Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.058
Filtrar
1.
Eur J Med Chem ; 238: 114502, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35696863

RESUMO

In medicinal chemistry, 2-aminothiophene is a central five-membered heterocyclic core that is mostly synthesized using Gewald methodology. Its incorporation into a molecule can confer broad biological activities, making 2-aminothiophene an attractive scaffold for drug discovery. Another interesting feature of 2-aminothiophene moiety is its ability to act as synthon for the synthesis of biological active thiophene-containing heterocycles, conjugates or hybrids. Compounds from the 2-aminothiophene family are promising selective inhibitors and modulators in medicinal chemistry, and even exhibit effective pharmacological properties in the various clinical phases of appropriate diseases. Likewise, the biological actions of 2-aminothiophenes or their 2-N-substituted analogs are still being investigated because of their diverse mechanisms of action (e.g., pharmacophore and pharmacokinetic properties). In this review, we focus on the structure-activity relationship, the synthesis and the biological activities of 2-aminothiophene derivatives, including antiprotozoal, antiproliferative, antiviral, antibacterial, antifungal, channel and cannabinoid receptor inhibitors. Most perspective drug-candidate hits were selected for discussion and described, along with additional synthetic pathways. Since there has been several contributions in this field recently, we emphasized on the literature dedicated to 2-aminothiophenes and 2-N-substituted derivatives which have been published from 2017 to 2022.


Assuntos
Química Farmacêutica , Descoberta de Drogas , Antifúngicos/farmacologia , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologia
2.
Plant Physiol Biochem ; 184: 126-136, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35640519

RESUMO

This study explored the repair effect of Selenium nanoparticles (Se-NPs) on tomato under the stress of Penthiopyrad (Pen), and expected to select out the optimal concentration and the application time of Se-NPs, to maximize the repair effect without causing phytotoxicity. The results showed that Pen induced severe oxidative stress on tomato and inhibited the growth and flavor quality of fruit. Compared with the control, the application of 1 mg/L Se-NPs at the immature green stage significantly improved the antioxidant capacity of tomato to reduce the MDA content. Besides, the plant hormones were synthesized normally, the contents of soluble sugars, volatile compounds and nutrients were increased, and the contents of organic acids were decreased in the 1 mg/L Se-NPs + Pen treatment group, which finally repaired the fruit flavor and quality. Therefore, the application of 1 mg/L Se-NPs and at the immature green stage represented a promising strategy for repairing the inhibitory effect of Pen on tomato fruit growth and flavor quality.


Assuntos
Lycopersicon esculentum , Nanopartículas , Selênio , Antioxidantes/farmacologia , Frutas , Pirazóis , Selênio/farmacologia , Tiofenos/farmacologia
3.
Brain Res ; 1788: 147941, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35550141

RESUMO

Acrylamide is a thermal process contaminant, which gets global attention due to its neurotoxic nature and its omnipresence in carbohydrate-rich foods. Chronic exposure to acrylamide leads to neuronal deterioration and motor dysfunction. Acrylamide could severely affect the antioxidant defense system, especially in the developing brain leading to premature neurological disorders. Acrylamide forms adduct in presynaptic neurons leading to neuroinflammation which is also a factor to consider. In this present study, we have explored whether our benzo[b]thiophene analogs, 1-(3-hydroxybenzo[b]thiophen-2-yl) ethanone (BP) and 1-(3-hydroxybenzo[b]thiophen-2-yl) propan-1-one hydrate (EP) with antioxidant activity, could inhibit the acrylamide-induced neurotoxicity-like behavior in zebrafish larvae. The experiment was set up to expose 3 days post fertilized (dpf) larvae to acrylamide (0.75 mM) for 3 days with or without compounds (80 µM). Locomotion behavioral analysis, antioxidants, glutathione, and acetylcholineesterase activity in the head region were analyzed after one day of the experimental procedure. We witnessed a restoration effect on glutathione redox dynamics. Since glutathione plays a crucial role in the detoxification of acrylamide, it is necessary to maintain the glutathione redox cycle to eliminate acrylamide from the body. BP and EP reduced the pro-inflammatory transcript in the head, which correlates with the reduction in oxidative stress. Finally, BP and EP showed a positive effect on synaptic vesicle cycling transcript and partially restores the motor neuron response to stimuli. Findings in this study showed the ability of compound BP and EP possess therapeutic value in oxidative stress-associated neurological disorders.


Assuntos
Acrilamida , Síndromes Neurotóxicas , Acrilamida/toxicidade , Animais , Antioxidantes/metabolismo , Glutationa/metabolismo , Larva , Síndromes Neurotóxicas/tratamento farmacológico , Oxirredução , Estresse Oxidativo , Tiofenos/farmacologia , Peixe-Zebra/metabolismo
4.
Biochem Biophys Res Commun ; 615: 70-74, 2022 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-35605408

RESUMO

Hepatic ischemia-reperfusion injury (IRI) is an important factor in the recovery of liver function and prognosis after liver surgery. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) small molecule inhibitor SW033291 is thought to play an important role in promoting tissue regeneration. The aim of this study was to investigate the effect of 15-PGDH on ischemia-reperfusion injury in mouse liver. In this study, mice in the administered group showed lower necrosis and inflammation than control mice, partly due to reduced macrophage and neutrophil infiltration in liver tissue, as well as reduced serum or tissue levels of pro-inflammatory cytokines and oxidative stress. In addition, mice in the administered group showed increased post-injury reparation due to IRI-induced injury compared to control mice. CONCLUSION: The small molecule inhibitor SW033291 played a better role in preventing hepatic ischemia-reperfusion injury in mice and may be a potential option to prevent the development and progression of hepatic I/R.


Assuntos
Traumatismo por Reperfusão , Animais , Fígado , Camundongos , Camundongos Endogâmicos C57BL , Piridinas/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controle , Tiofenos/farmacologia
5.
Future Med Chem ; 14(11): 795-808, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35543430

RESUMO

Background: Chagas disease is a neglected tropical disease that affects millions of people worldwide and for which no effective treatment is available. Materials & methods: 17 chalcones were synthesized, for which the inhibition of cruzain and trypanocidal activity were investigated. Results: Chalcone C8 showed the highest cruzain inhibitory (IC50 = 0.536 µm) and trypanocidal activity (IC50 = 0.990 µm). Molecular docking studies showed interactions involving Asp161 and the thiophen group interacting with the S2 subsite. Furthermore, quantitative structure-activity relationship (q2 = 0.786; r2 = 0.953) and density functional theory studies were carried out, and a correlation between the lowest unoccupied molecular orbital surface and trypanocidal activity was observed. Conclusion: These results demonstrate that these chalcones are worthwhile hits to be further optimized in Chagas disease drug discovery programs.


Assuntos
Doença de Chagas , Chalcona , Chalconas , Tripanossomicidas , Trypanosoma cruzi , Doença de Chagas/tratamento farmacológico , Chalcona/farmacologia , Chalconas/farmacologia , Cisteína Endopeptidases , Humanos , Ligantes , Simulação de Acoplamento Molecular , Proteínas de Protozoários , Relação Estrutura-Atividade , Tiofenos/farmacologia , Tripanossomicidas/farmacologia
6.
Molecules ; 27(8)2022 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-35458660

RESUMO

The treatment of a variety of protozoal infections, in particular those causing disabling human diseases, is still hampered by a lack of drugs or increasing resistance to registered drugs. However, in recent years, remarkable progress has been achieved to combat neglected tropical diseases by sequencing the parasites' genomes or the validation of new targets in the parasites by novel genetic manipulation techniques, leading to loss of function. The novel amino acid hypusine is a posttranslational modification (PTM) that occurs in eukaryotic initiation factor 5A (EIF5A) at a specific lysine residue. This modification occurs by two steps catalyzed by deoxyhypusine synthase (dhs) and deoxyhypusine hydroxylase (DOHH) enzymes. dhs from Plasmodium has been validated as a druggable target by small molecules and reverse genetics. Recently, the synthesis of a series of human dhs inhibitors led to 6-bromo-N-(1H-indol-4yl)-1-benzothiophene-2-carboxamide, a potent allosteric inhibitor with an IC50 value of 0.062 µM. We investigated this allosteric dhs inhibitor in Plasmodium. In vitro P. falciparum growth assays showed weak inhibition activity, with IC50 values of 46.1 µM for the Dd2 strain and 51.5 µM for the 3D7 strain, respectively. The antimalarial activity could not be attributed to the targeting of the Pfdhs gene, as shown by chemogenomic profiling with transgenically modified P. falciparum lines. Moreover, in dose-dependent enzymatic assays with purified recombinant P. falciparum dhs protein, only 45% inhibition was observed at an inhibitor dose of 0.4 µM. These data are in agreement with a homology-modeled Pfdhs, suggesting significant structural differences in the allosteric site between the human and parasite enzymes. Virtual screening of the allosteric database identified candidate ligand binding to novel binding pockets identified in P. falciparum dhs, which might foster the development of parasite-specific inhibitors.


Assuntos
Oxirredutases atuantes sobre Doadores de Grupo CH-NH , Plasmodium , Inibidores Enzimáticos/farmacologia , Humanos , Oxigenases de Função Mista/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Plasmodium/metabolismo , Proteínas Recombinantes/metabolismo , Tiofenos/farmacologia
7.
Bioorg Chem ; 122: 105726, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35364361

RESUMO

Inflammation is considered to be an alarming signal for the progress of varied biological complications. Based on the previous reports in the literature that proved the noticeable efficacy of thiophene scaffold as well as nitrogen heterocyclic based compounds against acute and chronic inflammatory disease, a new set of thiophen-2-ylmethylene-based derivatives incorporated with various nitrogenous heterocyclic rings was synthesized and evaluated for their in vivo anti-inflammatory efficiency via applying formalin-induced paw edema bioassay using celecoxib as a standard drug. Compounds 6 and 11a displayed fast onset as well as long duration of anti-inflammatory potency better than that of celecoxib. However, compounds 4a, 7a, 7b and 9b exhibited moderate anti-inflammatory efficiency compared with celecoxib. Ulcerogenic activity and histopathology studies were also carried out. Moreover, the analgesic evaluation of some bioactive candidates revealed that compound 6 showed a promising and long acting analgesic effect exceeding that of the reference drug. While, compounds 4a and 7a displayed mild analgesic activity. Furthermore, the inhibitory effects of some potent anti-inflammatory derivatives on the production of tumor necrosis factor-alpha (TNF-α) were tested. The obtained results revealed that compounds 6 and 11a displayed a remarkable inhibitory effect on the production of TNF-α greater than that of celecoxib. Otherwise, compounds 4a and 7a showed nearly the same inhibitory effect as celecoxib. Finally, the molecular docking study was performed for the tested derivatives 4a, 4b, 6, 7a, 9a and 11a to understand the binding interactions with the active site of TNF-α.


Assuntos
Tiofenos , Fator de Necrose Tumoral alfa , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/patologia , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiofenos/farmacologia , Tiofenos/uso terapêutico
8.
Molecules ; 27(8)2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35458602

RESUMO

A series of new thiophene-containing triaryl pyrazoline derivatives, 3a-3t, were synthesized and evaluated regarding PI3K inhibition activity and anti-tumor potency based on a trial of introducing significant moieties, including pyrazoline and thiophene, and simplifying the parallel ring structures. Most of the tested compounds indicated potent PI3K inhibitory potency, with this series of compounds showing more potency for PI3Kγ than PI3Kα. The top hit 3s seemed more potent than the positive control LY294002 on inhibiting PI3Kγ (IC50 values: 0.066 µM versus 0.777 µM) and more selective from PI3Kα (Index values: 645 versus 1.74). It could be inferred that the combination of para- and meta-, as well as the modification of the electron-donating moieties, led to the improvement in potency. The anti-proliferation inhibitory activity and the enzymatic inhibition potency indicated consistent tendencies. The top hit 3s could inhibit the phosphorylation of Akt by inhibiting PI3K through the PI3K-Akt-mTOR pathway. The molecular docking simulation indicated that the binding pattern of 3s into PI3Kγ was preferable than that of PI3Kα, with more hydrogen bond, more π-involved interactions, and fewer π-sulfur interactions. The information in this work is referable for the further development of selective inhibitors for specific isoforms of PI3K.


Assuntos
Antineoplásicos , Fosfatidilinositol 3-Quinases , Antineoplásicos/farmacologia , Proliferação de Células , Simulação de Acoplamento Molecular , Estrutura Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Relação Estrutura-Atividade , Tiofenos/farmacologia
9.
Eur J Med Chem ; 236: 114368, 2022 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-35429909

RESUMO

Cathepsin C (Cat C) is involved in inflammation regulation by activating neutrophil serine proteases (NSPs). Therefore, Cat C is an attractive target for treatment of inflammatory diseases mediated by NSPs overactivation. In previous study, compounds 54 and 77 were reported to be the first non-peptidyl non-covalent Cat C inhibitors, with good enzyme inhibitory activity and NSPs activation inhibition, but their pharmacokinetic (PK) properties were unsatisfactory. In this study, starting from 77, after several rounds of structure-based design and modification, compound SF38, a novel Cat C inhibitor bearing a unique thiophene structure was identified, which exhibited strong inhibitory activity against Cat C (IC50 = 59.9 nM). Further mechanism study and in vivo evaluation showed that SF38 inhibited the Cat C activity in bone marrow and blood, decreased the activation of NSPs, and exhibited anti-inflammatory activity in an animal model of acute lung injury, with acceptable PK properties (F = 42.07%). These results enriched the structure-activity relationship (SAR) of Cat C inhibitor with thiophene structure characteristic, and proved the broad prospect of non-peptidyl non-covalent Cat C inhibitor.


Assuntos
Catepsina C , Tiofenos , Animais , Anti-Inflamatórios , Piridinas/farmacologia , Serina Endopeptidases/metabolismo , Relação Estrutura-Atividade , Tiofenos/farmacologia
10.
Bioorg Chem ; 122: 105709, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35255344

RESUMO

Breast cancer is the most common cancer type amoung post-menopausal women. Aromatase inhibitors were used in the treatment of patients. However, drug resistance may develop in long-term drug use, especially in 3rd and 4th stage (advanced) cancer cases. Therefore, there is a constant need for new agents. In this study, new triazolothiadiazine derivatives were synthesized and their anticancer activities were investigated. Compounds 2k, 2s, and 2w showed inhibitor activity against MCF-7 cell line with IC50 = 4.63 ± 0.10; 2.23 ± 0.16; 3.13 ± 0.08 µM value, respectively. As a result of in vitro aromatase enzyme inhibition test, compound 2s was the most active derivative with IC50 = 0.058 ± 0.023 µM. In addition, DNA synthesis inhibition percentages of the compounds were measured by the BrdU method. The intermolecular interactions of the promising compounds with aromatase enzyme were investigated through the SP docking approach, which revealed significant binding interaction energies associated with these compounds. Following that, the interaction's stability was assessed using a typical atomistic 100 ns dynamic simulation study. A number of parameters derived from MD simulation trajectories were computed and validated for the protein-ligand complex's stability under the dynamic conditions.


Assuntos
Antineoplásicos , Simulação de Dinâmica Molecular , Antineoplásicos/química , Proliferação de Células , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Furanos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiofenos/farmacologia
11.
Life Sci ; 298: 120507, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35358593

RESUMO

AIMS: This study aims to elucidate a systematic free-radical quenching ability of synthesized benzo[b]thiophene derivatives using in vitro assays and acrylamide induced oxidatively stressed model in zebrafish larvae. MATERIALS AND METHODS: Antioxidant activity of the compounds was evaluated using in vitro methods. The toxicity of the compounds was evaluated in Madin-Darby Canine Kidney (MDCK) cell line and zebrafish embryos. Oxidative stress was generated by acrylamide (1 mM) in zebrafish larvae and treated with compounds to evaluate the in vivo antioxidant ability. Specific fluorescence dyes were used to detect ROS generation, lipid peroxidation, and cell death followed by gene expression using RT PCR. Density functional theory (DFT) and in silico pharmacokinetics were also studied. KEY FINDINGS: Compound BP and EP have a greater in vitro free radical scavenging ability. The maximum tolerated concentration (MTC) of the compounds in zebrafish larvae is 80 µM. The antioxidant system in zebrafish larvae was dysregulated due to acrylamide exposure and improvement was found while treating acrylamide exposed larvae with compounds 1-(3-hydroxybenzo[b]thiophen-2-yl) ethanone (BP) and 1-(3-hydroxybenzo[b]thiophen-2-yl) propan-1-one hydrate (EP). Compound BP and EP enhanced the SOD and CAT activity, reduced the ROS and lipid peroxidation level, thus decreasing cell death in zebrafish larvae. Compound BP and EP also improved the glutathione redox cycle by stabilizing glutathione-related gene expressions. SIGNIFICANCE: Hydroxyl-containing compounds BP and EP are promising lead molecules for pathological conditions related to oxidative stress, which showed an attenuated effect on acrylamide-induced oxidative stress in zebrafish larvae by enhancing the glutathione redox cycle and enzymatic antioxidants.


Assuntos
Acrilamida , Peixe-Zebra , Acrilamida/toxicidade , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Cães , Glutationa/metabolismo , Radical Hidroxila/metabolismo , Larva , Oxirredução , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Tiofenos/metabolismo , Tiofenos/farmacologia
12.
Eur J Med Chem ; 233: 114195, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35255313

RESUMO

Invasive fungal infections (IFIs) are emerging as serious infectious diseases worldwide, and due to the lack of effective antifungal agents and serious drug resistance, the limited efficacy of existing drugs has led to high morbidity and mortality in patients. We optimized the lead compound 7 by conformational restriction strategy to obtain a series of 3-thiophene phenyl compounds, of which compound 21b showed excellent inhibitory activity against pathogenic and drug-resistant fungi. In addition, the preferred compound 21b could prevent the formation of fungal biofilms and displayed satisfactory fungicidal activity. Furthermore, compound 21b was almost non-toxic to mammalian THLE2 and RAW264.7 cells and did not pose a risk of drug-drug interactions. These results strongly suggested that compound 21b is worthy of further study as a potential azole inhibitor.


Assuntos
Antifúngicos , Tiofenos , Animais , Antifúngicos/farmacologia , Azóis/farmacologia , Humanos , Indicadores e Reagentes , Mamíferos , Testes de Sensibilidade Microbiana , Tiofenos/farmacologia
13.
Eur J Pharm Sci ; 172: 106157, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35257876

RESUMO

BACKGROUND AND PURPOSE: Despite being a first-line clinical drug, thienopyridines have many unsatisfactory aspects, including the low bioavailability of clopidogrel(CLP) and the high bleeding risk of prasugrel. We synthesized deuterium clopidogrel(D-CL, patented in China) to alleviate the deficiency of CLP in clinical, such as a slow onset, a greater influence of gene polymorphism, and a high frequency of drug-drug interaction. EXPERIMENTAL APPROACH: Molecular docking was used to analyze the affinity between D-CL and the P2Y12 receptor. The levels of active metabolites of D-CL were detected using HPLC/MS-MS and the activities of main metabolic enzymes were analyzed; Subsequently, platelet aggregation function, thrombus model were used to evaluate the pharmacodynamics of D-CL. Finally, the safety of D-CL were evaluated through examination of blood routine, PT, APTT, bleeding time, serological tests, liver pathological biopsy, liver cell apoptosis and detection of apoptosis-related proteins. KEY RESULTS: The introduction of deuterium made the binding of CLP to P2Y12 receptor more stable, improved the concentration of active metabolites, and substantially reduced the inhibition of major metabolic enzymes, including CYP2B6, CYP2C9, and CYP2C19, thereby, exerting better antiplatelet effects without increasing the risk of bleeding, along with a concomitant decrease in the apoptosis of hepatocytes.


Assuntos
Hidrogênio , Inibidores da Agregação Plaquetária , Clopidogrel/farmacologia , Deutério/farmacologia , Ésteres do Ácido Fórmico , Hidrogênio/farmacologia , Simulação de Acoplamento Molecular , Agregação Plaquetária , Inibidores da Agregação Plaquetária/farmacologia , Tiofenos/farmacologia
14.
Arch Pharm (Weinheim) ; 355(6): e2100462, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35289443

RESUMO

Thiophene, as a member of the group of five-membered heterocycles containing one heteroatom, is one of the simplest heterocyclic systems. Many synthetic strategies allow the accurate positioning of various functionalities onto the thiophene ring. This review provides a comprehensive, systematic and detailed account of the developments in the field of antimicrobial compounds featuring at least one thiophene ring in their structure, over the last decade.


Assuntos
Anti-Infecciosos , Compostos Heterocíclicos , Antibacterianos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Compostos Heterocíclicos/química , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologia
15.
J Med Chem ; 65(4): 3359-3370, 2022 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-35148092

RESUMO

Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are emerging as attractive therapeutic targets in diseases, such as cancer, immunological disorders, and neurodegeneration, owing to their central role in regulating cell signaling pathways that are either dysfunctional or can be modulated to promote cell survival. Different modes of binding may enhance inhibitor selectivity and reduce off-target effects in cells. Here, we describe efforts to improve the physicochemical properties of the selective PI5P4Kγ inhibitor, NIH-12848 (1). These improvements enabled the demonstration that this chemotype engages PI5P4Kγ in intact cells and that compounds from this series do not inhibit PI5P4Kα or PI5P4Kß. Furthermore, the first X-ray structure of PI5P4Kγ bound to an inhibitor has been determined with this chemotype, confirming an allosteric binding mode. An exemplar from this chemical series adopted two distinct modes of inhibition, including through binding to a putative lipid interaction site which is 18 Å from the ATP pocket.


Assuntos
Trifosfato de Adenosina/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/síntese química , Quinazolinas/farmacologia , Tiofenos/síntese química , Tiofenos/farmacologia , Regulação Alostérica/efeitos dos fármacos , Ligação Competitiva , Cristalografia por Raios X , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Fosfotransferases (Aceptor do Grupo Álcool)/química , Especificidade por Substrato
16.
J Diabetes Res ; 2022: 7520632, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35224108

RESUMO

BACKGROUND: Several trials have assessed the antihyperglycemic effects of sodium/glucose cotransporter-2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM). We conducted a quantitative analysis to assess the impact of SGLT2is on serum uric acid (SUA) in patients with T2DM. METHODS: Placebo-controlled trials published before 13 August 2021 were identified by searching PubMed, Embase, Web of Science, and Scopus. The intervention group received SGLT2i as monotherapy or add-on treatment, and the control group received a placebo that was replaced with SGLT2i. Clinical trials providing changes in SUA were included. The mean change of SUA, glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and body weight were calculated (PROSPERO CRD42021287019). RESULTS: After screening of 1172 papers, 59 papers were included in the systematic review. A total of 55 trials (122 groups) of 7 types of SGLT2i on patients with T2DM were eligible for meta-analysis. All SGLT2is significantly decreased SUA levels compared with the placebo groups: empagliflozin mean difference (MD) = -40.98 µmol/L, 95% CI [-47.63, -34.32], dapagliflozin MD = -35.17 µmol/L, 95% CI [-39.68, -30.66], canagliflozin MD = -36.27 µmol/L, 95% CI [-41.62, -30.93], luseogliflozin MD = -24.269 µmol/L, 95% CI [-33.31, -15.22], tofogliflozin MD = -19.47 µmol/L, 95% CI [-27.40, -11.55], and ipragliflozin MD = -18.85 µmol/L, 95% CI [-27.20, -10.49]. SGLT2i also decreased FPG, body weight, and HbA1c levels. SUA reduction persisted during long-term treatment with SGLT2i (except for empagliflozin), while the SUA reduction was affected by the duration of diabetes. CONCLUSIONS: SGLT2i can be a valid therapeutic strategy for patients with T2DM and comorbid hyperuricemia. Besides reducing FPG, body weight, and HbA1c, SGLT2i can significantly decrease SUA levels compared to placebo (Total MD = -34.07 µmol/L, 95% CI [-37.00, -31.14]).


Assuntos
Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Ácido Úrico/metabolismo , Compostos Benzidrílicos/metabolismo , Compostos Benzidrílicos/farmacologia , Canagliflozina/metabolismo , Canagliflozina/farmacologia , Glucosídeos/metabolismo , Glucosídeos/farmacologia , Humanos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Tiofenos/metabolismo , Tiofenos/farmacologia
17.
Geriatr Gerontol Int ; 22(4): 298-304, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35212104

RESUMO

AIM: We carried out a randomized controlled trial using ipragliflozin. We analyzed changes in diastolic function using echocardiography in patients with type 2 diabetes and heart failure with preserved ejection fraction. METHODS: We carried out an open-label, multicenter, randomized, two-arm interventional trial. A total of eligible 68 participants were randomly assigned into two groups (ipragliflozin group n = 36; conventional treatment group n = 32). Primary end-points were the change in E/e' and e'. Secondary end-points were other parameters of echocardiography, plasma NT-proBNP level, New York Heart Association class, hemoglobin A1c and blood pressure. RESULTS: After 24 weeks of follow up, E/e' decreased in both groups (ipragliflozin: 11.0 vs 10.4; conventional treatment 10.5 vs 10.1; multivariate-adjusted P = 0.95). There were no significant differences in the amount of change in E/e', e', echocardiography parameters, plasma NT-proBNP level, New York Heart Association class, hemoglobin A1c and blood pressure between the two groups. In the subgroup analysis, ipragliflozin treatment decreased in left ventricular mass index in patients aged ≥70 years and also decreased in NT-proBNP levels in patients with baseline NT-proBNP ≥400 pg/mL. CONCLUSIONS: In this randomized controlled study carried out in patients with type 2 diabetes and heart failure with preserved ejection fraction, 24-week ipragliflozin treatment did not improve left ventricular diastolic function compared with conventional treatment. As the subgroup, ipragliflozin treatment decreased in left ventricular mass index in participants aged ≥70 years. Geriatr Gerontol Int 2022; 22: 298-304.


Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Idoso , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/farmacologia , Humanos , Peptídeo Natriurético Encefálico , Volume Sistólico , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Função Ventricular Esquerda/fisiologia
18.
Molecules ; 27(3)2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35164247

RESUMO

The reactivity of thiophene in Diels-Alder reactions is investigated with different maleimide derivatives. In this paper, we have synthesized for the first time the Diels-Alder adducts of thiophene at room temperature and atmospheric pressure. Maleimido-thiophene adducts were promoted by AlCl3. The effects of solvent, time, temperature and the use of different Lewis acids were studied, showing dramatic effects for solvent and Lewis acid. Furthermore, the catalysis with AlCl3 is highly stereoselective, preferably providing the exo form of the adduct. Additionally, we also discovered the ability of AlCl3 to catalyze the arylation of maleimides to yield 3-aryl succinimides in a straightforward manner following a Friedel-Crafts-type addition. The inclusion of a selenocyanate group contributes to the cytotoxic activity of the adduct. This derivatization (from compound 7 to compound 15) results in an average GI50 value of 1.98 µM in the DTP (NCI-60) cell panel, resulting in being especially active in renal cancer cells.


Assuntos
Antineoplásicos/farmacologia , Cianatos/farmacologia , Compostos de Selênio/farmacologia , Tiofenos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cianatos/química , Reação de Cicloadição , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ácidos de Lewis/química , Compostos de Selênio/química , Tiofenos/farmacologia
19.
Wiad Lek ; 75(1 pt 2): 151-155, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35182114

RESUMO

OBJECTIVE: The aim: To investigate effects of strontium ranelate on alveolar bone loss in rats with experimental diabetes. PATIENTS AND METHODS: Materials and methods: Histological examination of bone tissue was carried out for 24 white male rats, divided into three identical groups of 8 animals (the first group included animals with experimental type-2 diabetes, based on the use of Streptozotocin; in the second group, it was additionally reproduced periodontitis by the introduction of Penicillamine; and in the third group, in addition, it was used strontium ranelate) and 6 intact rats. RESULTS: Results: In the second group, osteoporosis phenomena were most significant, while in the third group the average specific area of the inter-root trabecular bone differed a little from the control. In the control group, the number of osteoclasts was 2.24 ± 1.41 cells per mm2, in the first group - 4.34 ± 1.37 cells per mm2, in the second group - 2.96 ± 1.26 cells per mm2 and in the third group - 2.24 ± 1.41 cells per mm2 (p>0.05). The samples of the third group have the most expressive manifestations of osteogenesis and the most intense expression of osteopontin, both in trabecular and compact bone tissue. CONCLUSION: Conclusions: The use of strontium drugs reliably slows down the processes of bone resorption due to both inhibition of the function of osteoclasts, and by activating osteoblasts, thus stimulating osteogenesis.


Assuntos
Perda do Osso Alveolar , Diabetes Mellitus Experimental , Compostos Organometálicos , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Masculino , Compostos Organometálicos/farmacologia , Tiofenos/farmacologia
20.
Bioorg Med Chem ; 58: 116653, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35152173

RESUMO

Aminothiophene is a scaffold that is widely present in drugs and biologically active small molecules as chemical probes. In this study, 43 compounds sharing a 2-aminothiophenone-3-carboxylate (ATPC) scaffold, known to activate the ribonuclease L (RNase L), were synthesized and selected ATPCs showed enhancement of thermal stability of RNase L upon binding. Screening of antiproliferation activities against human cancer cell lines revealed that ATPCs represented by compounds 4l and 50 showed potent single-digit micromolar antiproliferation activity against human cancer cell lines. Compounds 4l and 50 exhibited time- and dose-dependent proliferation inhibition, induced cellular apoptosis measured by cleaved PARP and via flow cytometry, inhibited cell migration, and inhibited cell colony formation. Combining the results reported in this work, ATPCs were evaluated as potential anticancer agents mediated by RNase L-binding and apoptosis induction. The work contributes to the study on the polypharmacological properties of aminothiophene-containing small molecules.


Assuntos
Antineoplásicos/farmacologia , Endorribonucleases/química , Tiofenos/farmacologia , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Endorribonucleases/metabolismo , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...