III, indicating the efficacy of PS-TBZ in controlling airway remodeling. Moreover, PS-TBZ also promoted epithelial repair, recovery of the bronchial and parenchyma structure and inhibited mucin production. Discussion: In conclusion, PS-TBZ offers an important opportunity to optimize the beneficial impact of corticosteroids on asthma features.

Design, Synthesis and Biological Evaluation of Novel N-Arylpiperazines Containing a 4,5-Dihydrothiazole Ring.

Arylpiperazines represent one of the most important classes of 5-HT1AR ligands and have attracted considerable interests for their versatile properties in chemistry and pharmacology, leading to the research of new derivatives that has been focused on the modification of one or more portions of such pharmacophore. An efficient protocol for the synthesis of novel thiazolinylphenyl-piperazines (2a-c) and the corresponding acetylated derivatives was used (3a-c). The new compounds were tested for their functional activity and affinity at 5-HT1A receptors, showing an interesting affinity profile with a Ki value of 412 nM for compound 2b. The cytotoxic activity of novel thiazolinylphenyl-piperazines (2a-c) and corresponding N-acetyl derivatives (3a-c) against human prostate and breast cancer cell lines (LNCAP, DU-145 and PC-3, MCF-7, SKBR-3 and MDA-MB231) was investigated according to the procedure described in the literature. The reported data showed a cytotoxic effect for 2a-c and 3a-c compounds (IC50 values ranging from 15 µM to 73 µM) on the investigated cancer cell lines, with no effect on noncancer cells. Future studies will be aimed to investigate the mechanism of action and therapeutic prospects of these new scaffolds.

Beneficial Effects of Two Hydrogen Sulfide (H2S)-Releasing Derivatives of Dexamethasone with Antioxidant Activity on Atopic Dermatitis in Mice.

Hydrogen sulfide (H2S) is particularly produced in the skin, where it participates in the regulation of inflammation, pruritus, cytoprotection, scarring, and angiogenesis. In this study, we compared the effects of dexamethasone (Dex) with two H2S-releasing Dex derivatives in a murine model of atopic dermatitis (AD) induced by topical application of 2,4-dinitrochlorobenzene (DNCB). After sensitization with DNCB, the animals were topically treated for five consecutive days with either the H2S-releasing compounds 4-hydroxy-thiobenzamide (TBZ) and 5-(p-hydroxyphenyl)-1,2-dithione-3-thione (ADT-OH), Dex, or the derivatives Dex-TBZ or Dex-ADT. Topical treatment with equimolar doses of either Dex, Dex-TBZ, or Dex-ADT resulted in similar reductions in dermatitis score, scratching behavior, edema, eosinophilia, splenomegaly, and histological changes. In contrast with Dex, the H2S-releasing derivatives prevented IL-4 elevation and oxidative modification of skin proteins. On an equimolar dose basis, Dex-TBZ, but not Dex-ADT, promoted the elevation of endogenous H2S production and GPx activity. Neither Dex-TBZ nor Dex-ADT decreased GR activity or caused hyperglycemia, as observed with Dex treatment. We conclude that the presence of H2S-releasing moieties in the Dex structure does not interfere with the anti-inflammatory effects of this corticosteroid and adds beneficial therapeutical actions to the parent compound.

Measurement of 6-cyanodopamine, 6-nitrodopa, 6-nitrodopamine and 6-nitroadrenaline by LC-MS/MS in Krebs-Henseleit solution. Assessment of basal release from rabbit isolated right atrium and ventricles.

This study presents the validation of a sensitive method for the determination of 6-nitrodopa, 6-nitrodopamine, 6-nitroadrenaline and 6-cyanodopamine in Krebs-Henseleit solution by LC-MS/MS with ESI+ . HRMS was used to precisely characterize the structures of the fragment ions. The method was applied to investigate the catecholamine basal release from rabbit isolated atria and ventricles. The atria and ventricles were suspended separately in a 5 ml organ bath containing Krebs-Henseleit solution with ascorbic acid (3 mM), gassed (95%O2 /5%CO2 ) at 37°C for 30 min. Strata-X 33 µm SPE cartridges were employed for the extraction of the catecholamines and the internal standard 6-nitrodopamine-d4 . The catecholamines were separated employing a 150 × 3 mm Shim-pack GIST C18-AQ (3 mm particle size), placed in an oven at 40°C and perfused by 65% of mobile phase A (MeCN/H2 O; 90/10, v/v) + 0.4% CH3 COOH and 35% mobile phase B (deionized H2 O) + 0.2% CH2 O2 at 320 µl/min in isocratic mode. The method was linear at 0.1-20 ng/ml. The method was used to identify for the first-time basal release of the three nitrocatecholamines mentioned above and a member of a novel class of catecholamines, the cyanocatecholamines.

The Application of Microwaves, Ultrasounds, and Their Combination in the Synthesis of Nitrogen-Containing Bicyclic Heterocycles.

The use of alternative energy sources, such as microwaves (MW) or ultrasounds (US), and their mutual cross-combination have been widely described in the literature in the development of new synthetic methodologies in organic and medicinal chemistry. In this review, our attention is focused on representative examples, reported in the literature in the year range 2013-2023 of selected N-containing bicyclic heterocycles, with the aim to highlight the advantages of microwave- and ultrasound-assisted organic synthesis.

Quantitative determination of BPA, BPB, BPF and BPS levels in canned legumes from Italian market.

The levels of bisphenol A (BPA), bisphenol B (BPB), bisphenol F (BPF) and bisphenol S (BPS) were monitored in twenty-three samples of canned legumes from popular brands marketed in Italy. BPB, BPS and BPF were not detected in any samples, while BPA was found in 91 % of the samples in the concentration range 1.51-21.22 ng/mL. The risk associated with the human exposure to BPA was categorized using the Rapid Assessment of Contaminant Exposure (RACE) tool promoted by the European Food Safety Authority (EFSA). The results showed that there is no risk for any of the population groups when the current TDI value for BPA of 4 µg/kg bw/day was used as toxicological reference point. In contrast, using the new TDI value for BPA of 0.04 ng/kg bw/day, proposed by EFSA in December 2021, the existing risk was found to be real for all population groups.

Phloroglucinol-Derived Medications are Effective in Reducing Pain and Spasms of Urinary and Biliary Tracts: Results of Phase 3 Multicentre, Open-Label, Randomized, Comparative Studies of Clinical Effectiveness and Safety.

INTRODUCTION: Pain and spasms of urinary and biliary tracts are conditions causing poor quality of life. Treatment with analgesic drugs such as non-steroidal anti-inflammatory drugs and modulators of the parasympathetic system are not always tolerated, and often additional therapeutic options are necessary. The present analysis aimed to evaluate the pharmacokinetics and effectiveness of oral and parenteral preparations based on phloroglucinol in reducing pain and spasms associated with renal or biliary colic in phase 3, multicentre, open-label, randomized, comparative studies on clinical effectiveness and safety. METHODS: Pharmacokinetic and pharmacodynamic studies were carried out. Four phase 3 multicentre, open-label, randomized, comparative studies were conducted to evaluate the clinical effectiveness and safety in patients with pain and spasms of urinary or biliary tracts. Eligible patients randomly received either phloroglucinol orally or via intramuscular (IM)/intravenous (IV) administration and reference drug, dexketoprofen for urinary spasms and pain, the non-steroidal anti-inflammatory drug metamizole or scopolamine-based reference drug for biliary colic. The primary outcomes were symptoms and observed frequency of spasms, while the secondary outcome was the duration of improvement or the time between the drug administration and the recurrence of symptoms. Comparison of groups by quantitative characteristics was performed using the T-test for independent samples or the Mann-Whitney test. Intragroup comparisons were performed using the Wilcoxon test, or the T-test for linked samples. Qualitative signs were analysed using the Pearson's χ2 test and Fisher's exact test. RESULTS: The pharmacokinetic studies showed that (i) most of the phloroglucinol (> 80% for IV and per os formulations) was eliminated in the first 6 h after dosing, (ii) the drug was eliminated in urine as unchanged phloroglucinol (1,3,5-trihydroxybenzene) in a small proportion (< 3% of the dose) and (iii) a considerable amount of the drug was detected after enzymatic deconjugation with ß-glucoronidase/arylsulfatase from Helix pomatia. As for the pharmacokinetic study, a total of 364 patients were enrolled, divided in four studies: two designed to test the effectiveness of oral and IM/IV preparations in biliary colic and two in urinary colic. Baseline characteristics between groups were similar. Phloroglucinol oral or IV/IM showed an effectiveness comparable to the reference drug in reducing pain and spasms associated with both urinary and biliary colic. There was no difference between all groups by survival analysis. CONCLUSION: Oral and parenteral preparations based on phloroglucinol are as effective in reducing pain and spasms associated with renal or biliary colic as current therapeutic options. Therefore, phloroglucinol may be considered as useful to treat pain and spasms associated with urinary and biliary colic.

Design, Synthesis and Evaluation of Novel Molecular Hybrids between Antiglaucoma Drugs and H2S Donors.

Glaucoma is a group of eye diseases consisting of optic nerve damage with corresponding loss of field vision and blindness. Hydrogen sulfide (H2S) is a gaseous neurotransmitter implicated in various pathophysiological processes. It is involved in the pathological mechanism of glaucomatous neuropathy and exerts promising effects in the treatment of this disease. In this work, we designed and synthetized new molecular hybrids between antiglaucoma drugs and H2S donors to combine the pharmacological effect of both moieties, providing a heightened therapy. Brinzolamide, betaxolol and brimonidine were linked to different H2S donors. The H2S-releasing properties of the new compounds were evaluated in a phosphate buffer solution by the amperometric approach, and evaluated in human primary corneal epithelial cells (HCEs) by spectrofluorometric measurements. Experimental data showed that compounds 1c, 1d and 3d were the hybrids with the best properties, characterized by a significant and long-lasting production of the gasotransmitter both in the aqueous solution (in the presence of L-cysteine) and in the intracellular environment. Because, to date, the donation of H2S by antiglaucoma H2S donor hybrids using non-immortalized corneal cells has never been reported, these results pave the way to further investigation of the potential efficacy of the newly synthesized compounds.

Synthesis, Docking Studies and Pharmacological Evaluation of Serotoninergic Ligands Containing a 5-Norbornene-2-Carboxamide Nucleus.

A new series of 5-norbornene-2-carboxamide derivatives was prepared and their affinities to the 5-HT1A, 5-HT2A, and 5-HT2C receptors were evaluated and compared to a previously synthesized series of derivatives characterized by exo-N-hydroxy-5-norbornene-2,3-dicarboximidenucleus, in order to identify selective ligands for the above-mentioned subtype receptors. Arylpiperazines represents one of the most important classes of 5-HT1AR ligands, and recent research concerning new derivatives has been focused on the modification of one or more portions of such pharmacophore. The combination of structural elements (heterocyclic nucleus, propyl chain and 4-substituted piperazine), known to be critical to the affinity to 5-HT1A receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. The most active compounds were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that Norbo-4 and Norbo-18 were the most active and promising derivatives for the serotonin receptor considered in this study.

H2S donating corticosteroids: Design, synthesis and biological evaluation in a murine model of asthma.

Introduction: Hydrogen sulfide (H2S) is a fundamental biological endogenous gas-mediator in the respiratory system. It regulates pivotal patho-physiological processes such as oxidative stress, pulmonary circulation, airway tone and inflammation. Objectives: We herein describe the design and synthesis of molecular hybrids obtained by the condensation of several corticosteroids with different hydrogen sulfide releasing moieties. Methods: All the molecules are characterized for their ability to release H2S both via amperometric approach and using a fluorescent probe. The chemical stability of the newly synthesized hybrid molecules has been investigated at differing pH values and in human serum. Results: Prednisone-TBZ hybrid (compound 7) was selected for further evaluations. The obtained results from the in vitro and in vivo studies clearly show evidence in favor of the anti-inflammatory properties of the released H2S. Conclusions: The protective effect on airway remodeling makes the hybrid Prednisone-TBZ (compound 7) as a promising therapeutic option in reducing allergic asthma symptoms and exacerbations.

Na+/Ca2+ exchanger isoform 1 takes part to the Ca2+-related prosurvival pathway of SOD1 in primary motor neurons exposed to beta-methylamino-L-alanine.

BACKGROUND: The cycad neurotoxin beta-methylamino-L-alanine (L-BMAA), one of the environmental trigger factor for amyotrophic lateral sclerosis/Parkinson-dementia complex (ALS/PDC), may cause neurodegeneration by disrupting organellar Ca2+ homeostasis. Through the activation of Akt/ERK1/2 pathway, the Cu,Zn-superoxide dismutase (SOD1) and its non-metallated form, ApoSOD1, prevent endoplasmic reticulum (ER) stress-induced cell death in motor neurons exposed to L-BMAA. This occurs through the rapid increase of intracellular Ca2+ concentration ([Ca2+]i) in part flowing from the extracellular compartment and in part released from ER. However, the molecular components of this mechanism remain uncharacterized. METHODS: By an integrated approach consisting on the use of siRNA strategy, Western blotting, confocal double- labeling immunofluorescence, patch-clamp electrophysiology, and Fura 2-/SBFI-single-cell imaging, we explored in rat motor neuron-enriched cultures the involvement of the plasma membrane proteins Na+/Ca2+ exchanger (NCX) and purinergic P2X7 receptor as well as that of the intracellular cADP-ribose (cADPR) pathway, in the neuroprotective mechanism of SOD1. RESULTS: We showed that SOD1-induced [Ca2+]i rise was prevented neither by A430879, a P2X7 receptor specific antagonist or 8-bromo-cADPR, a cell permeant antagonist of cADP-ribose, but only by the pan inhibitor of NCX, CB-DMB. The same occurred for the ApoSOD1. Confocal double labeling immunofluorescence showed a huge expression of plasmalemmal NCX1 and intracellular NCX3 isoforms. Furthermore, we identified NCX1 reverse mode as the main mechanism responsible for the neuroprotective ER Ca2+ refilling elicited by SOD1 and ApoSOD1 through which they promoted translocation of active Akt in the nuclei of a subset of primary motor neurons. Finally, the activation of NCX1 by the specific agonist CN-PYB2 protected motor neurons from L-BMAA-induced cell death, mimicking the effect of SOD1. CONCLUSION: Collectively, our data indicate that SOD1 and ApoSOD1 exert their neuroprotective effect by modulating ER Ca2+ content through the activation of NCX1 reverse mode and Akt nuclear translocation in a subset of primary motor neurons. Video Abstract.

Synthesis, Chiral Resolution and Enantiomers Absolute Configuration of 4-Nitropropranolol and 7-Nitropropranolol.

We recently identified 6-nitrodopamine and other nitro-catecholamines (6-nitrodopa, 6-nitroadrenaline), indicating that the endothelium has the ability to nitrate the classical catecholamines (dopamine, noradrenaline, and adrenaline). In order to investigate whether drugs could be subject to the same nitration process, we synthesized 4-nitro- and 7-nitropropranolol as probes to evaluate the possible nitration of the propranolol by the endothelium. The separation of the enantiomers in very high yields and excellent enantiopurity was achieved by chiral HPLC. Finally, we used Riguera's method to determine the absolute configuration of the enantiomers, through double derivatization with MPA and NMR studies.

H2S Donors and Their Use in Medicinal Chemistry.

Hydrogen sulfide (H2S) is a ubiquitous gaseous signaling molecule that has an important role in many physiological and pathological processes in mammalian tissues, with the same importance as two others endogenous gasotransmitters such as NO (nitric oxide) and CO (carbon monoxide). Endogenous H2S is involved in a broad gamut of processes in mammalian tissues including inflammation, vascular tone, hypertension, gastric mucosal integrity, neuromodulation, and defense mechanisms against viral infections as well as SARS-CoV-2 infection. These results suggest that the modulation of H2S levels has a potential therapeutic value. Consequently, synthetic H2S-releasing agents represent not only important research tools, but also potent therapeutic agents. This review has been designed in order to summarize the currently available H2S donors; furthermore, herein we discuss their preparation, the H2S-releasing mechanisms, and their -biological applications.

New Insights into the Structure-Activity Relationship and Neuroprotective Profile of Benzodiazepinone Derivatives of Neurounina-1 as Modulators of the Na+/Ca2+ Exchanger Isoforms.

Due to the neuroprotective role of the Na+/Ca2+ exchanger (NCX) isoforms NCX1 and NCX3, we synthesized novel benzodiazepinone derivatives of the unique NCX activator Neurounina-1, named compounds 1-19. The derivatives are characterized by a benzodiazepinonic nucleus linked to five- or six-membered cyclic amines via a methylene, ethylene, or acetyl spacer. The compounds have been screened on NCX1/NCX3 isoform activities by a high-throughput screening approach, and the most promising were characterized by patch-clamp electrophysiology and Fura-2AM video imaging. We identified two novel modulators of NCX: compound 4, inhibiting NCX1 reverse mode, and compound 14, enhancing NCX1 and NCX3 activity. Compound 1 displayed neuroprotection in two preclinical models of brain ischemia. The analysis of the conformational and steric features led to the identification of the molecular volume required for selective NCX1 activation for mixed NCX1/NCX3 activation or for NCX1 inhibition, providing the first prototypal model for the design of optimized isoform modulators.

Antagonizing S1P3 Receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis.

S1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P1-5). Increasing numbers of studies have indicated the importance of S1P3 in various pathophysiological processes. Recently, we have identified a pepducin (compound KRX-725-II) acting as an S1P3 receptor antagonist. Here, aiming to optimize the activity and selectivity profile of the described compound, we have synthesized a series of derivatives in which Tyr, in position 4, has been substituted with several natural aromatic and unnatural aromatic and non-aromatic amino acids. All the compounds were evaluated for their ability to inhibit vascular relaxation induced by KRX-725 (as S1P3 selective pepducin agonist) and KRX-722 (an S1P1-selective pepducin agonist). Those selective towards S1P3 (compounds V and VII) were also evaluated for their ability to inhibit skeletal muscle fibrosis. Finally, molecular dynamics simulations were performed to derive information on the preferred conformations of selective and unselective antagonists.

Hybrids between H2S-donors and betamethasone 17-valerate or triamcinolone acetonide inhibit mast cell degranulation and promote hyperpolarization of bronchial smooth muscle cells.

Glucocorticoids represent the standard gold treatment of inflammation in asthmatic patients. More recently, H2S has been described to exert positive effect on this disease. Bearing in mind that an improved pharmacological activity and a reduced toxicity can be obtained through hybridization of different molecules, simultaneously modulating multiple targets, we designed and synthesized novel betamethasone 17-valerate and triamcinolone acetonide hybrids with well-known H2S-donor moieties. Synthesized compounds have been evaluated for the potential H2S-releasing profile both in cell-free environment and into the cytosol of bronchial smooth muscle cells (BSMCs). The two hybrids 4b and 5b were investigated by molecular modelling studies and results indicated that the steric accessibility of the isothiocyanate carbon atom can account for their different H2S releasing properties. Furthermore, the most promising derivatives 4b and 5b have been tested for inhibitory effect on mast cell degranulation and for the ability to induce cell membrane hyperpolarization in BSMCs. Significant inhibitory effect on mast cell degranulation was assessed, resulting to reduce ß-hexosaminidase release more efficiently than the corresponding native drugs. Both compounds determined a massive membrane hyperpolarization of BSMCs and proved to be 4-fold more effective compared to reference compound NS1619. These effects represent an enrichment of the pharmacological activity of the native drugs.

Trends in H2S-Donors Chemistry and Their Effects in Cardiovascular Diseases.

Hydrogen sulfide (H2S) is an endogenous gasotransmitter recently emerged as an important regulatory mediator of numerous human cell functions in health and in disease. In fact, much evidence has suggested that hydrogen sulfide plays a significant role in many physio-pathological processes, such as inflammation, oxidation, neurophysiology, ion channels regulation, cardiovascular protection, endocrine regulation, and tumor progression. Considering the plethora of physiological effects of this gasotransmitter, the protective role of H2S donors in different disease models has been extensively studied. Based on the growing interest in H2S-releasing compounds and their importance as tools for biological and pharmacological studies, this review is an exploration of currently available H2S donors, classifying them by the H2S-releasing-triggered mechanism and highlighting those potentially useful as promising drugs in the treatment of cardiovascular diseases.

Synthesis, docking studies, and pharmacological evaluation of 2-hydroxypropyl-4-arylpiperazine derivatives as serotoninergic ligands.

A new series of norbornene and exo-N-hydroxy-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide derivatives was prepared, and their affinities to the 5-HT1A , 5-HT2A , and 5-HT2C receptors were evaluated and compared with a previously synthesized series of derivatives characterized by the same nuclei, to identify selective ligands for the subtype receptors. Arylpiperazines represent one of the most important classes of 5-HT1A R ligands, and the research of new derivatives has been focused on the modification of one or more portions of this pharmacophore. The combination of structural elements (heterocyclic nucleus, hydroxyalkyl chain, and 4-substituted piperazine), known to be critical for the affinity to 5-HT1A receptors, and the proper selection of substituents resulted in compounds with high specificity and affinity toward serotoninergic receptors. The most active compounds were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that 3e, 4j, and 4n were the most active and promising derivatives for the serotonin receptor considered in this study.

Structure-activity relationships study of isothiocyanates for H2S releasing properties: 3-Pyridyl-isothiocyanate as a new promising cardioprotective agent.

INTRODUCTION: The gasotransmitter hydrogen sulphide (H2S), an endogenous ubiquitous signalling molecule, is known for its beneficial effects on different mammalian systems. H2S exhibits cardioprotective activity against ischemia/reperfusion (I/R) or hypoxic injury. METHODS: A library of forty-five isothiocyanates, selected for their different chemical properties, has been evaluated for its hydrogen sulfide (H2S) releasing capacity. The obtained results allowed to correlate several factors such as steric hindrance, electronic effects and position of the substituents to the observed H2S production. Moreover, the chemical-physical profiles of the selected compounds have been studied by an in silico approach and from a combination of the obtained results, 3-pyridyl-isothiocyanate (25) has been selected as the most promising one. A detailed pharmacological characterization of its cardioprotective action has been performed. RESULTS: The results herein obtained strongly indicate 3-pyridyl-isothiocyanate (25) as a suitable pharmacological option in anti-ischemic therapy. The cardioprotective effects of compound 25 were tested in vivo and found to exhibit a positive effect. CONCLUSION: Results strongly suggest that isothiocyanate-based H2S-releasing drugs, such as compound 25, can trigger a ''pharmacological pre-conditioning" and could represent a suitable pharmacological option in antiischemic therapy.