RESUMEN

Curcumae Radix (CR) is a widely used traditional Chinese medicine with significant pharmaceutical importance, including enhancing blood circulation and addressing blood stasis. This study aims to establish an integrated and rapid quality assessment method for CR from various botanical origins, based on chemical components, antiplatelet aggregation effects, and Fourier transform near-infrared (FT-NIR) spectroscopy combined with multivariate algorithms. Firstly, ultra-performance liquid chromatography-photodiode array (UPLC-PDA) combined with chemometric analyses was used to examine variations in the chemical profiles of CR. Secondly, the activation effect on blood circulation of CR was assessed using an in vitro antiplatelet aggregation assay. The studies revealed significant variations in chemical profiles and antiplatelet aggregation effects among CR samples from different botanical origins, with constituents such as germacrone, ß-elemene, bisdemethoxycurcumin, demethoxycurcumin, and curcumin showing a positive correlation with antiplatelet aggregation biopotency. Thirdly, FT-NIR spectroscopy was integrated with various machine learning algorithms, including Artificial Neural Network (ANN), K-Nearest Neighbors (KNN), Logistic Regression (LR), Support Vector Machine (SVM), and Subspace K-Nearest Neighbors (Subspace KNN), to classify CR samples from four distinct sources. The result showed that FT-NIR combined with KNN and SVM classification algorithms after SNV and MSC preprocessing successfully distinguished CR samples from four plant sources with an accuracy of 100%. Finally, Quantitative models for active constituents and antiplatelet aggregation bioactivity were developed by optimizing the partial least squares (PLS) model with interval combination optimization (ICO) and competitive adaptive reweighted sampling (CARS) techniques. The CARS-PLS model achieved the best predictive performance across all five components. The coefficient of determination (R2p) and root mean square error (RMSEP) in the independent test sets were 0.9708 and 0.2098, 0.8744 and 0.2065, 0.9511 and 0.0034, 0.9803 and 0.0066, 0.9567 and 0.0172 for germacrone, ß-elemene, bisdemethoxycurcumin, demethoxycurcumin and curcumin, respectively. The ICO-PLS model demonstrated superior predictive capabilities for antiplatelet aggregation biotency, achieving an R2p of 0.9010, and an RMSEP of 0.5370. This study provides a valuable reference for the quality evaluation of CR in a more rapid and comprehensive manner.

Asunto(s)

Curcuma , Inhibidores de Agregación Plaquetaria , Agregación Plaquetaria , Espectroscopía Infrarroja Corta , Curcuma/química , Espectroscopía Infrarroja Corta/métodos , Agregación Plaquetaria/efectos de los fármacos , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Inhibidores de Agregación Plaquetaria/análisis , Inhibidores de Agregación Plaquetaria/química , Animales , Cromatografía Líquida de Alta Presión/métodos , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/análisis , Algoritmos , Extractos Vegetales/química

RESUMEN

Antiplatelet agents, particularly P2Y12 receptor inhibitors, are critical medicines in the prevention and treatment of thrombotic diseases in the clinic. However, their long-term use introduces a significant risk of bleeding in patients with cardiovascular diseases. Whether the bleeding is caused by the drug itself or due to surgical procedures or trauma, the need to rapidly reverse the effects of antiplatelet agents in the circulation is essential; however, no such agents are currently available. To address this need, here we describe a strategy that uses cell-membrane-wrapped nanoparticles (CM-NPs) for the rapid reversal of P2Y12 inhibitors. CM-NPs are fabricated with membranes derived from 293T cells genetically engineered to overexpress the P2Y12 receptor. Our findings support the potential of CM-NPs as a strategy for managing bleeding complications associated with P2Y12 receptor inhibitors, offering an approach to improve the safety in the use of these drugs in clinical settings.

Asunto(s)

Membrana Celular , Clopidogrel , Nanopartículas , Inhibidores de Agregación Plaquetaria , Antagonistas del Receptor Purinérgico P2Y , Receptores Purinérgicos P2Y12 , Ticagrelor , Humanos , Receptores Purinérgicos P2Y12/genética , Receptores Purinérgicos P2Y12/metabolismo , Ticagrelor/farmacología , Ticagrelor/química , Ticagrelor/uso terapéutico , Nanopartículas/química , Clopidogrel/farmacología , Antagonistas del Receptor Purinérgico P2Y/farmacología , Antagonistas del Receptor Purinérgico P2Y/química , Membrana Celular/metabolismo , Membrana Celular/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/uso terapéutico , Células HEK293

RESUMEN

ACKR3, an atypical chemokine receptor, has been associated with prothrombotic events and the development of cardiovascular events. We designed, synthesized, and evaluated a series of novel small molecule ACKR3 agonists. Extensive structure-activity relationship studies resulted in several promising agonists with potencies ranging from the low micromolar to nanomolar range, for example, 23 (EC50 = 111 nM, Emax = 95%) and 27 (EC50 = 69 nM, Emax = 82%) in the ß-arrestin-recruitment assay. These compounds are selective for ACKR3 versus ACKR2, CXCR3, and CXCR4. Several agonists were subjected to investigations of their P-selectin expression reduction in the flow cytometry experiments. In particular, compounds 23 and 27 showed the highest potency for platelet aggregation inhibition, up to 80% and 97%, respectively. The most promising compounds, especially 27, exhibited good solubility, metabolic stability, and no cytotoxicity, suggesting a potential tool compound for the treatment of platelet-mediated thrombosis.

Asunto(s)

Diseño de Fármacos , Inhibidores de Agregación Plaquetaria , Agregación Plaquetaria , Receptores CXCR , Humanos , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Relación Estructura-Actividad , Agregación Plaquetaria/efectos de los fármacos , Receptores CXCR/agonistas , Receptores CXCR/metabolismo , Animales , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Selectina-P/metabolismo , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo

RESUMEN

Compound L-36, a new derivative of 6H-1,3,4-thiadiazine, was studied in in vitro and in vivo experiments. This compound exhibits high antiplatelet and antithrombogenic activity. In in vitro experiments, compound L-36 by its antiplatelet activity (by IC50) was superior to acetylsalicylic acid by 9.4 times. In in vivo experiments, compound L-36 by its ED50 value was close to the comparison drug. On the model of pulmonary artery thrombosis, compound L-36 ensured better survival of experimental animals than acetylsalicylic acid. Morphological studies showed that compound L-36 effectively attenuated the thrombosis processes in the pulmonary tissue induced by intravenous injection of a thrombogenic mixture (epinephrine and collagen).

Asunto(s)

Aspirina , Fibrinolíticos , Inhibidores de Agregación Plaquetaria , Agregación Plaquetaria , Tiadiazinas , Animales , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/química , Tiadiazinas/farmacología , Tiadiazinas/química , Fibrinolíticos/farmacología , Fibrinolíticos/química , Agregación Plaquetaria/efectos de los fármacos , Aspirina/farmacología , Masculino , Trombosis/tratamiento farmacológico , Trombosis/prevención & control , Ratas , Arteria Pulmonar/efectos de los fármacos , Colágeno , Epinefrina/farmacología , Ratones , Plaquetas/efectos de los fármacos

RESUMEN

A series of stilbene analogues, in which a phenyl ring was replaced by the pyridazin-3(2H)-one nucleus, was designed and synthesized to be explored as platelet aggregation inhibitors. The proposed stilbene-pyridazinone hybrids were successfully obtained from simple starting materials and by Wittig's reaction. Most of the target compounds displayed improved in vitro activity in comparison with the standard drug, resveratrol, highlighting as the most potent the analogues 10d and 10e, with inhibition percentages of 94.15 % at 100 µM and 100 % at 50 µM, respectively. The pharmacokinetic and toxicity (ADME/T) properties of the novel hybrids were also estimated with the SwissADME and ProTox-II web servers.

Asunto(s)

Diseño de Fármacos , Inhibidores de Agregación Plaquetaria , Agregación Plaquetaria , Piridazinas , Estilbenos , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/síntesis química , Piridazinas/química , Piridazinas/farmacología , Piridazinas/síntesis química , Estilbenos/química , Estilbenos/farmacología , Estilbenos/síntesis química , Relación Estructura-Actividad , Humanos , Estructura Molecular , Agregación Plaquetaria/efectos de los fármacos , Relación Dosis-Respuesta a Droga

RESUMEN

The main goal of the study was to improve the compliance and convenience of patients by designing and development of an immediate release (IR) fixed-dose combination (Clopidogrel bisulphate and Aspirin) tablets. The proposed combination product utilizes Clopidogrel to protect the moisture-sensitive aspirin component, enhancing its stability against atmospheric conditions. Response-surface approach (Design Expert vs. 13) was used to generate this IR tablet by calculating the right composition of independent variables such as Microcrystalline cellulose 102, pregelatinized starch and Hydroxypropyl cellulose. 32 factorial design was used to estimate the effects of these independent variables on the responses of dependent variables (disintegration & friability) and constructed a total of nine (9) formulations. Pre and Post formulation, quality control parameters were investigated as per pharmacopeia. A systematic approach was used for the optimization process and a prototype checkpoint batch (CPB) based on the better contrast of independent variables was prepared. In vitro analysis of formulations was carried out to estimate the responses. Friability was found in the range of 0.088-1.076%w/w, except F1 = 1.076 all are within limits (NMT 1.0%). Disintegration time was recorded 7.3 ± 1.20 as lower and 24.5 ± 1.63 min was the highest. The release of drugs from their dosage form was fast and rapid, for clopidogrel after 15min was 70.42-96.82% with SD ± 8.71 and aspirin was 69.88-91.49% in 15 min with SD ± 6.41, all the tablets were released more than 80% in 20 min. The stability outcomes of CPB tablets after 15 days of stress study (60 ± 2°C and 75 ± 5%) indicated good compatibility and stability of APIs with excipients. It was concluded that the direct compression method can be preferred to prepare a combination product with cost-effectiveness. It was also concluded that the proposed methodology could increase Aspirin's stability and allow for an aqueous coating system to finish the product with a film coating. By using Design Expert software, the best composition of the formulation can be selected and optimized in a short period of time with minimum trial and errors. The results also demonstrated that the use of a fixed-dose combination tablet instead of the individual is expected to be more convenient to patients and thus improves patient compliance and decreases the occurrence of adverse effects and side effects.

Asunto(s)

Aspirina , Clopidogrel , Comprimidos , Clopidogrel/química , Clopidogrel/administración & dosificación , Aspirina/química , Aspirina/administración & dosificación , Comprimidos/química , Ticlopidina/análogos & derivados , Ticlopidina/química , Ticlopidina/administración & dosificación , Combinación de Medicamentos , Humanos , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/administración & dosificación , Composición de Medicamentos/métodos , Química Farmacéutica/métodos

RESUMEN

The delicate balance between ischemic and bleeding risks is a critical factor in antiplatelet therapy administration. Clopidogrel and prasugrel, belonging to the thienopyridine class of antiplatelet drugs, are known for their variability in individual responsiveness and high incidence of bleeding events, respectively. The present study is centered on the development and assessment of a range of deuterated thienopyridine derivatives, leveraging insights from structure-pharmacokinetic relationships of clopidogrel and prasugrel. Our approaches were grounded in the molecular framework of clopidogrel and incorporated the C2-pharmacophore design from prasugrel. The selection of ester or carbamate substituents at the C2-position facilitated the generation of the 2-oxointermediate through hydrolysis, akin to prasugrel, thereby bypassing the issue of CYP2C19 dependency. The bulky C2-pharmacophore in our approach distinguishes itself from prasugrel's acetyloxy substituent by exhibiting a moderated hydrolysis rate, resulting in a more gradual formation of the active metabolite. Excessive and rapid release of the active metabolite, believed to be linked with an elevated risk of bleeding, is thus mitigated. Our proposed structural modification retains the hydrolysis-sensitive methyl ester of clopidogrel but substitutes it with a deuterated methyl group, shown to effectively reduce metabolic deactivation. Three promising compounds demonstrated a pharmacokinetic profile similar to that of clopidogrel at four times the dose, while also augmenting its antiplatelet activity. SIGNIFICANCE STATEMENT: Inspired by the structure-pharmacokinetic relationship of clopidogrel and prasugrel, a range of clopidogrel derivatives were designed, synthesized, and assessed. Among them, three promising compounds have been identified, striking a delicate balance between efficacy and safety for antiplatelet therapy. Additionally, the ozagrel prodrug conjugate was discovered to exert a synergistic therapeutic effect alongside clopidogrel.

Asunto(s)

Clopidogrel , Inhibidores de Agregación Plaquetaria , Clorhidrato de Prasugrel , Clopidogrel/farmacocinética , Clopidogrel/farmacología , Inhibidores de Agregación Plaquetaria/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/química , Humanos , Clorhidrato de Prasugrel/farmacocinética , Clorhidrato de Prasugrel/farmacología , Citocromo P-450 CYP2C19/metabolismo , Relación Estructura-Actividad , Activación Metabólica , Masculino , Hidrólisis , Microsomas Hepáticos/metabolismo , Microsomas Hepáticos/efectos de los fármacos

RESUMEN

Sweet potatoes are rich in cardioprotective phytochemicals with potential anti-platelet aggregation activity, although this benefit may vary among cultivars/genotypes. The phenolic profile [HPLC-ESI(-)-qTOF-MS2], cheminformatics (ADMET properties, affinity toward platelet proteins) and anti-PA activity of phenolic-rich hydroalcoholic extracts obtained from orange (OSP) and purple (PSP) sweet potato storage roots, was evaluated. The phenolic richness [Hydroxycinnamic acids> flavonoids> benzoic acids] was PSP > OSP. Their main chlorogenic acids could interact with platelet proteins (integrins/adhesins, kinases/metalloenzymes) but their bioavailability could be poor. Just OSP exhibited a dose-dependent anti-platelet aggregation activity [inductor (IC50, mg.ml-1): thrombin receptor activator peptide-6 (0.55) > Adenosine-5'-diphosphate (1.02) > collagen (1.56)] and reduced P-selectin expression (0.75-1.0 mg.ml-1) but not glycoprotein IIb/IIIa secretion. The explored anti-PA activity of OSP/PSP seems to be inversely related to their phenolic richness. The poor first-pass bioavailability of its chlorogenic acids (documented in silico) may represent a further obstacle for their anti-PA in vivo.

Asunto(s)

Ipomoea batatas , Fenoles , Extractos Vegetales , Raíces de Plantas , Inhibidores de Agregación Plaquetaria , Agregación Plaquetaria , Ipomoea batatas/química , Fenoles/química , Agregación Plaquetaria/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología , Raíces de Plantas/química , Humanos , Quimioinformática , Animales , Plaquetas/metabolismo , Plaquetas/efectos de los fármacos

RESUMEN

Platelets are the critical target for preventing and treating pathological thrombus formation. However, despite current antiplatelet therapy, cardiovascular mortality remains high, and cardiovascular events continue in prescribed patients. In this study, first results were obtained with ortho-carbonyl hydroquinones as antiplatelet agents; we found that linking triphenylphosphonium cation to a bicyclic ortho-carbonyl hydroquinone moiety by a short alkyl chain significantly improved their antiplatelet effect by affecting the mitochondrial functioning. The mechanism of action involves uncoupling OXPHOS, which leads to an increase in mitochondrial ROS production and a decrease in the mitochondrial membrane potential and OCR. This alteration disrupts the energy production by mitochondrial function necessary for the platelet activation process. These effects are responsive to the complete structure of the compounds and not to isolated parts of the compounds tested. The results obtained in this research can be used as the basis for developing new antiplatelet agents that target mitochondria.

Asunto(s)

Plaquetas , Hidroquinonas , Potencial de la Membrana Mitocondrial , Compuestos Organofosforados , Inhibidores de Agregación Plaquetaria , Humanos , Plaquetas/metabolismo , Plaquetas/efectos de los fármacos , Hidroquinonas/farmacología , Hidroquinonas/química , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Compuestos Organofosforados/farmacología , Compuestos Organofosforados/química , Fosforilación Oxidativa/efectos de los fármacos , Activación Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/química , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

Four undescribed ginkgolides, including two rare sesquiterpene ginkgolides (compounds 1 and 2) and two diterpenoid ginkgolides (compounds 3 and 4), were isolated from Ginkgo biloba L. The structures of these four ginkgolides were identified based on extensive spectroscopic analysis, DP4+ probability analysis and X-ray diffraction. Compounds 1 and 2 exhibited excellent antiplatelet aggregation activities with IC50 values of 1.20 ± 0.25 and 4.11 ± 0.34 µM, respectively.

Asunto(s)

Ginkgo biloba , Ginkgólidos , Fitoquímicos , Inhibidores de Agregación Plaquetaria , Ginkgo biloba/química , Estructura Molecular , Ginkgólidos/farmacología , Ginkgólidos/aislamiento & purificación , Ginkgólidos/química , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/aislamiento & purificación , Inhibidores de Agregación Plaquetaria/química , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Animales , Agregación Plaquetaria/efectos de los fármacos

RESUMEN

Drugs with anti-platelet aggregation and neuroprotection are of great significance for the treatment of ischemic stroke. A series of edaravone and 6-phenyl-4,5-dihydropyridazin-3(2H)-one hybrids were designed and synthesized. Among them, 6g showed the most effective cytoprotective effect against oxygen-glucose deprivation/reoxygenation-induced damage in BV2 cells and an excellent inhibitory effect on platelet aggregation induced by adenosine diphosphate and arachidonic acid. Additionally, 6g could prevent thrombosis caused by ferric chloride in rats and pose a lower risk of causing bleeding compared with aspirin. It provides better protection against ischemia/reperfusion injury in rats compared with edaravone and alleviates the oxidative stress related to cerebral ischemia/reperfusion by increasing the GSH and SOD levels and decreasing the MDA concentration. Finally, molecular docking results showed that 6g probably acts on PDE3 A and plays an anti-platelet aggregation effect. Overall, 6g could be a potential candidate compound for the treatment of ischemic stroke.

Asunto(s)

Edaravona , Accidente Cerebrovascular Isquémico , Fármacos Neuroprotectores , Inhibidores de Agregación Plaquetaria , Agregación Plaquetaria , Animales , Edaravona/farmacología , Edaravona/química , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Ratas , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/síntesis química , Agregación Plaquetaria/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/síntesis química , Simulación del Acoplamiento Molecular , Masculino , Ratones , Estructura Molecular , Relación Estructura-Actividad , Ratas Sprague-Dawley , Descubrimiento de Drogas , Piridazinas/farmacología , Piridazinas/química , Estrés Oxidativo/efectos de los fármacos

RESUMEN

This study isolated pure compounds from Canna edulis aerial parts and assessed their antiplatelet and anticoagulant potential. Structural elucidation resulted in the identification of two new compounds: caneduloside A (1) and caneduloside B (2), and eleven known compounds: 6'-acetyl-3,6,2'-tri-p-coumaroyl sucrose (3), 6'-acetyl-3,6,2'-triferuloyl sucrose (4), tiliroside (5), afzelin (6), quercitrin (7), 2-hydroxycinnamaldehyde (8), cinnamic acid (9), 3,4-dimethoxycinnamic acid (10), dehydrovomifoliol (11), 4-hydroxy-3,5-dimethoxybenzaldehyde (12), and (S)-(-)-rosmarinic acid (13). Compounds 3, 4, 6-9, 13 were previously reported for antithrombotic properties. Hence, antithrombotic tests were conducted for 1, 2, 5, 10-12. All tested compounds demonstrated a dose-dependent antiaggregatory effect, and 10 and 12 were the most potent for both ADP and collagen activators. Additionally, 10 and 12 showed anticoagulant effects, with prolonged prothrombin time and activated partial thromboplastin time. The new compound 1 displayed antiplatelet and anticoagulant activity, while 2 mildly inhibited platelet aggregation. C. edulis is a potential source for developing antithrombotic agents.

Asunto(s)

Anticoagulantes , Componentes Aéreos de las Plantas , Inhibidores de Agregación Plaquetaria , Sacarosa , Anticoagulantes/farmacología , Anticoagulantes/química , Anticoagulantes/aislamiento & purificación , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/aislamiento & purificación , Sacarosa/química , Sacarosa/farmacología , Sacarosa/metabolismo , Componentes Aéreos de las Plantas/química , Componentes Aéreos de las Plantas/metabolismo , Humanos , Ésteres/química , Ésteres/farmacología , Ésteres/aislamiento & purificación , Agregación Plaquetaria/efectos de los fármacos , Myristicaceae/química , Relación Dosis-Respuesta a Droga , Estructura Molecular , Relación Estructura-Actividad , Animales

RESUMEN

Thrombosis plays an important role in the occurrence and development of cardiovascular and cerebrovascular diseases that contribute to high mortality and morbidity in patients. L-(-)-Quebrachitol (QCT), a natural product, was first isolated from quebracho bark. It can inhibit PAF receptor and decrease gastric damage induced by indomethacin, as a drug against platelet aggregation. Here, five QCT derivatives were synthesized and investigated for their inhibitory effects on platelet aggregation. Among them, compound 3a showed anticoagulant effects comparable to aspirin, while compound 4b showed dose-independent inhibitory activities in rats that were stronger than aspirin.

Asunto(s)

Inhibidores de Agregación Plaquetaria , Agregación Plaquetaria , Animales , Agregación Plaquetaria/efectos de los fármacos , Ratas , Estructura Molecular , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Aspirina/farmacología , Anticoagulantes/farmacología , Anticoagulantes/química , Anticoagulantes/síntesis química , Corteza de la Planta/química , Masculino

RESUMEN

BACKGROUND: Thrombosis is one of the major causes of morbidity and mortality in a wide range of vessel diseases. Several studies have been conducted to identify antithrombotic agents from medicinal plants, and phenolic compounds (PCs) have been shown to effectively inhibit plasma coagulation and platelet aggregation. OBJECTIVES: This study aimed to conduct a survey of the natural PCs with proven antithrombotic and antiplatelet activities, as well as to evaluate by computational modeling the physicochemical and toxicological properties of these compounds using drug-likeness approaches. METHODS: The data were collected from the scientific database: 'Web of Science', 'Scifinder', 'Pubmed', 'ScienceDirect' and 'Google Scholar', the different classes of PCs with antithrombotic or antiplatelet effects were used as keywords. These molecules were also evaluated for their Drug-Likeness properties and toxicity to verify their profile for being candidates for new antithrombotic drugs. RESULTS: In this review, it was possible to register 85 lignans, 73 flavonoids, 28 coumarins, 21 quinones, 23 phenolic acids, 8 xanthones and 8 simple phenols. Activity records for tannins were not found in the researched databases. Of these 246 compounds, 213 did not violate any of Lipinski's rules of five, of which 125 (59%) showed non-toxicity, being promising candidates for new potential antithrombotic drugs. CONCLUSION: This review arouses interest in the isolation of phenolic compounds that may allow a new approach for the prevention of both arterial and venous thrombosis, with the potential to become alternatives in the prevention and treatment of cardiovascular diseases.

Asunto(s)

Fibrinolíticos , Fenoles , Inhibidores de Agregación Plaquetaria , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/química , Fibrinolíticos/farmacología , Fibrinolíticos/química , Humanos , Fenoles/química , Fenoles/farmacología , Trombosis/tratamiento farmacológico , Animales , Productos Biológicos/química , Productos Biológicos/farmacología , Productos Biológicos/aislamiento & purificación , Agregación Plaquetaria/efectos de los fármacos

RESUMEN

BACKGROUND: Cyclooxygenase-2 (COX-2), the key enzyme in the arachidonic acid conversion to prostaglandins, is one of the enzymes associated with different pathophysiological conditions, such as inflammation, cancers, Alzheimer's, and Parkinson's disease. Therefore, COX-2 inhibitors have emerged as potential therapeutic agents in these diseases. OBJECTIVE: The objective of this study was to design and synthesize novel imidazo[1,2-a]pyridine derivatives utilizing rational design methods with the specific aim of developing new potent COX-2 inhibitors. Additionally, we sought to investigate the biological activities of these compounds, focusing on their COX-2 inhibitory effects, analgesic activity, and antiplatelet potential. We aimed to contribute to the development of selective COX-2 inhibitors with enhanced therapeutic benefits. METHODS: Docking investigations were carried out using AutoDock Vina software to analyze the interaction of designed compounds. A total of 15 synthesized derivatives were obtained through a series of five reaction steps. The COX-2 inhibitory activities were assessed using the fluorescent Cayman kit, while analgesic effects were determined through writing tests, and Born's method was employed to evaluate antiplatelet activities. RESULTS: The findings indicated that the majority of the tested compounds exhibited significant and specific inhibitory effects on COX-2, with a selectivity index ranging from 51.3 to 897.1 and IC50 values of 0.13 to 0.05 µM. Among the studied compounds, derivatives 5e, 5f, and 5j demonstrated the highest potency with IC50 value of 0.05 µM, while compound 5i exhibited the highest selectivity with a selectivity index of 897.19. In vivo analgesic activity of the most potent COX-2 inhibitors revealed that 3-(4-chlorophenoxy)-2-[4-(methylsulfonyl) phenyl] imidazo[1,2-a]pyridine (5j) possessed the most notable analgesic activity with ED50 value of 12.38 mg/kg. Moreover, evaluating the antiplatelet activity showed compound 5a as the most potent for inhibiting arachidonic acidinduced platelet aggregation. In molecular modeling studies, methylsulfonyl pharmacophore was found to be inserted in the secondary pocket of the COX-2 active site, where it formed hydrogen bonds with Arg-513 and His-90. CONCLUSION: The majority of the compounds examined demonstrated selectivity and potency as inhibitors of COX-2. Furthermore, the analgesic effects observed of potent compounds can be attributed to the inhibition of the cyclooxygenase enzyme.

Asunto(s)

Inhibidores de la Ciclooxigenasa 2 , Ciclooxigenasa 2 , Diseño de Fármacos , Piridinas , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Piridinas/farmacología , Piridinas/química , Piridinas/síntesis química , Ciclooxigenasa 2/metabolismo , Animales , Relación Estructura-Actividad , Estructura Molecular , Humanos , Relación Dosis-Respuesta a Droga , Imidazoles/farmacología , Imidazoles/química , Imidazoles/síntesis química , Analgésicos/farmacología , Analgésicos/síntesis química , Analgésicos/química , Simulación del Acoplamiento Molecular , Masculino , Ratas , Ratones , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química

RESUMEN

BACKGROUND: Classical anticoagulants and antiplatelets are associated with high frequencies of bleeding complications or treatment failure when used as single agents. Thrombin plays an important role in the blood coagulation system. GP IIb/IIIa is the central receptor of platelets, which can recognize the Arg-Gly-Asp (RGD) sequence and activate platelets. MATERIAL AND METHODS: Molecular simulation and homology modeling were performed to design a novel dual-target anticoagulant short peptide (PTIP ). The activities of PTIP on coagulation and platelet in vitro were analyzed. The antithrombotic activity of PTIP was determined by pulmonary thromboembolism model, ferric chloride injury model and arteriovenous bypass thrombosis model. Bleeding effect and toxicity of PTIP were evaluated. RESULTS: We have constructed a novel dual-target peptide (PTIP) based on the direct thrombin inhibitor peptide (DTIP). PTIP was expressed at high levels in Pichia pastoris. PTIP interfered with thrombin-mediated coagulation and ADP-induced platelet aggregation in vitro. When injected intravenously or subcutaneously, PTIP showed potent and dose-dependent extension of aPTT and PT which were similar to DTIP; but only PTIP was capable of inhibiting platelet aggregation. PTIP (1.0 mg/kg) decelerated thrombosis formation in venous and arterial vessels induced by FeCl3 injury. PTIP (1.0 mg/kg) also prevented deep venous thrombosis and increased the survival rate associated with pulmonary thromboembolism. And PTIP effectively reduced thrombus length in arteriovenous bypass thrombosis model. Moreover, the antithrombotic dose of PTIP could not induce bleeding. CONCLUSION: These data establish that PTIP represents a novel antithrombotic agent whose effects involve both inhibition of platelet activation and reduction of fibrin generation. And PTIP not only can be used in venous thrombosis and arterial thrombosis, it can also replace the combined treatment of antiplatelet and anticoagulant drugs in thrombotic diseases.

Asunto(s)

Embolia Pulmonar , Trombosis , Humanos , Agregación Plaquetaria , Trombina , Fibrinolíticos/farmacología , Fibrinolíticos/uso terapéutico , Hemorragia/tratamiento farmacológico , Anticoagulantes/uso terapéutico , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Inhibidores de Agregación Plaquetaria/química , Trombosis/tratamiento farmacológico , Trombosis/prevención & control , Antitrombinas/uso terapéutico , Péptidos/farmacología , Péptidos/uso terapéutico , Embolia Pulmonar/tratamiento farmacológico

RESUMEN

Canna indica L. has been traditionally used to treat various diseases. Based on previously reported antithrombotic effect for this plant, two new phenylpropanoid sucrose esters (canindicoside A (1) and canindicoside B (2)) and seven known compounds: nepetoidin B (3), caffeic acid (4), ferulic acid (5), (R)-(+)-rosmarinic acid (6), isorinic acid (7), (S)-(-)-rosmarinic acid (8) and (S)-(-)-rosmarinic acid methyl ester (9) were isolated from the ethyl acetate extract. Compounds were elucidated by NMR and MS spectroscopic methods. The antiplatelet effect was evaluated using turbidimetric method. Anticoagulant activity was examined by measuring activated partial thromboplastine time (APTT), prothrombin time, and thrombine time (TT). It was shown for the first time that both new phenylpropanoid sucrose esters 1 and 2, 7 and 9 displayed dose-dependent antiplatelet effects. 2 and 9 had the highest inhibitory activity on both adenosine diphosphate (ADP)- and collagen-induced platelet aggregation. Moreover, 1, 7 and 9 also exhibited anticoagulant activity. At 0.4 mg/mL, both 1 and 7 prolonged APTT compared to the negative control (p < 0.05), suggesting the possible inhibitory impact on the intrinsic coagulation pathway. Moreover, 9 at 0.4 mg/mL exerted higher TT values than the negative control (p < 0.05). C. indica and its bioactive phytochemicals are potential candidates for development of anti-thrombosis therapy.

Asunto(s)

Inhibidores de Agregación Plaquetaria , Zingiberales , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/química , Fibrinolíticos/farmacología , Ésteres/farmacología , Sacarosa/farmacología , Rizoma , Anticoagulantes/farmacología , Anticoagulantes/química

RESUMEN

Venous thromboembolism is a serious problem because it significantly increases the risk of developing vascular complications in elderly patients with obesity or immobilization, cancer, and many other diseases. Thus, there is a need to study new therapeutic strategies, including new medicinal agents for the efficient and safe correction of thrombus disorders. In this work, we have synthesized a number of new amides and peptides of 4-amino-5-oxoprolines and studied their antiplatelet and antithrombotic activity in experiments in vitro and in vivo. It has been found that the newly obtained compounds slow down the process of thrombus formation in a model of arterial and venous thrombosis, without affecting plasma hemostasis parameters. (2S,4S)-4-Amino-1-(4-fluorophenyl)-5-oxoprolyl-(S)-phenylalanine proved to be the most efficient among the studied derivatives. The results obtained indicate the advisability of further studies on 5-oxoproline derivatives in order to design pharmaceutical agents for the prevention and treatment of the consequences of thrombosis.

Asunto(s)

Ácido Pirrolidona Carboxílico , Trombosis , Humanos , Anciano , Ácido Pirrolidona Carboxílico/química , Fibrinolíticos/farmacología , Fibrinolíticos/uso terapéutico , Amidas/farmacología , Trombosis/tratamiento farmacológico , Péptidos/farmacología , Péptidos/uso terapéutico , Inhibidores de Agregación Plaquetaria/química

RESUMEN

Eleven new abietane-type diterpene lactones, salpratlactones D-N (1-11), including five 11,12-seco-11-nor-abietane diterpenes (1-5), four 11,12-seco-abietane diterpenes (6-9), two 20(10 â†’ 5)-abeo-4,5;11,12-bis-seco-abietane diterpenes (10-11), and two known analogues (12-13), were characterized from Salvia prattii. Notably, compounds 1-3 were characterized by a unique linear 6/6/6 tricyclic skeleton. The structures were established by spectroscopic data interpretation, calculated NMR-DP4+ and electronic circular dichroism analysis, as well as single-crystal X-ray diffraction. A bioactivity study showed that 1, 2, 5, 11, and 12 can potently inhibit platelet aggregation induced by arachidonic acid (AA), with IC50 values of 5.66-16.10 µg/ml, stronger than aspirin. In addition, the lactate dehydrogenase assay showed that they had no effect on platelet integrity. Structurally, the same 1,2-benzopyrone fragments of 1, 2, and 5 should be the important pharmacophore for antiplatelet activity.

Asunto(s)

Abietanos , Inhibidores de Agregación Plaquetaria , Salvia , Abietanos/farmacología , Aspirina , Lactonas/farmacología , Pruebas de Enzimas , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología

RESUMEN

Integrins are a family of heterodimeric transmembrane receptors which link the extracellular matrix to the cell cytoskeleton. These receptors play a role in many cellular processes: adhesion, proliferation, migration, apoptosis, and platelet aggregation, thus modulating a wide range of scenarios in health and disease. Therefore, integrins have been the target of new antithrombotic drugs. Disintegrins from snake venoms are recognized by the ability to modulate the activity of integrins, such as integrin αIIbß3, a fundamental platelet glycoprotein, and αvß3 expressed on tumor cells. For this reason, disintegrins are unique and potential tools for examining integrin-matrix interaction and the development of novel antithrombotic agents. The present study aims to obtain the recombinant form of jararacin and evaluate the secondary structure and its effects on hemostasis and thrombosis. rJararacin was expressed in the Pichia pastoris (P. pastoris) expression system and purified the recombinant protein with a yield of 40 mg/L of culture. The molecular mass (7722 Da) and internal sequence were confirmed by mass spectrometry. Structure and folding analysis were obtained by Circular Dichroism and 1H Nuclear Magnetic Resonance spectra. Disintegrin structure reveals properly folded with the presence of ß-sheet structure. rJararacin significantly demonstrated inhibition of the adhesion of B16F10 cells and platelets to the fibronectin matrix under static conditions. rJararacin inhibited platelet aggregation induced by ADP (IC50 95 nM), collagen (IC50 57 nM), and thrombin (IC50 22 nM) in a dose-dependent manner. This disintegrin also inhibited 81% and 94% of the adhesion of platelets to fibrinogen and collagen under continuous flow, respectively. In addition, rjararacin efficaciously prevents platelet aggregation in vitro and ex vivo with rat platelets and thrombus occlusion at an effective dose (5 mg/kg). The data here provides evidence that rjararacin possesses the potential as an αIIbß3 antagonist, capable of preventing arterial thrombosis.

Asunto(s)

Venenos de Crotálidos , Trombosis , Ratas , Animales , Desintegrinas/farmacología , Desintegrinas/química , Desintegrinas/metabolismo , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/química , Venenos de Crotálidos/química , Venenos de Crotálidos/farmacología , Agregación Plaquetaria , Hemostasis , Integrinas/metabolismo , Trombosis/tratamiento farmacológico