Antiaggregatory Activity Research Articles

Поиск фармакологически активных соединений 2-диалкиламинобензимидазолов

Нагреванием замещенных бензимидазол-2-сульфокислот в избытке вторичных аминов получены диалкиламинобензимидазолы. В результате экспериментального изучения возможного наличия антиаритмической, антиагрегантной, гемореологической, AT1-ангиотензиновой, NHE-1-ингибирующей и антисеротониновой активности выявлены активные соединения. 1-[2-(5-Метил)бензимидазол]пирролидин превосходит по NHE-ингибирующей активности зонипорид. Дигидрохлорид 1-{[2-(5-метокси)бензимидазол]-4-n-метил}пиперазина превосходит по антиагрегантному действию ацетилсалициловую кислоту 1-[2-(5-метил)бензимидазол]пиперидин соответствует по уровню 5-HT2А- антагонистической активности ципрогептадину. Для дигидрохлорида 1-(2-бензимидазол)пирролидина и 1-[2-(5-хлор)бензимидазол]пирролидина характерна 5-HT3-антагонистическая активность, равная трописетрону.

Buddleja globosa (matico) prevents collagen-induced platelet activation by decreasing phospholipase C-gamma 2 and protein kinase C phosphorylation signaling

Platelets play a key role in thrombosis and cardiovascular diseases. Medicinal plants could be one of the most important factors that influence risks for platelet activation. Buddleja globosa (known as “matico”) is a medicinal plant with many biological activities. The high content of polyphenols suggest that matico could have antiplatelet activity. The present study was aimed at evaluating mechanisms of antiplatelet action of an extract of matico. We demonstrated that matico extract at low concentrations and in a concentration dependent manner (0.05–1 mg/mL) was a potent inhibitor of platelet aggregation in response to collagen, convulsion and ADP (IC50 values was 61 μg/mL, 72 μg/mL and 290 μg/mL, respectively). In this sense matico extract exerted the greatest antiaggregant activity induced by collagen. Similarly, matico showed a decrease in % of positive platelet for P-selectina (vehicle, 0.01, 0.05, 0.1, 0.5 and 1 mg/mL were 32 ± 2%, 29 ± 2 (p < 0.05), 19 ± 1 (p < 0.01), 15 ± 2 (p < 0.01), 10 ± 1% (p < 0.01) and 7 ± 2% (p < 0.01), respectively) and PAC-1 binding (vehicle, 0.01, 0.05, 0.1, 0.5 and 1 mg/mL were 59 ± 1, 58 ± 3 (n.s), 55 ± 2 (p < 0.05), 50 ± 2 (p < 0.01), 38 ± 1 (p < 0.01), 36 ± 2 (p < 0.01). The cellular mechanism for the antiplatelet activity of matico might be mediated by the inhibition of phospholipase C-gamma 2 and protein kinase C phosphorylation. This beneficial property of matico may be of importance in thrombosis, in which platelet activation and aggregation are important determinants of thrombus initiation and development, and may contribute to the beneficial effects of matico intake in the prevention of cardiovascular diseases.

New insight into the antiaggregant activity of furoxans

The measurement of the antiaggregant properties of 3-cyano-4-phenylfuroxan and 3-nitro-4-phenylfuroxan has demonstrated that these compounds effectively inhibit platelet agglutination induced by adenosine diphosphate and adrenaline but not ristocetin. When collagen was used as an inducer, only a slight delay of aggregate formation was observed. Therefore, these furoxan derivatives could be considered as a basis for the development of next generation agents with improved antiaggregant activity.

Phytochemistry Profile, Nutritional Properties and Pharmacological Activities of Mauritia flexuosa.

Mauritia flexuosa L. (Arecaceae) is a popular Brazilian fruit known as "buriti" and belonging to the category of functional foods. This work reviewed the phytochemistry profile, nutritional and pharmacological activities of M. flexuosa. The main bioactive compounds reported to buriti were carotenoids, tocopherols, ascorbic acid, phenolic compounds, fiber, phytosterols, and mono- and poly-unsaturated fatty acids. These compounds were mainly related to antioxidant, hypolipemiant, photoprotector, antiaggregant, antithrombotic, anti-inflammatory, hypoglycemiant, antimicrobial, and antitumor activities. Furthermore, some compounds present in buriti fruit and its properties were tested in vitro and in vivo and showed biotechnology applications, especially for extraction of fiber, polysaccharides, pigments, antioxidants, and oil. Howerer, the buriti fruit shows great relevance to the development of new products in food, pharmaceutical and chemical industry, this fruit is still underexploited and it has need to expand its production chain and processing to encourage their consumption and utilization.

Polyamine Conjugation as a Promising Strategy To Target Amyloid Aggregation in the Framework of Alzheimer's Disease.

Spermine conjugates 2–6, carrying variously decorated 3,5-dibenzylidenepiperidin-4-one as bioactive motives, were designed to direct antiaggregating properties into mitochondria, using a polyamine functionality as the vehicle tool. The study confirmed mitochondrial import of the catechol derivative 2, which displayed effective antiaggregating activity and neuroprotective effects against Aβ-induced toxicity. Notably, a key functional role for the polyamine motif in Aβ molecular recognition was also unraveled. This experimental readout, which was supported by in silico studies, gives important new insight into the polyamine’s action. Hence, we propose polyamine conjugation as a promising strategy for the development of neuroprotectant leads that may contribute to decipher the complex picture of Aβ toxicity.

ChemInform Abstract: Cyclodextrins as Protective Agents of Protein Aggregation: An Overview

AbstractReview: 72 refs.

Design, synthesis, and evaluation of Trolox-conjugated amyloid-β C-terminal peptides for therapeutic intervention in an in vitro model of Alzheimer’s disease

Two hallmarks of Alzheimer’s disease (AD) observed in the brains of patients with the disease include oxidative injury and deposition of protein aggregates comprised of amyloid-β (Aβ) variants. To inhibit these toxic processes, we synthesized antioxidant-conjugated peptides comprised of Trolox and various C-terminal motifs of Aβ variants, TxAβx–n (x=34, 36, 38, 40; n=40, 42, 43). Most of these compounds were found to exhibit anti-aggregation activities. Among them, TxAβ36–42 significantly inhibited Aβ1–42 aggregation, showed potent antioxidant activity, and protected SH-SY5Y cells from Aβ1–42-induced cytotoxicity. Thus, this method represents a promising strategy for developing multifunctional AD therapeutic agents.

Mechanistic study of the inhibitory activity of Geum urbanum extract against α-Synuclein fibrillation

The presence of Lewy bodies and Lewy neurites is a major pathological hallmark of Parkinson's disease and is hypothesized to be linked to disease development, although this is not yet conclusive. Lewy bodies and Lewy neurites primarily consist of fibrillated α-Synuclein; yet, there is no treatment available targeting stabilization of α-Synuclein in its native state. The aim of the present study was to investigate the inhibitory activity of an ethanolic extract of Geum urbanum against α-Synuclein fibrillation and examine the structural changes of α-Synuclein in the presence of the extract. The anti-fibrillation and anti-aggregation activities of the plant extract were monitored by thioflavin T fibrillation assays and size exclusion chromatography, while structural changes were followed by circular dichroism, Fourier transform infrared spectroscopy, intrinsic fluorescence, small angle X-ray scattering and electron microscopy. Since the extract is a complex mixture, structure-function relationships could not be determined. Under the experimental conditions investigated, Geum urbanum was found to inhibit α-Synuclein fibrillation in a concentration dependent way, and to partly disintegrate preformed α-Synuclein fibrils. Based on the structural changes of α-Synuclein in the presence of extract, we propose that Geum urbanum delays α-Synuclein fibrillation either by reducing the fibrillation ability of one or more of the aggregation prone intermediates or by directing α-Synuclein aggregation towards a non-fibrillar state. However, whether these alterations of the fibrillation pathway lead to less pathogenic species is yet to be determined.

Антиагрегантная активность нового трициклического производного 2,3,4,5-тетрагидро[1,3]диазепино[1,2-&lt;i&gt;a&lt;/i&gt;]бензимидазола

Изучена острая токсичность и антиагрегантная активность нового производного бензимидазола — 2,3,4,5-тетрагидро[1,3]диазепино[1,2-a]бензимидазола (ДАБ-15) — на модели АДФ, адреналин и коллаген-индуцированной агрегации тромбоцитов in vitro. Соединение ДАБ-15 оказало дозозависимое антиагрегантное действие и на модели АДФ-индуцированной агрегации тромбоцитов по EC50 превосходило ацетилсалициловую кислоту и незначительно уступало тиклопидину. В отношении агрегации тромбоцитов, вызванной коллагеном и адреналином, соединение ДАБ-15 по EC50 достоверно превосходило препараты сравнения.

Cyclodextrins as Protective Agents of Protein Aggregation: An Overview.

Cyclodextrins are extensively used in different fields (e.g., catalysis, chromatography, pharma, supramolecular chemistry, bioorganic chemistry, and bioinorganic chemistry), and their applications have been widely reviewed. Their main application in the field of pharmaceutical is as a drug carrier. This review overviews, for the first time, the use of cyclodextrins and their derivatives as antiaggregant agents in a number of proteins (e.g., amyloid-β, insulin, recombinant human growth hormone, prion protein, transthyretin, and α-synuclein) and some multimeric enzymes. There are many diseases that are correlated to protein misfolding and amyloid formation processes affecting numerous organs and tissues. There are over 30 different amyloid proteins and a number of corresponding diseases. Alzheimer's disease is the most common neurodegenerative disease. Treatment of these diseases is still a goal to reach, and many molecules are studied in this perspective. Cyclodextrins have also been studied, and they show great potential; as such, further studies could be very promising. This review aims to be a stimulus for the design of new cyclodextrin derivatives to obtain multifunctional systems with antiaggregant activity.

Tropoxin – Drug for the Treatment of Migraine

Anew antimigraine drug – Tropoxin (3-(3,4,5-trimethoxybenzoyloxyimino)-8-methyl-8-azabicyclo[1–3]octane hydrochloride) – was developed and was found to prevent or significantly weaken the constrictor reactions of cerebral arteries evoked by serotonin (5-HT) or the 5-HT2B/2C receptor agonist meta-chlorophenylpiperazine (m-CPP) in intact animals and in animals with ischemic brain damage. Tropoxin showed affinity for5-HT2 receptors in the brain and had antiaggregatory actions. It had no marked neurotropic properties and did not alter blood pressure responses to noradrenaline, acetylcholine, or histamine. Pilot clinical trials of Tropoxin provided evidence that it has high efficacy in the interictal treatment of frequent and severe migraine attacks.

Thin-layer chromatographic identification of flavonoids and phenolic acids contained in cosmetic raw materials

ABSTRACTPolyphenols, widespread in the kingdom of plants, are targeted in numerous chemical, biochemical, and clinical studies. Flavonoids make a particularly interesting group of polyphenols due to their diverse biological activities. In both in vivo and in vitro studies, they strongly demonstrate antioxidant, anti-inflammatory, anticancer, and anti-aggregation activities, and they are also known for tightening the capillary blood vessels. Due to their remarkable biological activities, flavonoids find a wide spectrum of practical applications and the botanical materials rich in flavonoids are omnipresent in traditional medicines, phytotherapy, pharmacotherapy, and cosmetics. Particularly attractive biological properties and, hence, considerable valor of the cosmetics are attributed to such flavonoids, as rutin, quercetin, naringenin, catechin, catechin hydrate, and apigenin. In our study, we selected a simple and cost-friendly thin-layer chromatographic technique to identify the aforementioned flavonoids, and also caffeic, ferulic, gallic, and coumaric acids, in the commercially available cosmetic raw materials (such as extracts derived from red wine, grape skins, pomegranate peels and juice, green tea, etc.) Quercetin and rutin proved to be the two flavonoids most frequently encountered in the examined cosmetic raw materials. The results of such investigations provide the phenolics-oriented evaluation of the quality of the cosmetic raw materials and, hence, better judgment on the applicability thereof, e.g., as components of specific cosmetics prepared to treat various skin problems.

Synthesis, biological evaluation and molecular docking studies of 2-piperazin-1-yl-quinazolines as platelet aggregation inhibitors and ligands of integrin αIIbβ3

A series of 2-piperazin-1-yl-quinazolines were synthesized and evaluated for their antiaggregative activity. The synthesized small molecule compounds have potently inhibited platelet aggregation in vitro and blocked FITC-Fg binding to αIIbβ3 integrin in a suspension of washed human platelets. The key αIIbβ3 protein–ligand interactions were determined in docking experiments and some correlations have been observed between values of the affinity and docking scores.

1-Substituted 2-Benzylaminobenzimidazoles with Phenyl Methoxyls: Synthesis, Computer Prediction, and Pharmacological Activity

Condensation of 1-substituted 2-aminobenzimidazoles with aromatic aldehydes produced the corresponding azomethines, reduction of which by sodium borohydride afforded 1-substituted 2-benzylaminobenzimidazoles. The Microcosm information technology (IT) tool was used to assess in silico the potential for antiarrhythmic, antiaggregant, antioxidant, hemorheologic, and antiglycating activity in this series of compounds. Pharmacological screening identified which of the synthesized compounds were active. It was shown that the computer predictions correlated with the experimental data.

Design and Synthesis of Non-peptide RGD Mimics for Evaluation of Their Utility as Anti-platelet Agents.

Arg-Gly-Asp (RGD) mimics were synthesized and their anti-platelet activity was evaluated. A concise method was developed for the synthesis of the target compounds from dehydroepiandrosterone and Wieland-Miescher and Hajos-Parrish ketones, which are suitable for readily available platform. Among the synthesized compounds, the perhydronaphthalene framework with a 3-(4-piperidinyl)propoxyl structure 3e possessed the highest anti-aggregative activity. The IC50 values of 3e were 0.91 mM (ADP initiation) and 0.54 mM (collagen initiation).

Вплив Lys-плазміногену на секрецію тромбоцитів людини

The effects of Lys-plasminoge on platelet α-granule secretion were studied. The level of P-selectin exposed on the surface of plasma membranes of washed human platelets was measured by flow cytometry as a market of α-granule secretion. It was shown that Lys-plasminogen facilitates partial release of α-granules, but impedes thrombin-induced platelet exocytosis. It is suggested that Lys-plasminogen may affect platelet secretion rather through interaction of its non-catalytic (kringle) domains with membrane receptors than due to contaminating plasmin activity. In contrast to Lys-form, native proenzyme (Glu-plasminogen) had no effects on α-granule releasing. Here, we provide the first experimental demonstration that Lys-form of plasminogen is able to modulate platelet α-granule secretion, and this effect can be considered as one of the plausible mechanisms of its anti-aggregating activity.

The search of compounds with antiaggregation activity among S-esters of thiosulfonic acids

According to the current understanding, the hyperactivation of platelets may lead to increased intravascular coagulation and thrombosis. Today a relevant issue is the search for new anti-thrombotic agents that are able to modulate the activity of platelet receptors, thus, influence the processes of activation and aggregation of platelets. The aim of this study was to investigate the effects of newly synthesized thiosulfonate derivatives on platelet aggregation. The activity of the compounds was tested in vitro using platelet-rich plasma. As a result of the screening test, structural formulas of four agents with high antiaggregative activity were established. These compounds inhibited ADP- and collagen-induced platelet aggregation in a dose-dependent manner. Two of these compounds were shown to be more effective inhibitors of aggregation induced by ADP (IC50 - 8-10 μM), as well as collagen (IC50 - 1.5-2.0 μM).

Anti-aggregant activity of new xanthine derivative under conditions of hyper aggregation of platelets in vitro

Aim. To study the anti-aggregant activity and the effectiveness of firstly synthesized cyclohexilammonium salt of 2-[1-ethil-3-methyl-7-(dioxotiethanyl-3)-xantinyl-8-thio]acetic acid as a potential antiplatelet agent under in vitro conditions.&#x0D; Methods. Experimental work was carried out on the blood of healthy donors and 74 male patients diagnosed with thrombosis of various localization. Thromboelastography of citrate blood samples was performed in the presence of the test substances on the device TEG 5000. The analysis determined the overall trend of coagulation, functional activity of platelets and fibrinogen, fibrinolytic activity and physico-mechanical properties of clots formed. ADP-, collagen-, and epinephrine-induced platelet aggregations were registered. Agregatogramm analysis was performed using software AGGR. We evaluated the general nature of the aggregation, the maximum aggregate, maximum aggregation rate, the average size of platelet aggregates.&#x0D; Results. Cyclohexilammonium salt of 2-[1-ethil-3-methyl-7-(dioxotiethanyl-3)-xantinyl-8-thio]acetic acid in in vitro conditions showed anti-aggregant activity greater than the reference substance, and effectively suppress hypercoagulation caused by an excess of thrombin and tissue factor.&#x0D; Conclusion. The results of the study make it possible to establish in a potentially high ex vivo therapeutic effect of a cyclohexilammonium salt of 2-[1-ethil-3-methyl-7-(dioxotiethanyl-3)-xantinyl-8-thio]acetic acid under conditions involving platelet hyperaggregation.

Influence of Lentiviral β-Synuclein Overexpression in the Hippocampus of a Transgenic Mouse Model of Alzheimer's Disease on Amyloid Precursor Protein Metabolism and Pathology

Background: β-Synuclein (β-Syn) is a member of the highly homologous synuclein protein family. The most prominent family member, α-synuclein (α-Syn), abnormally accumulates in so-called Lewy bodies, one of the major pathological hallmarks of α-synucleinopathies. Notably, parts of the peptide backbone, called the nonamyloid component, are also found in amyloid plaques. However, β-Syn seems to have beneficial effects by reducing α-Syn aggregation, and amyloid antiaggregatory activity has been described. Objective: The aim of the study was to analyze if wild-type β-Syn can counteract functional and pathological changes in a murine Alzheimer model over different time periods. Methods: At the onset of pathology, lentiviral particles expressing human β-Syn were injected into the hippocampus of transgenic mice overexpressing human amyloid precursor protein with Swedish and London mutations (APP_SL). An empty vector served as the control. Behavioral analyses were performed 1, 3 and 6 months after injection followed by biochemical and histological examinations of brain samples. Results: β-Syn expression was locally concentrated and rather modest, but nevertheless changed its effect on APP expression and plaque load in a time- and concentration-dependent manner. Interestingly, the phosphorylation of glycogen synthase kinase 3 beta was enhanced in APP_SL mice expressing human β-Syn, but an inverse trend was observed in wild-type animals. Conclusion: The initially reported beneficial effects of β-Syn could be partially reproduced, but locally elevated levels of β-Syn might also cause neurodegeneration. To enlighten the controversial pathological mechanism of β-Syn, further examinations considering the relationship between concentration and exposure time of β-Syn are needed.

Evaluation of the antiaggregant activity of ascorbyl phenolic esters with antioxidant properties.

Beneficial effects of the antioxidant L-ascorbic acid (Asc) in human health are well known. Its particular role in hemostasis deserves further consideration, since it has been described a dose-dependent effect of Asc in platelet activity. Contrary, it has been demonstrated that phenolic compounds have inhibitory effects on platelet aggregation stimulated by the physiological agonist thrombin (Thr). Here, we have evaluated the actions of three synthetic phenolic esters of Asc: L-ascorbyl 6-protocatechuate (Prot Asc), L-ascorbyl 6-gallate (Gal Asc), and L-ascorbyl 6-caffeate (Caf Asc). All these Asc derivatives exhibited greater radical scavenging activity than Asc, and in experiments using human platelets from healthy subjects, they do not evoke changes in platelet viability upon their administration. Nevertheless, these compounds altered platelet calcium homeostasis in response to Thr, although Prot Asc induced a smaller effect than Gal Asc, Caf Asc, and Asc. As a consequence, platelet aggregation was also impaired by these compounds, reporting Prot Asc and Caf Asc a weaker antiaggregant action than Gal Asc and Asc. Treatments with Gal Asc and Caf Asc altered in larger extent the phosphorylation pattern of pp60(Src) and mammalian target of rapamycin (mTOR) evoked by stimulating human platelets with Thr. Summarizing, Prot Asc is the ascorbyl phenolic ester with the strongest antioxidant properties and weakest antiaggregant actions, and its use as antioxidant may be safer than the rest of derivatives in order to prevent thrombotic alteration in patients that need treatment with antioxidant therapies.