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1.
Life Sci ; 258: 118179, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32758626

RESUMO

OBJECTIVE: To evaluate whether approved gastroprokinetic agent, acotiamide exerts a direct excitatory effect on bladder to help explain the reported meaningful reduction of post-void residual urine volume (PVR) in detrusor underactivity (DU) patients after thrice daily oral intake of acotiamide 100 mg for 2 weeks. METHODS: Effect of acotiamide [1-16 µM] was assessed on nerve-mediated contractions evoked by electrical field stimulation (EFS) for 5 s with 5 ms pulse trains of 10 V in longitudinal, mucosa intact rat and human bladder strips to construct frequency response curve (1-32 Hz) and repeat 10 Hz stimulation at 60s interval. Effect of acotiamide 2 µM on spontaneous and carbachol evoked contractions was also assessed. RESULTS: Acotiamide 2 µM significantly enhanced the Atropine and Tetrodotoxin (TTX)-sensitive EFS evoked contractions of rat and human bladder at 8-32 Hz (Two-way ANOVA followed Sidak's multiple comparison; *p < 0.01) and on repeat 10 Hz stimulation (Paired Student's t-test; *p < 0.05), while producing a modest effect on the spontaneous contractions and a negligible effect on the carbachol evoked contractions. CONCLUSIONS: Enhancement of TTX-sensitive evoked contractions of rat and human bladder by acotiamide is consistent with the enhancement of excitatory neuro-effector transmission mainly through prejunctional mechanisms. Findings highlight immense therapeutic potential of antimuscarinics with low M3 receptor affinity like acotiamide in Underactive bladder (UAB)/DU treatment.


Assuntos
Benzamidas/uso terapêutico , Tiazóis/uso terapêutico , Bexiga Inativa/tratamento farmacológico , Bexiga Urinária/patologia , Animais , Benzamidas/química , Benzamidas/farmacologia , Carbacol/farmacologia , Estimulação Elétrica , Humanos , Masculino , Contração Muscular/efeitos dos fármacos , Ratos Sprague-Dawley , Tiazóis/química , Tiazóis/farmacologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/inervação
2.
Chemosphere ; 261: 127762, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32738715

RESUMO

The presence of microplastics (MPs) and their effects have been widely investigated in the aquatic environment, whereas the research done in the terrestrial environment is incomparably lacking. MPs are considered a pollutant in soil on agricultural land, where they can act as a vector for other pollutants, namely organic chemical compounds, such as pesticides. In soil, presence of MPs is affecting the growth and life of microorganisms in it. The interactions between two types of MPs and three pesticides in the mixture with alluvial soil were studied. Adsorption of acetamiprid, chlorantraniliprole and flubendiamide in concentrations of 1, 5 and 10 mg L-1 onto polyester fibres and polypropylene particles of 0.5-1 mm size was studied at 1% and 5% (w/w) of their content in soil. Results showed that the adsorption of pesticides was dependent on their octanol/water partition coefficient, with the most highly adsorbed pesticide also being the most hydrophobic, regardless of the type and form of MPs. Adsorption of pesticides onto MP particles was confirmed in soil-MPs mixtures with 5% polypropylene and 5% polyester at all tested pesticides' concentrations, proving that MPs in soil systems act as carriers to pollutants. MPs in soil decreased the soil's intrinsic capacity to retain pesticides, indicating the possibility of a greater mobility of pesticides on MPs through the soil system.


Assuntos
Benzamidas/química , Microplásticos/química , Neonicotinoides/química , Poluentes do Solo/química , Sulfonas/química , ortoaminobenzoatos/química , Adsorção , Agricultura , Poluentes Ambientais , Praguicidas/química , Plásticos , Solo , Poluentes do Solo/análise
3.
Bull Environ Contam Toxicol ; 105(2): 261-269, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32666192

RESUMO

Persistence and sorption behaviour of flubendiamide in two different Indian soils as affected by maize stalk biochar was studied. The persistence was more in West Bengal soil (178.6 days) than Sikkim soil (165.3 days) at 10 µg g-1 fortification level. Biochar amendment addition to soil at 5% enhanced the degradation process and half-life (T1/2) values were 103.5 and 117.4 days, respectively for biochar amended Sikkim and West Bengal soil. Sorption study through batch equilibrium method resulted the 4 h equilibrium time with adsorption 6.22% ± 0.16% and 5.26% ± 0.16% in Sikkim and West Bengal soil, respectively. Biochar addition at 5% increased the adsorption of flubendiamide to 8.12% ± 0.16% and 5.88% ± 0.16% indicating a greater influence in this process. The adsorption was more in biochar amended Sikkim soil than West Bengal soil. The values of desorption was slower than adsorption indicating a hysteresis effect having hysteresis coefficient (H1) ranges between 0.025 and 0.151 in two test soils.


Assuntos
Benzamidas/química , Carvão Vegetal/química , Recuperação e Remediação Ambiental/métodos , Poluentes do Solo/química , Sulfonas/química , Adsorção , Benzamidas/análise , Biomassa , Carvão Vegetal/economia , Solo , Poluentes do Solo/análise , Sulfonas/análise , Zea mays
4.
Ann N Y Acad Sci ; 1475(1): 43-51, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32483859

RESUMO

There is a significant need to study the binding of active compounds to the specific sites on insect ryanodine receptors (RyRs) that are the targets of two novel classes of diamide insecticides to which insects are becoming increasingly resistant. Here, we describe a rapid assay to study the action of potential compounds on the flubendiamide (Flu) binding site of insect RyRs that uses a fluorescence polarization assay with the fluorescence probe Flu-R-L that we synthesized. The IC50 of Flu for inhibiting probe binding on insect RyR was 18.82 ng/mL. The binding of 86 novel phthalic diamide derivatives on insect RyRs was studied using this newly established assay, and the compounds that exhibited high-affinity binding in the assay also possessed in vivo insecticidal activity against Plutella xylostella. Thus, Flu-R-L is a highly selective and sensitive fluorescence probe for studying the binding affinity of novel compounds to the Flu binding site of insect RyRs. The assay based on Flu-R-L is a rapid, accurate, and sensitive method for the screening of potentially bioactive molecules that bind specifically to insect RyRs.


Assuntos
Corantes Fluorescentes/metabolismo , Mariposas/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Benzamidas/química , Sítios de Ligação , Bioensaio , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Cinética , Pirazóis/química , Reprodutibilidade dos Testes , Sulfonas/química , ortoaminobenzoatos/química
5.
J Med Chem ; 63(13): 7211-7225, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32490678

RESUMO

The recent Ebola epidemics in West Africa underscore the great need for effective and practical therapies for future Ebola virus outbreaks. We have discovered a new series of remarkably potent small molecule inhibitors of Ebola virus entry. These 4-(aminomethyl)benzamide-based inhibitors are also effective against Marburg virus. Synthetic routes to these compounds allowed for the preparation of a wide variety of structures, including a conformationally restrained subset of indolines (compounds 41-50). Compounds 20, 23, 32, 33, and 35 are superior inhibitors of Ebola (Mayinga) and Marburg (Angola) infectious viruses. Representative compounds (20, 32, and 35) have shown good metabolic stability in plasma and liver microsomes (rat and human), and 32 did not inhibit CYP3A4 nor CYP2C9. These 4-(aminomethyl)benzamides are suitable for further optimization as inhibitors of filovirus entry, with the potential to be developed as therapeutic agents for the treatment and control of Ebola virus infections.


Assuntos
Antivirais/farmacologia , Benzamidas/farmacologia , Doença pelo Vírus Ebola/virologia , Doença do Vírus de Marburg/virologia , Internalização do Vírus/efeitos dos fármacos , Células A549 , Animais , Antivirais/química , Benzamidas/química , Chlorocebus aethiops , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/farmacologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Toremifeno/química , Toremifeno/metabolismo , Toremifeno/farmacologia , Células Vero , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/metabolismo
6.
Toxicol Lett ; 329: 12-19, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32380122

RESUMO

Being highly potent, New Synthetic Opioids (NSO) have become a public health concern. Little is known though about the metabolism and toxicokinetics (TK) of many of the non fentanyl NSO such as U-47700. Obtaining such data in humans is challenging and so we investigated if pigs were a suitable model species as TK model for U-47700. The metabolic fate of U-47700 was elucidated after intravenous administration to one pig in vivo and results were compared to metabolic patterns formed by different other in vitro systems (human and pig liver microsomes, human liver S9 fraction) and compared to rat and human in vivo data. Furthermore, monooxygenase isozymes responsible for the major metabolic steps were elucidated. In total, 12 phase I and 8 phase II metabolites of U-47700 could be identified. The predominant reactions were N-demethylation, hydroxylation, and combination of them followed by glucuronidation or sulfation. The most predominant monooxygenase catalyzed conversions were N-demethylation, and hydroxylation by CYP3A4 and 2B6, and FMO3 catalyzed N-oxidation. Similar main phase I metabolites were found in vitro as compared to in vivo (pig/human). The metabolic pattern elucidated in the pig was comparable to human in vivo data. Thus, pigs seem to be a suitable animal model for metabolism and further TK of U-47700.


Assuntos
Benzamidas/metabolismo , Psicotrópicos/metabolismo , Suínos/metabolismo , Animais , Benzamidas/sangue , Benzamidas/química , Benzamidas/urina , Modelos Animais de Doenças , Humanos , Masculino , Estrutura Molecular , Psicotrópicos/sangue , Ratos
7.
Chem Biol Interact ; 326: 109137, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32442417

RESUMO

In the present study eighteen inhibitors of the hydrolytic enzymes of the endocannabinoid system were investigated for antioxidant activity using lipid peroxidation (LP) method. Among the assayed compounds ten belong to carbamates with phenyl [1,1'-biphenyl]-3-ylcarbamate (6), reported for the first time, and eight are retro-amide derivatives of palmitamine. Interestingly, results indicated that most of the tested compounds have good antioxidant properties. In particular, 1,3-di([1,1'-biphenyl]-3-yl)urea (3) shows IC50 = 26 ± 6 µM comparable to ones obtained for standard antioxidants trolox and quercetin (IC50 = 22 ± 6 µM and 23 ± 6 µM, respectively). Compound 3 was investigated further by means of DFT calculations, to clarify a possible mechanism of the antioxidant action. In order to estimate the capability of 3 to act as radical scavenger the structure was optimized at B3LYP/6-311++G** level and the respective bond dissociation enthalpies were calculated. The calculations in non-polar medium predicted as favorable mechanism a donation of a hydrogen atom to the free radical and formation of N-centered radical, while in polar solvents the mechanism of free radical scavenging by SPLET dominates over HAT H-abstraction. The possible radical scavenging mechanisms of another compound with potent antioxidant properties (IC50 = 53 ± 12 µM), the retro-amide derivative of palmitamine (compound 18), was estimated computationally based on the reaction enthalpies of a model compound (structural analogue to 18). The computations indicated that the most favorable mechanisms are hydrogen atom transfer from the hydroxyl group in meta-position of the benzamide fragment in nonpolar medium, and proton transfer from the hydroxyl group in ortho-position of the benzamide fragment in polar medium.


Assuntos
Compostos de Bifenilo/química , Peroxidação de Lipídeos/efeitos dos fármacos , Ureia/química , Anilidas/química , Antioxidantes/química , Benzamidas/química , Ácidos Graxos/química , Depuradores de Radicais Livres/química , Radicais Livres/química , Hidrogênio/química , Ácidos Palmíticos/química , Solventes/química
8.
Int J Pharm Compd ; 24(3): 242-245, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401744

RESUMO

Revefenacin inhalation solution, a long-acting muscarinic antagonist (LAMA), and formoterol fumarate inhalation solution, a long-acting ß-agonist (LABA), are indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease. LAMA or LABA monotherapy, or a combination of LAMA/LABA for more severe symptoms, is recommended as first-line treatment in this patient population. We conducted a study to test the physicochemical properties of revefenacin and formoterol fumarate inhalation solution admixture in support of a clinical trial evaluating the safety of these nebulized bronchodilators, administered in sequence, and as a combination, in patients with chronic obstructive pulmonary disease (NCT03573817). The admixture of these two products was evaluated for changes in appearance, pH, osmolality, active drug content, purity, and impurity/degradant levels at 25°C for up to 25 hours. No substantial changes were observed in the physicochemical properties of revefenacin inhalation solution and formoterol fumarate inhalation solution admixture, demonstrating the physicochemical compatibility and stability of the two drugs in solution for up to 25 hours at room temperature.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Benzamidas/farmacologia , Carbamatos/farmacologia , Fumarato de Formoterol/farmacologia , Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/química , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Benzamidas/química , Carbamatos/química , Quimioterapia Combinada , Humanos
9.
Nat Protoc ; 15(5): 1760-1774, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32296151

RESUMO

The direct cleavage of otherwise inert C-H bonds has emerged as a sustainable approach for organic synthesis; in contrast to other approaches, these reactions result in the formation of fewer undesired by-products and do not require pre-functionalization steps. In recent years, oxidative C-H/N-H alkyne annulations and C-H oxygenations were realized by 3d metals. Unfortunately, most of these reactions require stoichiometric amounts of often toxic chemical oxidants. This protocol provides a general method for cobaltaelectro-catalyzed C-H activations of benzamides. Here, anodic oxidation obviates the need for a chemical oxidant and uses 10-20% of a more environmentally benign, inexpensive catalyst. We outline a detailed and precise description of the designed electrolytic cell for metallaelectrocatalysis, including readily available electrode materials and electrode holders. The custom-made device is further compared with the commercially available and standardized ElectraSyn 2.0 electrochemistry kit. As example applications of this approach, we describe cobaltaelectro-catalyzed C-H activation protocols for the direct C-H oxygenation of benzamides and resource-economical synthesis of isoquinolones. The cobaltaelectrocatalysis setup and reaction take about 17 h, while an additional 5 h have to be anticipated for workup and chromatographic purification. The methods described herein feature broad functional group tolerance, operational simplicity, low waste-product formation and an overall exceptional level of resource economy.


Assuntos
Benzamidas/química , Técnicas de Química Sintética/métodos , Cobalto/química , Técnicas Eletroquímicas/métodos , Catálise , Oxirredução
10.
Biochim Biophys Acta Proteins Proteom ; 1868(6): 140412, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32179183

RESUMO

Matrix metalloproteinases (MMPs) are zinc-dependent extracellular matrix remodeling endopeptidases. MMPs cleave various matrix proteins such as collagen, elastin, gelatin and casein. MMPs are often implicated in pathological processes, such as cancer progression including metastasis. Meanwhile, microorganisms produce various secondary metabolites having unique structures. We designed and synthesized dehydroxymethylepoxyquinomicin (DHMEQ) based on the structure of epoxyquinomicin C derived from Amycolatopsis as an inhibitor of NF-κB. This compound inhibited cancer cell migration and invasion. Since DHMEQ is comparatively unstable in the body, we designed and synthesized a stable DHMEQ analog, SEMBL. SEMBL also inhibited cancer cell migration and invasion. We also looked for inhibitors of cancer cell migration and invasion from microbial culture filtrates. As a result, we isolated a known compound, ketomycin, from Actinomycetes. DHMEQ, SEMBL, and ketomycin are all NF-κB inhibitors, and inhibited the expression of MMPs in the inhibition of cellular migration and invasion. These are all compounds with comparatively low toxicity, and may be useful for the development of anti-metastasis agents.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/antagonistas & inibidores , Cicloexanonas/antagonistas & inibidores , Metaloproteinases da Matriz/efeitos dos fármacos , Metaloproteinases da Matriz/metabolismo , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Actinobacteria/metabolismo , Animais , Antineoplásicos/química , Benzamidas/síntese química , Benzamidas/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Cicloexanonas/síntese química , Glioxilatos/antagonistas & inibidores , Glioxilatos/metabolismo , Humanos , Metaloproteinase 11 da Matriz/efeitos dos fármacos , Metaloproteinase 11 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Modelos Moleculares , Subunidade p50 de NF-kappa B/metabolismo , Invasividade Neoplásica , Neoplasias , Quinonas/química
11.
Eur J Med Chem ; 192: 112158, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32171161

RESUMO

Microtubule-targeting agents (MTA) have enjoyed significant clinical success for decades. However, several mechanisms may cause inactivation of such drugs, leading to acquired resistance in patients treated with them. Therefore, drugs containing a stilbene-like skeleton and possessing dual inhibitory activity may provide a new and differentiated treatment for patients to overcome challenging acquired resistance. A new compound (16c) displays promising anticancer activity with GI50 of 22 ± 2 and 12 ± 0.1 nM in vincristine-resistant nasopharyngeal (KB-Vin) cancer cells and etoposide-resistant nasopharyngeal (KB-7D) cancer cells and is better than vincristine, etoposide, ABT-751, and MS-275. A mechanistic study revealed that 16c interferes with the cell cycle distribution and induces cell cycle arrest at the G2/M phase and severe mitotic spindle defects followed by apoptosis. In addition, it produces much more significant cytotoxicity than vincristine and etoposide in the corresponding resistant cells, indicating that it may be a promising candidate to overcome drug resistance in cancer cells. Compound 16c also displays inhibitory activity against HDAC 1 and HDAC 2 with IC50 values of 1.07 µM, and 1.47 µM, respectively. These findings may lead to a new type of structural motif for future development of drugs that could overcome acquired resistance to MTAs.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Microtúbulos/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Benzamidas/síntese química , Benzamidas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade , Vincristina/farmacologia
12.
PLoS One ; 15(2): e0229149, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32097423

RESUMO

The paper presents the results of studies conducted with the use of stationary and time-resolved fluorescence spectroscopy for the new derivative 2-Hydroxy-N-(2-phenylethyl)benzamide (SAL-3) in aqueous solutions with various concentrations of hydrogen ions as well as in solvent mixtures (i.e. media with changing polarity/polarizability). For the compound selected for the study placed in aqueous solutions with varying concentrations of hydrogen ions, the fluorescence emission spectra revealed a single emission band within most of the pH range, however, at low pH (pH<3) a significant broadening (noticeable effect of dual fluorescence) and shifting of the band was observed. Whereas, for water and polar (protic) solvents, we observed a very interesting phenomenon of dual fluorescence never before reported for this particular group of analogues (with the specific substituent system). Based on the results of the experiments, it was observed that the presented effects may be related both with conformational effects (related to the possible positioning of the-OH group on the side of the carbonyl system, which facilitates the possibility of proton transfer) as well as, most importantly, the effects of excited state intramolecular proton transfer (ESIPT-Excited State Intramolecular Proton Transfer) related in this case with the necessary (new/previously unobserved in published literature) presence of ionic and non-ionic forms of the compound). Both the conducted quantum-mechanical [TD]DFT-Time-Dependent Density Functional Theory) calculations and excited state dipole moment change calculations for the analyzed molecule in solvents with varying pH confirmed the association between the observed fluorescence phenomena and the two aforementioned effects.


Assuntos
Benzamidas/química , Espectrometria de Fluorescência , Corantes Fluorescentes/química , Concentração de Íons de Hidrogênio , Solventes/química
13.
J Med Chem ; 63(10): 5102-5118, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32083858

RESUMO

Bruton's tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a central role in immunity and is considered an attractive target for treating autoimmune diseases. The use of currently marketed covalent BTK inhibitors is limited to oncology indications based on their suboptimal kinase selectivity. We describe the discovery and preclinical profile of LOU064 (remibrutinib, 25), a potent, highly selective covalent BTK inhibitor. LOU064 exhibits an exquisite kinase selectivity due to binding to an inactive conformation of BTK and has the potential for a best-in-class covalent BTK inhibitor for the treatment of autoimmune diseases. It demonstrates potent in vivo target occupancy with an EC90 of 1.6 mg/kg and dose-dependent efficacy in rat collagen-induced arthritis. LOU064 is currently being tested in phase 2 clinical studies for chronic spontaneous urticaria and Sjoegren's syndrome.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Descoberta de Drogas/métodos , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Tirosina Quinase da Agamaglobulinemia/química , Animais , Benzamidas/química , Benzamidas/metabolismo , Benzamidas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Cristalografia por Raios X/métodos , Cães , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Ligação Proteica/fisiologia , Inibidores de Proteínas Quinases/química , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Ratos , Ratos Endogâmicos Lew , Ovinos
14.
Biochim Biophys Acta Mol Cell Res ; 1867(6): 118689, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32092308

RESUMO

The non-activating allosteric modulator AZ1729, specific for free fatty acid receptor 2 (FFAR2), transfers the orthosteric FFAR2 agonists propionate and the P2Y2R specific agonist ATP into activating ligands that trigger an assembly of the neutrophil superoxide generating NADPH-oxidase. The homologous priming effect on the propionate response and the heterologous receptor cross-talk sensitized ATP response mediated by AZ1729 are functional characteristics shared with Cmp58, another non-activating allosteric FFAR2 modulator. In addition, AZ1729 also turned Cmp58 into a potent activator of the superoxide generating neutrophil NADPH-oxidase, and in agreement with the allosteric modulation concept, the effect was reciprocal in that Cmp58 turned AZ1729 into a potent activating allosteric agonist. The activation signals down-stream of FFAR2 when stimulated by the two interdependent allosteric modulators were biased in that, unlike for orthosteric agonists, the two complementary modulators together triggered an activation of the NADPH-oxidase, but not any transient rise in the cytosolic concentration of free calcium ions (Ca2+). Furthermore, following AZ1729/Cmp58 activation, the signaling by the desensitized FFAR2s was functionally selective in that the orthosteric agonist propionate could still induce a transient rise in intracellular Ca2+. The novel neutrophil activation and receptor down-stream signaling pattern mediated by the two cross-sensitizing allosteric FFAR2 modulators represent a new regulatory mechanism that controls receptor signaling.


Assuntos
Benzamidas/farmacologia , Neutrófilos/metabolismo , Fenilbutiratos/farmacologia , Receptores de Superfície Celular/agonistas , Trifosfato de Adenosina/metabolismo , Regulação Alostérica/efeitos dos fármacos , Benzamidas/química , Cálcio/metabolismo , Sinergismo Farmacológico , Humanos , Estrutura Molecular , NADPH Oxidases/metabolismo , Ativação de Neutrófilo , Neutrófilos/efeitos dos fármacos , Fenilbutiratos/química , Propionatos/metabolismo , Receptores de Superfície Celular/química , Transdução de Sinais/efeitos dos fármacos
15.
Molecules ; 25(2)2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31963723

RESUMO

Glutamate plays a crucial role in the treatment of depression by interacting with the metabotropic glutamate receptor subtype 5 (mGluR5), whose negative allosteric modulators (NAMs) are thus promising antidepressants. At present, to explore the structural features of 106 newly synthesized aryl benzamide series molecules as mGluR5 NAMs, a set of ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses were firstly carried out applying comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. In addition, receptor-based analysis, namely molecular docking and molecular dynamics (MD) simulations, were performed to further elucidate the binding modes of mGluR5 NAMs. As a result, the optimal CoMSIA model obtained shows that cross-validated correlation coefficient Q2 = 0.70, non-cross-validated correlation coefficient R2ncv = 0.89, predicted correlation coefficient R2pre = 0.87. Moreover, we found that aryl benzamide series molecules bind as mGluR5 NAMs at Site 1, which consists of amino acids Pro655, Tyr659, Ile625, Ile651, Ile944, Ser658, Ser654, Ser969, Ser965, Ala970, Ala973, Trp945, Phe948, Pro903, Asn907, Val966, Leu904, and Met962. This site is the same as that of other types of NAMs; mGluR5 NAMs are stabilized in the "linear" and "arc" configurations mainly through the H-bonds interactions, π-π stacking interaction with Trp945, and hydrophobic contacts. We hope that the models and information obtained will help understand the interaction mechanism of NAMs and design and optimize NAMs as new types of antidepressants.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Benzamidas/química , Benzamidas/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Receptor de Glutamato Metabotrópico 5/química , Sítios de Ligação , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade
16.
Eur J Med Chem ; 189: 112073, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31991336

RESUMO

In the current study, we reported a series of novel 1-H-pyrazole-3-carboxamide-based inhibitors targeting histone deacetylase (HDAC) and cyclin-dependent kinase (CDK). The representative compounds N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-(2,6-dichlorobenzamido)-1H-pyrazole-3-carboxamide (7c) and N-(4-(2-((2-aminophenyl)amino)-2-oxoethyl)phenyl)-4-(2,6-dichlorobenzamido)-1H-pyrazole-3-carboxamide (14a) with potent antiproliferative activities towards five solid cancer cell lines, showed excellent inhibitory activities against HDAC2 (IC50 = 0.25 and 0.24 nM respectively) and CDK2 (IC50 = 0.30 and 0.56 nM respectively). In addition, compounds 7c and 14a significantly inhibited the migration of A375 and H460 cells. Further studies revealed that compounds 7c and 14a could arrest cell cycle in G2/M phase and promote apoptosis in A375, HCT116, H460 and Hela cells, which was associated with increasing the intracellular reactive oxygen species (ROS) levels. More importantly, compound 7c possessed favorable pharmacokinetic properties with the intraperitoneal bioavailability of 63.6% in ICR mice, and potent in vivo antitumor efficacy in the HCT116 xenograft model. Our study demonstrated that compound 7c provides a promising strategy for the treatment of malignant tumors.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Neoplasias do Colo/tratamento farmacológico , Quinases Ciclina-Dependentes/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/química , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/química , Apoptose , Benzamidas/química , Ciclo Celular , Proliferação de Células , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Inibidores de Histona Desacetilases/química , Humanos , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Inibidores de Proteínas Quinases/química , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Environ Sci Pollut Res Int ; 27(8): 7957-7966, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31893363

RESUMO

The increased use of pesticides is the origin of multiple damages to the environment and to humans; thus, the search for new strategies to reduce or even protect the toxic effects caused by these synthetic products became a necessity. In this context, our study attempted to evaluate the protective effects of fennel essential oil (FEO), the main essential oil extracted from Faeniculum vulgare Mill., a plant with aromatic, flavorful, and medicinal uses, against toxicity induced by an insecticide-triflumuron (TFM)-in human carcinoma cells (HCT116). Our methodological approach consists of the cytotoxicity assay starting with the cell viability test, the ROS generation, the malondialdehyde (MDA) production, the DNA fragmentation, and the measurement of some antioxidant enzymes activities such as catalase (CAT) and superoxide dismutase (SOD). Also, we measured the mitochondrial transmembrane potential. The outcome of the current study showed clearly that after 2 h of HCT 116 cell pretreatment with FEO, there were increase in cell viability, reduction in ROS generation, and modulation in CAT and SOD activities induced by TFM. In the same manner, significant decreases in MDA levels were found. Mainly, the results indicated a perceptible decrease in DNA damages and a significant reduction in the mitochondrial membrane potential loss. Our work demonstrates that FEO can be an important protector against toxic effects induced by TFM in HCT 116 cells.


Assuntos
Antioxidantes/química , Benzamidas/química , Catalase/química , Neoplasias do Colo/fisiopatologia , Foeniculum , Inseticidas , Óleos Voláteis , Superóxido Dismutase/química , Benzamidas/toxicidade , Catalase/metabolismo , Neoplasias do Colo/química , Dano ao DNA , Humanos , Estresse Oxidativo
18.
Arch Pharm (Weinheim) ; 353(2): e1900231, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31808975

RESUMO

A series of 4-methoxy-3-arylamido-N-(substitutedphenyl)benzamides 6a-u were designed according to the splicing principle of structural design in the medicinal chemistry theory and were synthesized in five steps: nitration, acylation, ammoniation, reduction, and secondary ammoniation. The structures of the target compounds were characterized and verified by infrared, 1 H nuclear magnetic resonance (NMR), 13 C NMR, and electron spray ionization spectroscopy. Their in vitro antiplatelet aggregation activities induced by adenosine diphosphate (ADP) or arachidonic acid (AA) were assessed by Born's method. The biological evaluation revealed that all compounds exhibited certain levels of activities in both of the antiplatelet aggregation assays; compounds 6c (IC50 = 3.84 µM) and 6f (IC50 = 3.12 µM) displayed the strongest antiplatelet aggregation activities in the ADP-induced and AA-induced assay, separately. Moreover, compounds that had stronger activities were chosen for cell toxicity testing via the cell counting kit-8 assay. The results indicated that none of the compounds had obvious cell toxicity against L929 cells at the doses of 10 and 20 µM. It is worth pointing out that compound 6c showed the highest antiplatelet activity and the lowest cell toxicity. In general, 4-methoxy-3-arylamido-N-(substitutedphenyl)benzamides have the potential to become a kind of safer and more effective antiplatelet agents.


Assuntos
Benzamidas/farmacologia , Desenho de Fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Difosfato de Adenosina/farmacologia , Benzamidas/síntese química , Benzamidas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores da Agregação de Plaquetas/síntese química , Inibidores da Agregação de Plaquetas/química , Relação Estrutura-Atividade
19.
J Chromatogr A ; 1610: 460572, 2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-31606155

RESUMO

Recently it has been reported that immobilized chlorinated-type chiral stationary phases based on cellulose tris(3,5-dichlorophenylcarbamate) are able to express an outstanding enantioselectivity towards the structure of 2-(benzylsulfinyl)benzamide. We now introduce two homologue series of chiral sulfoxides based on the same 2-(sulfinyl)benzoyl core as the prototype of new selectands for HPLC, whose enantioselectivity could be modulable through the replacement of the benzyl group with an unbranched alkyl chain varying in length from 1 to 5 carbon atoms. HPLC parameters such as mobile phase composition and column temperature have been carefully evaluated in order to get pertinent structure-enantioselectivity relationships. The enantiomer elution order was unambiguously determined by a combined strategy involving theoretical and experimental procedures. Two cases of temperature-dependent inversion of the elution order of enantiomers in the operative temperature range of chiral chromatographic support were observed.


Assuntos
Benzamidas/química , Benzamidas/isolamento & purificação , Celulose/análogos & derivados , Cromatografia Líquida de Alta Pressão/métodos , Fenilcarbamatos/química , Fenilcarbamatos/isolamento & purificação , Celulose/química , Celulose/isolamento & purificação , Entropia , Estereoisomerismo , Sulfóxidos/química , Temperatura
20.
Nat Chem Biol ; 16(1): 7-14, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31686031

RESUMO

The investigational drugs E7820, indisulam and tasisulam (aryl-sulfonamides) promote the degradation of the splicing factor RBM39 in a proteasome-dependent mechanism. While the activity critically depends on the cullin RING ligase substrate receptor DCAF15, the molecular details remain elusive. Here we present the cryo-EM structure of the DDB1-DCAF15-DDA1 core ligase complex bound to RBM39 and E7820 at a resolution of 4.4 Å, together with crystal structures of engineered subcomplexes. We show that DCAF15 adopts a new fold stabilized by DDA1, and that extensive protein-protein contacts between the ligase and substrate mitigate low affinity interactions between aryl-sulfonamides and DCAF15. Our data demonstrate how aryl-sulfonamides neo-functionalize a shallow, non-conserved pocket on DCAF15 to selectively bind and degrade RBM39 and the closely related splicing factor RBM23 without the requirement for a high-affinity ligand, which has broad implications for the de novo discovery of molecular glue degraders.


Assuntos
Indóis/química , Peptídeos e Proteínas de Sinalização Intracelular/química , Proteólise/efeitos dos fármacos , Proteínas com Motivo de Reconhecimento de RNA/química , Sulfonamidas/química , Motivos de Aminoácidos , Animais , Benzamidas/química , Benzamidas/farmacologia , Microscopia Crioeletrônica , Transferência Ressonante de Energia de Fluorescência , Humanos , Indóis/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Cinética , Ligação Proteica , Domínios Proteicos , Mapeamento de Interação de Proteínas , Estrutura Secundária de Proteína , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Proteínas de Ligação a RNA , Spodoptera , Sulfonamidas/farmacologia , Ubiquitina-Proteína Ligases/química , Xenopus
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