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Dihydropyrimidines are widely recognized for their diverse biological properties and are often synthesized by the Biginelli reactions. In this backdrop, a novel series of Biginelli dihydropyrimidines were designed, synthesized, purified, and analyzed by FT-IR, 1H NMR, 13C NMR, and mass spectrometry. Anticancer activity against MCF-7 breast cancer cells was evaluated as part of their cytotoxicity in comparison with the normal Vero cells. The cytotoxicity of dihydropyrimidines ranges from moderate to significant. Among the 38 dihydropyrimidines screened, compounds 16, 21, and 39 exhibited significant cytotoxicity. These 3 compounds were subjected to flow cytometry studies and EGFRwt Kinase inhibition assay using lapatinib as a standard. The study included evaluation for the inhibition of EGFR and HER2 expression at five different concentrations. At a concentration of 1000 nM compound 21 showed 98.51 % and 96.79 % inhibition of EGFR and HER2 expression. Moreover, compounds 16, 21 and 39 significantly inhibited EGFRwt activity with IC50 = 69.83, 37.21 and 76.79 nM, respectively. In addition, 3D-QSAR experiments were conducted to elucidate Structure activity relationships in a 3D grid space by comparing the experimental and predicted cytotoxic activities. Molecular docking studies were performed to validate the results by in silico method. All together, we developed a new series of Biginelli dihydropyrimidines as dual EGFR/HER2 inhibitors.
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Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas , Pirimidinas , Receptor ErbB-2 , Humanos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/metabolismo , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Animales , Chlorocebus aethiops , Células MCF-7 , Relación Estructura-Actividad Cuantitativa , Células Vero , Relación Estructura-ActividadRESUMEN
A series of novel symmetrical and asymmetrical dihydropyridines (HD 1-15) were designed, subjected to in silico ADMET prediction, synthesized, analyzed by IR, NMR, Mass analytical techniques and evaluated against epidermal growth factor receptor (EGFR) as inhibitors against Breast cancer. The results of predicted ADMET studies demonstrated the drug-likeness properties of the reported compounds. The in vitro cytotoxicity assessment of the synthesized compounds revealed that all of them showed good activity (IC50 ranging from 16.75 to 66.54 µM) towards MCF-7 breast cancer cells compared to the standard drug, Lapatinib (IC50 = 2.02 µM). Among these, compounds HD-6, HD-7, and HD-8 displayed the most potent activity with IC50 value of 21.26, 16.75, and 18.33 µM, respectively. Cytotoxicity of all compounds was tested on normal vero cells for comparison at different concentrations using the MTT assay. In addition to the MTT assay, the potent dihydropyridines derivatives were screened for EGFRwt kinase inhibition assay at concentrations ranging from 1 nM to 360 nM. Among the three compounds tested, HD-8 showed reasonably good inhibition with an IC50 value of 15.90 ± 1.20 nM compared to a standard Lapatinib IC50 value of 10.28 ± 1.01 nM. Based on the molecular docking study against EGFR, the most active derivatives HD-7 and HD-8 were docked against the active site of the protein and showed better binding affinity than the standard lapatinib. Additionally, molecular dynamics (MD) simulations were performed to explore the stability of the protein-ligand complex, its dynamic behavior, and the binding affinity.
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Diabetic nephropathy and peripheral neuropathy are the two main complications of chronic diabetes that contribute to high morbidity and mortality. These conditions are characterized by the dysregulation of multiple molecular signaling pathways and the presence of specific biomarkers such as inflammatory cytokines, indicators of oxidative stress, and components of the renin-angiotensin system. In this review, we systematically collected and collated the relevant information from MEDLINE, EMBASE, ELSEVIER, PUBMED, GOOGLE, WEB OF SCIENCE, and SCOPUS databases. This review was conceived with primary objective of revealing the functions of these biomarkers and signaling pathways in the initiation and progression of diabetic nephropathy and peripheral neuropathy. We also highlighted the potential therapeutic effectiveness of rutin and quercetin, two plant-derived flavonoids known for their antioxidant and anti-inflammatory properties. The findings of our study demonstrated that both flavonoids can regulate important disease-promoting systems, such as inflammation, oxidative stress, and dysregulation of the renin-angiotensin system. Importantly, rutin and quercetin have shown protective benefits against nephropathy and neuropathy in diabetic animal models, suggesting them as potential therapeutic agents. These findings provide a solid foundation for further comprehensive investigations and clinical trials to evaluate the potential of rutin and quercetin in the management of diabetic nephropathy and peripheral neuropathy. This may contribute to the development of more efficient and comprehensive treatment approaches for diabetes-associated complications.
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Diabetes mellitus is a chronic disease that is now considered a global epidemic. Chronic diabetes conditions include type 1 and type 2 diabetes, both of which are normally irreversible. As a result of long-term uncontrolled high levels of glucose, diabetes can progress to hyperglycaemic pathologies, such as cardiovascular diseases, retinopathy, nephropathy and neuropathy, among many other complications. The complete mechanism underlying diabetes remains unclear due to its complexity. In this scenario, zebrafish (Danio rerio) have arisen as a versatile and promising animal model due to their good reproducibility, simplicity, and time- and cost-effectiveness. The Zebrafish model allows us to make progress in the investigation and comprehension of the root cause of diabetes, which in turn would aid in the development of pharmacological and surgical approaches for its management. The current review provides valuable reference information on zebrafish models, from the first zebrafish diabetes models using genetic, disease induction and chemical approaches, to the newest ones that further allow for drug screening and testing. This review aims to update our knowledge related to diabetes mellitus by gathering the most authoritative studies on zebrafish as a chemical, dietary and insulin induction, and genetic model for diabetes research.
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Modelos Animales de Enfermedad , Descubrimiento de Drogas , Pez Cebra , Animales , Descubrimiento de Drogas/métodos , Diabetes Mellitus/tratamiento farmacológico , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéuticoRESUMEN
Diabetes mellitus, a prevalent global health concern, is characterized by hyperglycemia. However, recent research reveals a more intricate landscape where oxidative stress and endoplasmic reticulum (ER) stress orchestrate a dual assault, profoundly impacting diabetic disorders. This review elucidates the interplay between these two stress pathways and their collective consequences on diabetes. Oxidative stress emanates from mitochondria, where reactive oxygen species (ROS) production spirals out of control, leading to cellular damage. We explore ROS-mediated signaling pathways, which trigger ß-cell dysfunction, insulin resistance, and endothelial dysfunction the quintessential features of diabetes. Simultaneously, ER stress unravels, unveiling how protein folding disturbances activate the unfolded protein response (UPR). We dissect the UPR's dual role, oscillating between cellular adaptation and apoptosis, significantly influencing pancreatic ß-cells and peripheral insulin-sensitive tissues. Crucially, this review exposes the synergy between oxidative and ER stress pathways. ROS-induced UPR activation and ER stress-induced oxidative stress create a detrimental feedback loop, exacerbating diabetic complications. Moreover, we spotlight promising therapeutic strategies that target both stress pathways. Antioxidants, molecular chaperones, and novel pharmacological agents offer potential avenues for diabetes management. As the global diabetes burden escalates, comprehending the dual assault of oxidative and ER stress is paramount. This review not only unveils the intricate molecular mechanisms governing diabetic pathophysiology but also advocates a holistic therapeutic approach. By addressing both stress pathways concurrently, we may forge innovative solutions for diabetic disorders, ultimately alleviating the burden of this pervasive health issue.
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Diabetes Mellitus , Glucosa , Humanos , Especies Reactivas de Oxígeno/metabolismo , Estrés del Retículo Endoplásmico/fisiología , Diabetes Mellitus/diagnóstico , Estrés OxidativoRESUMEN
The main objective of this research was to develop novel compounds from readily accessed natural products especially eugenol with potential biological activity. Eugenol, the principal chemical constituent of clove (Eugenia caryophyllata) from the family Myrtaceae is renowned for its pharmacological properties, which include analgesic, antidiabetic, antioxidant, anticancer, and anti-inflammatory effects. According to reports, PPARγ regulates inflammatory reactions. The synthesized compounds were structurally analyzed using FT-IR, 1HNMR, 13CNMR, and mass spectroscopy techniques. Molecular docking was performed to analyze binding free energy and important amino acids involved in the interaction between synthesized derivatives and the target protein. The development of the structure-activity relationship is based on computational studies. Additionally, the stability of the best-docked protein-ligand complexes was assessed using molecular dynamic modeling. The in-vitro PPARγ competitive binding Lanthascreen TR-FRET assay was used to confirm the affinity of compounds to the target protein. All the synthesized derivatives were evaluated for an in vitro anti-inflammatory activity using an albumin denaturation assay and HRBC membrane stabilization at varying concentrations from 6.25 to 400 µM. In this background, with the aid of computational research, we were able to design six novel derivatives of eugenol synthesized, analyzed, and utilized TR-FRET competitive binding assay to screen them for their ability to bind PPARγ. Anti-inflammatory activity evaluation through in vitro albumin denaturation and HRBC method revealed that 1f exhibits maximum inhibition of heat-induced albumin denaturation at 50% and 85% protection against HRBC lysis at 200 and 400 µM, respectively. Overall, we found novel derivatives of eugenol that could potentially reduce inflammation by PPARγ agonism.
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Eugenol , PPAR gamma , Humanos , Eugenol/farmacología , PPAR gamma/metabolismo , Simulación del Acoplamiento Molecular , Agonistas de PPAR-gamma , Espectroscopía Infrarroja por Transformada de Fourier , Antiinflamatorios/farmacología , Inflamación , Relación Estructura-Actividad , Simulación de Dinámica Molecular , AlbúminasRESUMEN
PPARα and PPARγ are isoforms of the nuclear receptor superfamily which regulate glucose and lipid metabolism. Activation of PPARα and PPARγ receptors by exogenous ligands could transactivate the expression of PPARα and PPARγ-dependent genes, and thereby, metabolic pathways get triggered, which are helpful to ameliorate treatment for the type 2 diabetes mellitus, and related metabolic complications. Herein, by understanding the structural requirements for ligands to activate PPARα and PPARγ proteins, we developed a multilevel in silico-based virtual screening protocol to identify novel chemical scaffolds and further design and synthesize two distinct series of glitazone derivatives with advantages over the classical PPARα and PPARγ agonists. Moreover, the synthesized compounds were biologically evaluated for PPARα and PPARγ transactivation potency from nuclear extracts of 3T3-L1 cell. Furthermore, glucose uptake assay on L6 cells confirmed the potency of the synthesized compounds toward glucose regulation. Percentage lipid-lowering potency was also assessed through triglyceride estimate from 3T3-L1 cell extracts. Results suggested the ligand binding mode was in orthosteric fashion as similar to classical agonists. Thus molecular docking and molecular dynamics (MD) simulation experiments were executed to validate our hypothesis on mode of ligands binding and protein complex stability. Altogether, the present study developed a newer protocol for virtual screening and enables to design of novel glitazones for activation of PPARα and PPARγ-mediated pathways. Accordingly, present approach will offer benefit as a therapeutic strategy against type 2 diabetes mellitus and associated metabolic complications.
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Diabetes Mellitus Tipo 2 , Simulación de Dinámica Molecular , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , PPAR alfa/agonistas , PPAR alfa/metabolismo , Simulación del Acoplamiento Molecular , Agonistas de PPAR-gamma , PPAR gamma/agonistas , PPAR gamma/metabolismo , Glucosa/uso terapéuticoRESUMEN
Previously, solid-state electrode materials have been utilized for the fabrication of energy storage devices; however, their application is impeded by their brittle nature and ion mobility problems. To address issues faced in such a modern era where energy saving and utility is of prior importance, a novel approach has been applied for the preparation of electrode materials based on polyacrylamide hydrogels embedded with reduced graphene oxide and transition metals, namely, Cu2+ and Zn2+. The fabricated hydrogel exhibits high electrical properties and flexibility that make it a favorable candidate to be used in energy storage devices, where both elastic and electrical properties are desired. For the first time, a multi-cross-linked polyacrylamide hydrogel was constructed and compared in the presence of other electro-active materials such as reduced graphene oxide and transition metals. Polyacrylamide hydrogels embedded with reduced graphene oxide demonstrate excellent electrical properties such as specific capacitance, least impedance, low phase angle shift and AC conductivity of 22.92 F g-1, 2115 Ω, 2.88° and 0.67 µÎ´ m-1 respectively as compared to Cu2+- and Zn2+-loaded hydrogels, which block all available active sites causing an increase in impedance with a parallel decrease in capacitance. The capacitance retention and coulombic efficiency calculated were 88.22% and 77.23% respectively, indicating high stability up to 150 cycles at 0.1 A g-1. Storage moduli obtained were 10.52 kPa, which infers the more elastic nature of the hydrogel loaded with graphene oxide than that of other synthesized hydrogels.
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Eugenol is a natural product abundantly found in clove buds known for its pharmacological activities such as anti-inflammatory, antidiabetic, antioxidant, and anticancer activities. It is well known from the literature that peroxisome proliferator-activated receptors (PPARγ) have been reported to regulate inflammatory responses. In this backdrop, we rationally designed semi-synthetic derivatives of eugenol with the aid of computational studies, and synthesized, purified, and analyzed four eugenol derivatives as PPARγ agonists. Compounds were screened for PPARγ protein binding by time-resolved fluorescence (TR-FRET) assay. The biochemical assay results were favorable for 1C which exhibited significant binding affinity with an IC50 value of 10.65 µM as compared to the standard pioglitazone with an IC50 value of 1.052 µM. In addition to the protein binding studies, as a functional assay, the synthesized eugenol derivatives were screened for in vitro anti-inflammatory activity at concentrations ranging from 6.25 µM to 400 µM. Among the four compounds tested 1C shows reasonably good anti-inflammatory activity with an IC50 value of 133.8 µM compared to a standard diclofenac sodium IC50 value of 54.32 µM. Structure-activity relationships are derived based on computational studies. Additionally, molecular dynamics simulations were performed to examine the stability of the protein-ligand complex, the dynamic behavior, and the binding affinity of newly synthesized molecules. Altogether, we identified novel eugenol derivatives as potential anti-inflammatory agents via PPARγ agonism.
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Biginelli 1,4-dihydropyrimidines are extensively screened for their potential anticancer activity in the last decade. In this context, a series of Biginelli 1,4-dihydropyrimidines were designed and synthesised using PTSA as an efficient catalyst. The synthesised 1,4-dihydropyrimidines were screened for their anticancer activity against MCF-7 breast cancer cells by measuring cytotoxicity. The compounds exhibited activity ranging from weak to significant in terms of percentage cytotoxicity which is proportional to the anticancer activity. Amongst the screened compounds, compounds 4, 6 and 8 exhibited potential anticancer activity. Furthermore, CoMSIA studies were performed to derive the structure activity relationships in a 3D grid space by plotting experimental vs predicted cytotoxic activities. We have an opinion that, this developed model helps us in future to develop more potential 1,4-dihydropyrimidines for their cytotoxicity or anticancer activity.
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Antineoplásicos/farmacología , Diseño de Fármacos , Pirimidinas/farmacología , Relación Estructura-Actividad Cuantitativa , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/químicaRESUMEN
Peroxisome proliferator-activated receptor gamma (PPARγ), a member of the nuclear receptor superfamily is an excellent example of targets that orchestrates cancer, inflammation, lipid and glucose metabolism. We report a protocol for the development of novel PPARγ antagonists by employing 3D QSAR based virtual screening for the identification of ligands with anticancer properties. The models are generated based on a large and diverse set of PPARγ antagonist ligands by the HYPOGEN algorithm using Discovery Studio 2019 drug design software. Among the 10 hypotheses generated, Hypotheses 2 showed the highest correlation coefficient values of 0.95 with less RMS deviation of 1.193. Validation of the developed pharmacophore model was performed by Fischer's randomization and screening against test and decoy set. The GH score or goodness score was found to be 0.81 indicating moderate to a good model. The selected pharmacophore model Hypo 2 was used as a query model for further screening of 11,145 compounds from the PubChem, sc-PDB structure database, and designed novel ligands. Based on fit values and ADMET filter, the final 10 compounds with the predicated activity of ≤ 3 nM were subjected for docking analysis. Docking analysis revealed the unique binding mode with hydrophobic amino acid that can cause destabilization of the H12 which is an important molecular mechanism to prove its antagonist action. Based on high CDocker scores, Cpd31 was synthesized, purified, analyzed and screened for PPARγ competitive binding by TR-FRET assay. The biochemical protein binding results matched the predicted results. Further, Cpd31 was screened against cancer cells and validated the results.
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Anilidas/farmacología , Antineoplásicos/farmacología , Diseño de Fármacos , PPAR gamma/antagonistas & inhibidores , Algoritmos , Anilidas/síntesis química , Anilidas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Unión Competitiva/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , PPAR gamma/metabolismoRESUMEN
Chronic diseases are the leading cause of morbidity, disability and mortality worldwide. It is well established that the majority of chronic diseases can be prevented by targeting modifiable lifestyle-related risk factors. Thus, early risk assessment and mitigation at the individual level can significantly reduce the health and economic burden of chronic diseases. Lifetime health has emerged as a potential paradigm to assist individuals to avoid harmful lifestyle-related habits to reduce the risk of chronic morbidity. In this paper, we leverage eHealth and Quantified Self technologies, novel health data visualizations, and artificial intelligence methods to develop a digital-based lifetime health platform (PRISM) to empower individuals to self-assess, self-monitor, and self-manage their risks for multiple chronic diseases and associated morbidities.
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Multimorbilidad , Medición de Riesgo , Telemedicina , Enfermedad Crónica , Humanos , Factores de RiesgoRESUMEN
Actinorhizal plants contain numerous antioxidants that may play a crucial role in preventing the formation of tumors. H-Ras p21, a member of the Ras-GTPase family, is a promising target to treat various kinds of cancers. An in silico docking study was carried out to identify the inhibitory potential of compounds of these plants against H-Ras by using Discovery Studio 3.5 and by using Autodock 4.2. Docking studies revealed that four compounds, isorhamnetin-7-rhamnoside, quercetin-3-glucoside-7-rhamnoside (present in H. rhamnoides), zeaxanthin, and translutein (present in H. salicifolia) significantly bind with binding energies -17.1534, -14.7936, -10.2105 and -17.2217â Kcal/mol, respectively, even though they slightly deviate from Lipinski's rule. Absorption, distribution, metabolism, excretion and toxicity (ADME/tox) analyses of these compounds and their stereoisomers showed that they were less toxic and non-mutagenic. Amongst them, isorhamntein-7-rhamnoside showed hepatotoxicity. Hence, these compounds can be further investigated in vivo to optimize their formulation and concentration and to develop potential chemical entities for the prevention and treatment of cancers.
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Type 2 diabetes is an inevitably progressive disease, with irreversible beta cell failure. Glycogen synthase kinase and Glukokinase, two important enzymes with diverse biological actions in carbohydrate metabolism, are promising targets for developing novel antidiabetic drugs. A combinatorial structure-based molecular docking and pharmacophore modelling study was performed with the compounds of Hippophae salicifolia and H. rhamnoides as inhibitors. Docking with Discovery Studio 3.5 revealed that two compounds from H. salicifolia, viz Lutein D and an analogue of Zeaxanthin, and two compounds from H. rhamnoides, viz Isorhamnetin-3-rhamnoside and Isorhamnetin-7-glucoside, bind significantly to the GSK-3 beta receptor and play a role in its inhibition; whereas in the case of Glucokinase, only one compound from both the plants, i.e. vitamin C, had good binding characteristics capable of activation. The results help to understand the type of interactions that occur between the ligands and the receptors. Toxicity predictions revealed that none of the compounds had hepatotoxic effects and had good absorption as well as solubility characteristics. The compounds did not possess plasma protein-binding, crossing blood-brain barrier ability. Further, in vivo and in vitro studies need to be performed to prove that these compounds can be used effectively as antidiabetic drugs.
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Inhibidores Enzimáticos/química , Glucoquinasa/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Hippophae/enzimología , Hipoglucemiantes/química , Simulación del Acoplamiento Molecular , Ácido Ascórbico/química , Dominio Catalítico , Bases de Datos de Compuestos Químicos , Descubrimiento de Drogas , Glucoquinasa/química , Glucósidos/química , Glucógeno Sintasa Quinasa 3/química , Glucógeno Sintasa Quinasa 3 beta , Hippophae/química , Cinética , Luteína/química , Unión Proteica , Termodinámica , Xantófilas/química , ZeaxantinasRESUMEN
INTRODUCTION: Package insert is an officially approved document that accompanies a drug. It is intended to provide information for the safe and effective use of a drug and contains information based on regulatory guidelines. Sometimes, information provided in the package inserts is suboptimal which can led to medication errors. This study was undertaken to assess the presentation and completeness of clinical information provided in the currently available package inserts for anti-diabetic, anti-hypertensive and hypolipedemic drugs in India. MATERIAL AND METHODS: Around 130 package inserts were collected from pharmacies located at different areas of Bangalore. They were analyzed based on criteria mentioned in Schedule D of Drug and Cosmetic act 1945. RESULTS AND OBSERVATIONS: Out of 134 package inserts, 64 were anti-diabetics, 40 anti-hypertensives, and 30 hypolipedemics. Out of them, 31 (23.14%) belonged to Grade 'A' (including all injectable preparations) and remaining 76.86% to Grade 'B'. None of the PIs belonged to Grade 'C'. The inserts were inadequate in many aspects; for example, they had unclear instructions about generic name of other ingredients used, about handling, undesirable effects, pediatric and geriatric use, and guidelines for use of the drugs. CONCLUSION: This study indicated that information relevant to the safe and effective use of medication was not mentioned in the analyzed package inserts. It is, therefore, recommended to update the existing package inserts based on criteria mentioned in the Schedule D of Drug and Cosmetic Act, 1945.