Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 26.649
Filtrar
1.
Zhongguo Zhong Yao Za Zhi ; 47(16): 4292-4304, 2022 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-36046855

RESUMO

Sesquiterpene pyridine alkaloids are important components in Tripterygium plants, possessing a wide range of pharmacological activities, such as anti-inflammation immunosuppression, anti-tumor, anti-virus, and deinsectization, and are of great research value. They are composed of highly oxidized dihydro-ß-furansquiterpene and pyridine dicarboxylic acid through ester bonds. According to the structural characteristics of pyridine dicarboxylic acid fragments, they can be divided into various structural subtypes. Up to now, more than 110 sesquiterpene pyridine alkaloids have been isolated and identified from Tripterygium plants. This study reviewed the structural features and spectral(i.e., UV, IR, MS, and NMR) characteristics of sesquiterpene pyridine alkaloids and summarized the structural elucidation process in detail to provide references for their further research and development.


Assuntos
Alcaloides , Medicamentos de Ervas Chinesas , Sesquiterpenos , Alcaloides/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Estrutura Molecular , Piridinas/química , Piridinas/farmacologia , Tripterygium/química
2.
J Agric Food Chem ; 70(37): 11782-11791, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36067412

RESUMO

In this work, a series of derivatives with disulfide bonds containing pyridine, pyrimidine, thiophene, thiazole, benzothiazole, and quinoline were designed and synthesized based on the various biological activities of allicin disulfide bond functional groups. The antimicrobial activities of the target compounds were determined, and the structure-activity relationships were discussed. Among them, compound S8 demonstrated the most potent antifungal activity in vitro against Monilinia fructicola (M. fructicola), with an EC50 value of 5.92 µg/mL. Furthermore, an in vivo bioassay revealed that compound S8 exhibited equivalent curative and higher protective effects as the positive drug thiophanate methyl at a concentration of 200 µg/mL. The preliminary mechanism experiments showed that compound S8 could inhibit the growth of M. fructicola' s hyphae in a time- and concentration-dependent manner, and compound S8 could induce the shrinkage of hyphae, disrupt the integrity of the plasma membrane, and cause the damage and leakage of cell contents. More than that, compound S5 also demonstrated an excellent antibacterial effect on Xanthomonas oryzae (X. oryzae), with a MIC90 value of 1.56 µg/mL, which was superior to the positive control, thiodiazole copper.


Assuntos
Oryza , Quinolinas , Xanthomonas , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Benzotiazóis/farmacologia , Cobre/farmacologia , Dissulfetos/farmacologia , Testes de Sensibilidade Microbiana , Oryza/microbiologia , Doenças das Plantas/microbiologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Quinolinas/farmacologia , Relação Estrutura-Atividade , Ácidos Sulfínicos , Tiofanato , Tiofenos/farmacologia
3.
J Med Chem ; 65(18): 12095-12123, 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36068975

RESUMO

Few targeted drugs were approved for treatment of colorectal cancer (CRC). Cyclin-dependent kinase 8 played a vital role in regulating transcription and was a key colorectal oncogene associated to colorectal cancer. Here, through de novo drug design and in depth structure-activity relationship analysis, title compound 22, (3-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)propenamide), was discovered as a potent type II CDK8 inhibitor, which exhibited potent kinase activity with an IC50 value of 48.6 nM and could significantly inhibit tumor growth in xenografts of CRC in vivo. Further mechanism studies indicated that it could target CDK8 to indirectly inhibit ß-catenin activity, which caused downregulation of the WNT/ß-catenin signal and inducing cell cycle arrest in G2/M and S phases. More importantly, the title compound exhibited low toxicity with good bioavailability (F = 39.8%). These results could provide the reference for design of new type II CDK8 inhibitors against colorectal cancer.


Assuntos
Antineoplásicos , Neoplasias Colorretais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/patologia , Quinase 8 Dependente de Ciclina , Desenho de Fármacos , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Relação Estrutura-Atividade , beta Catenina/metabolismo
4.
Biomaterials ; 288: 121730, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35995622

RESUMO

Transforming growth factor ß (TGF-ß) is a well-known key mediator for the progression and metastasis of lung carcinoma. However, cost-effective anti-TGF-ß therapeutics for lung cancer remain to be explored. Specifically, the low efficacy in drug delivery greatly limits the clinical application of small molecular inhibitors of TGF-ß. In the present study, specific inhibitor of Smad3 (SIS3) is developed into a self-carried nanodrug (SCND-SIS3) using the reprecipitation method, which largely improves its solubility and bioavailability while reduces its nephrotoxicity. Compared to unmodified-SIS3, SCND-SIS3 demonstrates better anti-cancer effects through inducing tumor cell apoptosis, inhibiting angiogenesis, and boosting NK cell-mediated immune responses in syngeneic Lewis Lung Cancer (LLC) mouse model. Better still, it could achieve comparable anti-cancer effect with just one-fifth the dose of unmodified-SIS3. Mechanistically, RNA-sequencing analysis and cytokine array results unveil a TGF-ß/Smad3-dependent immunoregulatory landscape in NK cells. In particular, SCND-SIS3 promotes NK cell cytotoxicity by ameliorating Smad3-mediated transcriptional inhibition of Ndrg1. Furthermore, improved NK cell cytotoxicity by SCND-SIS3 is associated with higher expression of activation receptor Nkp46, and suppressed levels of Trib3 and TSP1 as compared with unmodified-SIS3. Taken together, SCND-SIS3 possesses superior anti-cancer effects with enhanced bioavailability and biocompatibility, therefore representing as a novel therapeutic strategy for lung carcinoma with promising clinical potential.


Assuntos
Carcinoma , Neoplasias Pulmonares , Nanopartículas , Animais , Carcinoma/tratamento farmacológico , Linhagem Celular Tumoral , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Nanopartículas/uso terapêutico , Piridinas/farmacologia , Pirróis/uso terapêutico , Transdução de Sinais , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo
5.
Chem Commun (Camb) ; 58(74): 10392-10395, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36039808

RESUMO

An Rh-catalyzed tandem reaction was performed to construct an AIE-active furo[2,3-c]pyridine-based photosensitizer, named LIQ-TF. LIQ-TF showed near-infrared emission with high quantum yield, and high 1O2 and ˙OH generation efficiency, and could be used for specific imaging and photodynamic ablation of Gram-positive bacteria in vitro and in vivo, showing great potential for combating multiple drug-resistant bacteria.


Assuntos
Fotoquimioterapia , Fármacos Fotossensibilizantes , Diagnóstico por Imagem , Bactérias Gram-Positivas , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Piridinas/farmacologia
6.
mBio ; 13(4): e0105622, 2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-35938724

RESUMO

Amino acid substitutions I38T and E23K in the influenza polymerase acidic (PA) protein lead to reduced susceptibility to the influenza antiviral drug baloxavir. The in vivo effectiveness of baloxavir and oseltamivir for treatment of these viruses is currently unknown. Using patient-derived influenza isolates, combination therapy was equally effective as monotherapy in reducing viral titers in the upper respiratory tract of ferrets infected with A(H1N1pdm09)-PA/E23K or A(H3N2)-PA/I38T. When treated with baloxavir plus oseltamivir, infection with a mixture of PA/I38T or PA/E23K and corresponding wild-type virus was characterized by a lower selection of viruses with reduced baloxavir susceptibility over the course of infection compared to baloxavir monotherapy. De novo emergence of the oseltamivir resistance mutation NA/H275Y occurred in ferrets treated with oseltamivir alone but not in ferrets treated with baloxavir plus oseltamivir. Our data suggest that combination therapy with influenza drugs with different mechanisms of action decreased the selection pressure for viruses with reduced drug susceptibility. IMPORTANCE Influenza viruses cause significant morbidity and mortality worldwide but can be treated with antiviral drugs. In 2018, a highly effective antiviral drug, baloxavir marboxil, was licensed. However, the selection of viruses with baloxavir resistance was relatively high following treatment, which may compromise the effectiveness of the drug. Here, we took two different influenza viruses that are resistant to baloxavir and tested the effectiveness alone and in combination with oseltamivir (a second influenza antiviral drug) in the ferret model. Our findings suggest that combination treatment may be a more effective method than monotherapy to reduce the selection of resistant viruses. These results may have important clinical implications for the treatment of influenza.


Assuntos
Influenza Humana , Tiepinas , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Dibenzotiepinas , Farmacorresistência Viral/genética , Furões , Humanos , Vírus da Influenza A Subtipo H3N2/genética , Morfolinas , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Oxazinas/farmacologia , Oxazinas/uso terapêutico , Piridinas/farmacologia , Piridonas/farmacologia , Piridonas/uso terapêutico , Tiepinas/farmacologia , Tiepinas/uso terapêutico , Triazinas/farmacologia , Triazinas/uso terapêutico
7.
J Med Chem ; 65(17): 11607-11632, 2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-35959635

RESUMO

Undesirable activation of endosomal toll-like receptors TLR7 and TLR9 present in specific immune cells in response to host-derived ligands is implicated in several autoimmune diseases and other contexts of autoreactive inflammation, making them important therapeutic targets. We report a drug development strategy identifying a new chemotype for incorporating relevant structural subunits into the basic imidazopyridine core deemed necessary for potent TLR7 and TLR9 dual antagonism. We established minimal pharmacophoric features in the core followed by hit-to-lead optimization, guided by in vitro and in vivo biological assays and ADME. A ligand-receptor binding hypothesis was proposed, and selectivity studies against TLR8 were performed. Oral absorption and efficacy of lead candidate 42 were established through favorable in vitro pharmacokinetics and in vivo pharmacodynamic studies, with IC50 values of 0.04 and 0.47 µM against TLR9 and TLR7, respectively. The study establishes imidazopyridine as a viable chemotype to therapeutically target TLR9 and TLR7 in relevant clinical contexts.


Assuntos
Receptor 7 Toll-Like , Receptor Toll-Like 9 , Imidazóis/farmacologia , Ligantes , Piridinas/farmacologia , Receptor 7 Toll-Like/metabolismo
8.
Eur J Pharmacol ; 931: 175183, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35940239

RESUMO

Tumor-specific growth signal inhibition is a major anticancer strategy. Receptor tyrosine kinases (RTKs) are the most upstream receptors for growth signaling in cancer. Therefore, inhibition of RTKs has been proposed as an efficient therapeutic target. Masitinib, a c-kit inhibitor of the c-kit RTK, was developed to treat mastocytoma in dogs. In humans, however, the antitumor efficacy of masitinib was found to be attenuated against tumor cells with mutations of the c-kit gene. Here, we report that masitinib induced cell death via the intrinsic apoptotic pathway in HepG2, a c-kit-negative hepatocellular carcinoma cell line. In masitinib-treated HepG2 cells, increases in intracellular reactive oxygen species levels, loss of mitochondrial membrane potential, and cleavage of caspase-9 were observed, activating the intrinsic apoptotic pathway. Moreover, the cytotoxicity of masitinib to HepG2 cells was suppressed by treatment with the antioxidant N-acetyl-L-cysteine or a c-Jun N-terminal kinase/stress-activated protein kinase (JNKs) inhibitor. Thus, we demonstrated that the anticancer effects of masitinib are not due to its targeting c-kit, but rather to its targeting the redox balance via the JNK pathway in HepG2 cells. These results suggest that masitinib has the potential to provide a robust antitumor effect in tumor lesions and could also be applied to a broad range of other anticancer therapies.


Assuntos
Apoptose , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Piridinas , Animais , Benzamidas , Linhagem Celular Tumoral , Cães , Células Hep G2 , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Piperidinas , Proteínas Proto-Oncogênicas c-kit/metabolismo , Piridinas/metabolismo , Piridinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Tiazóis
10.
Pestic Biochem Physiol ; 186: 105168, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35973773

RESUMO

Sulfoxaflor is a widely used pesticide in agriculture. However, the molecular effects of sublethal sulfoxaflor on honeybees (Apis mellifera L.) remain elusive. Here, the effects of a sublethal dose of sulfoxaflor (0.05 µg/bee) on the brain and midgut proteome response of the honeybee were investigated. Exposure to sublethal sulfoxaflor doses did not cause significant honeybee death, but it induced significant alterations in the brain and midgut proteomes. After sulfoxaflor challenge, 135 and 28 proteins were differentially regulated in the brain and midgut, respectively. The up-regulated proteins were mainly implicated in energy metabolism, neurotransmitter transport and drug metabolism processes, and included in particular enzymes of the citrate cycle and cellular respiration process, such as ATP citrate synthase, malate dehydrogenase, cytochrome b-c1 complex subunits, and NADH dehydrogenase. These findings suggest that honeybees enhance energy metabolism in the midgut and brain to resist sulfoxaflor challenge. Notably, treatment with sulfoxaflor resulted in a 6.8 times increase in expression levels of the major royal jelly protein 1 (MRJP1) in the brain, and knockdown of MRJP1 mRNA expression using RNA interference significantly decreased the survival rate, indicating that MRJP1 may play an important role in sulfoxaflor tolerance. Our data reveals that sulfoxaflor influences multiple processes related to both metabolism and the nervous system, and provides novel insights into the molecular basis of the honeybee brain and midgut response to sublethal dose of sulfoxaflor.


Assuntos
Proteínas de Insetos , Proteoma , Animais , Abelhas , Encéfalo , Proteínas de Insetos/metabolismo , Proteoma/análise , Proteoma/genética , Proteoma/metabolismo , Piridinas/farmacologia , Compostos de Enxofre
11.
Exp Mol Med ; 54(8): 1225-1235, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35999455

RESUMO

Crizotinib is a clinically approved tyrosine kinase inhibitor for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EML4-ALK fusion. Crizotinib was originally developed as an inhibitor of MET (HGF receptor), which is involved in the metastatic cascade. However, little is known about whether crizotinib inhibits tumor metastasis in NSCLC cells. In this study, we found that crizotinib suppressed TGFß signaling by blocking Smad phosphorylation in an ALK/MET/RON/ROS1-independent manner in NSCLC cells. Molecular docking and in vitro enzyme activity assays showed that crizotinib directly inhibited the kinase activity of TGFß receptor I through a competitive inhibition mode. Cell tracking, scratch wound, and transwell migration assays showed that crizotinib simultaneously inhibited TGFß- and HGF-mediated NSCLC cell migration and invasion. In addition, in vivo bioluminescence imaging analysis showed that crizotinib suppressed the metastatic capacity of NSCLC cells. Our results demonstrate that crizotinib attenuates cancer metastasis by inhibiting TGFß signaling in NSCLC cells. Therefore, our findings will help to advance our understanding of the anticancer action of crizotinib and provide insight into future clinical investigations.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Crizotinibe/farmacologia , Crizotinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Fator de Crescimento Transformador beta
12.
Bioorg Chem ; 128: 106074, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35987188

RESUMO

The imidazo[1,2-a]pyridine-3-carboxyamides (IAPs) are a unique class of compounds endowed with impressive nanomolar in vitro potency against Mycobacterium tuberculosis (Mtb) as exemplified by clinical candidate Telacebec (Q203). These compounds target mycobacterial respiration through inhibition of the QcrB subunit of cytochrome bc1:aa3 super complex resulting in bacteriostatic efficacy in vivo. Our labs have had a long-standing interest in the design and development of IAPs. However, some of these compounds suffer from short in vivo half-lives, requiring multiple daily dosing or the addition of a cytochrome P450 inhibitor for murine efficacy evaluations. Deuteration has been shown to decrease metabolism as the C-D bond is stronger than the CH bond. Herein we describe our efforts on design and synthesis of potent deuterated IAPs and the effect that deuteration has upon metabolism through microsomal stability studies.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Animais , Antituberculosos/química , Humanos , Camundongos , Piridinas/metabolismo , Piridinas/farmacologia , Tuberculose/microbiologia
13.
J Med Chem ; 65(16): 11257-11269, 2022 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-35922963

RESUMO

Cryptococcus neoformans and Cryptococcus gattii can cause fatal invasive infections, especially in immunocompromised patients. However, few antifungal drugs are available to help treat cryptococcosis. In this study, by compound library screening, we presented the first report of hit compound P163-0892, which had potent in vitro and in vivo antifungal activity against Cryptococcus spp. In vitro tests showed that P163-0892 was not cytotoxic and had highly selective and strong antifungal activities against Cryptococcus spp. with MIC values less than 1 µg/mL. Synergism of P163-0892 and fluconazole was also observed in vitro. The in vivo antifungal efficacy of P163-0892 was assessed in a wax moth larval fungal infection model, and treatment with 10 mg/kg P163-0892 caused a significant reduction in fungal burden and significant extension of the survival time. Taken together, our data indicate that the hit compound P163-0892 warrants further investigation as a novel anti-Cryptococcus agent.


Assuntos
Criptococose , Cryptococcus gattii , Cryptococcus neoformans , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Criptococose/tratamento farmacológico , Criptococose/microbiologia , Fluconazol/farmacologia , Testes de Sensibilidade Microbiana , Oxotremorina/análogos & derivados , Piridinas/farmacologia , Piridinas/uso terapêutico
14.
Neurourol Urodyn ; 41(7): 1528-1538, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35870169

RESUMO

OBJECTIVE: To examine the effects of the selective 5-HT1A receptor agonist, NLX-112, on urethral function in streptozotocin-induced diabetic rats. MATERIALS AND METHODS: Female Sprague-Dawley rats (n = 32) were divided into two groups: rats with type 1 diabetes mellitus (T1DM) and age-matched normal control rats (NC). T1DM was induced by intraperitoneal injection of streptozotocin (65 mg/kg). Isovolumetric cystometry and urethral perfusion pressure (UPP) were evaluated 10 weeks postinjection in rats (n = 9 per group). The selective 5-HT1A receptor antagonist, WAY-100635 maleate salt, was administered after NLX-112 hydrochloride dose-response curve was generated (intravenously). The remaining rats were used for immunofluorescence and Western blot assays. RESULTS: Compared to controls, type 1 diabetic rats (T1D rats) had lower maximal intravesical pressure (IP max) and UPP changes. In T1D rats, NLX-112 hydrochloride (0.003-1.0 mg/kg) induced dose-dependent decreases in UPP nadir, IP max, high-frequency oscillations (HFOs) rate; and increases in UPP change and HFOs amplitude. WAY-100635 maleate salt (0.3 mg/kg) partially or completely reversed the NLX-112-induced changes. Immunofluorescence revealed that 5-HT1A receptors were found in the L6-S1 spinal cord dorsolateral nucleus, but the expression was significantly higher in the T1D rats. Additionally, Western blot showed there were significantly more 5-HT1A receptors in the ventral L6-S1 spinal cord of T1D rats. CONCLUSIONS: Urethral dysfunction in T1D rats was improved by NLX-112. 5-HT1A receptors were upregulated in the dorsolateral nucleus of L6-S1 spinal cord in T1D rats. These findings suggest that NLX-112 may constitute a novel therapeutic strategy to treat diabetic urethral dysfunction.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Piperidinas , Piridinas , Antagonistas do Receptor 5-HT1 de Serotonina , Uretra , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/complicações , Feminino , Maleatos , Piperidinas/farmacologia , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina , Serotonina , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Estreptozocina , Uretra/fisiopatologia
15.
Nature ; 607(7920): 816-822, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35831507

RESUMO

Wnt signalling is essential for regulation of embryonic development and adult tissue homeostasis1-3, and aberrant Wnt signalling is frequently associated with cancers4. Wnt signalling requires palmitoleoylation on a hairpin 2 motif by the endoplasmic reticulum-resident membrane-bound O-acyltransferase Porcupine5-7 (PORCN). This modification is indispensable for Wnt binding to its receptor Frizzled, which triggers signalling8,9. Here we report four cryo-electron microscopy structures of human PORCN: the complex with the palmitoleoyl-coenzyme A (palmitoleoyl-CoA) substrate; the complex with the PORCN inhibitor LGK974, an anti-cancer drug currently in clinical trials10; the complex with LGK974 and WNT3A hairpin 2 (WNT3Ap); and the complex with a synthetic palmitoleoylated WNT3Ap analogue. The structures reveal that hairpin 2 of WNT3A, which is well conserved in all Wnt ligands, inserts into PORCN from the lumenal side, and the palmitoleoyl-CoA accesses the enzyme from the cytosolic side. The catalytic histidine triggers the transfer of the unsaturated palmitoleoyl group to the target serine on the Wnt hairpin 2, facilitated by the proximity of the two substrates. The inhibitor-bound structure shows that LGK974 occupies the palmitoleoyl-CoA binding site to prevent the reaction. Thus, this work provides a mechanism for Wnt acylation and advances the development of PORCN inhibitors for cancer treatment.


Assuntos
Aciltransferases , Proteínas de Membrana , Via de Sinalização Wnt , Acilação/efeitos dos fármacos , Aciltransferases/antagonistas & inibidores , Aciltransferases/metabolismo , Antineoplásicos , Sítios de Ligação , Coenzima A/metabolismo , Microscopia Crioeletrônica , Histidina , Humanos , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Pirazinas/farmacologia , Piridinas/farmacologia , Serina , Especificidade por Substrato , Via de Sinalização Wnt/efeitos dos fármacos , Proteína Wnt3A
16.
Antimicrob Agents Chemother ; 66(8): e0008322, 2022 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-35861550

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the infectious agent that has caused the current coronavirus disease (COVID) pandemic. Viral infection relies on the viral S (spike) protein/cellular receptor ACE2 interaction. Disrupting this interaction would lead to early blockage of viral replication. To identify chemical tools to further study these functional interfaces, 139,146 compounds from different chemical libraries were screened through an S/ACE2 in silico virtual molecular model. The best compounds were selected for further characterization using both cellular and biochemical approaches, reiterating SARS-CoV-2 entry and the S/ACE2 interaction. We report here two selected hits, bis-indolyl pyridine AB-00011778 and triphenylamine AB-00047476. Both of these compounds can block the infectivity of lentiviral vectors pseudotyped with the SARS-CoV-2 S protein as well as wild-type and circulating variant SARS-CoV-2 strains in various human cell lines, including pulmonary cells naturally susceptible to infection. AlphaLISA and biolayer interferometry confirmed a direct inhibitory effect of these drugs on the S/ACE2 association. A specific study of the AB-00011778 inhibitory properties showed that this drug inhibits viral replication with a 50% effective concentration (EC50) between 0.1 and 0.5 µM depending on the cell lines. Molecular docking calculations of the interaction parameters of the molecules within the S/ACE2 complex from both wild-type and circulating variants of the virus showed that the molecules may target multiple sites within the S/ACE2 interface. Our work indicates that AB-00011778 constitutes a good tool for modulating this interface and a strong lead compound for further therapeutic purposes.


Assuntos
COVID-19 , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2 , COVID-19/tratamento farmacológico , Humanos , Simulação de Acoplamento Molecular , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Peptidil Dipeptidase A/farmacologia , Ligação Proteica , Piridinas/farmacologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus
17.
Exp Brain Res ; 240(9): 2339-2348, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35859208

RESUMO

Cerebellar ataxia is a neurodegenerative disorder leading to severe motor incoordination. Recently, it has been suggested that cannabinoids play a role in modulating ataxic symptoms. To understand the possible therapeutic effect of cannabinoids for the management of cerebellar ataxia, we used cannabinoid agonist/antagonists to target the cannabinoid type 1 receptor (CB1R) in the 3 acetyl pyridine (3AP) rat model of ataxia. The role of the CB1R was examined using three different doses of the CB1R agonist, WIN-55,212-2 (WIN; 0.1, 0.5, 1 mg/kg) administrated 30 min prior to 3AP (55 mg/kg, i.p.) which leads to motor impairment through destruction of the inferior olive. In some groups, the CB1R antagonist AM251 (1 mg/kg) was given in combination with WIN. Locomotor activity and motor coordination were impaired by 3AP, and the application of WIN did not ameliorate this effect. However, the abnormal gait, rearing and grooming caused by 3AP were prevented by co-administration of AM251 with WIN. While the addition of the CB1R antagonist improved some ataxic symptoms, there was no effect of AM251 on balance or locomotor activity when co-administrated with WIN. Behavioral testing indicated that not only did WIN fail to exert any protective effect on ataxic symptoms; it exacerbated ataxic symptoms, suggesting that CB1R agonists may not be the ideal therapeutic drug in this disorder. When taken together, the findings from the present study indicate that cannabinoid modulation of ataxia symptoms may not act solely through CB1Rs and other cannabinoid receptors should be considered in future studies.


Assuntos
Canabinoides , Ataxia Cerebelar , Animais , Agonistas de Receptores de Canabinoides/farmacologia , Agonistas de Receptores de Canabinoides/uso terapêutico , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Ataxia Cerebelar/tratamento farmacológico , Piridinas/farmacologia , Piridinas/uso terapêutico , Ratos , Receptor CB1 de Canabinoide
18.
Int J Mol Sci ; 23(13)2022 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-35805988

RESUMO

New antithrombotic medications with less effect on haemostasis are needed for the long-term treatment of acute coronary syndromes (ACS). The platelet receptor glycoprotein VI (GPVI) is critical in atherothrombosis, mediating platelet activation at atherosclerotic plaque. The inhibition of spleen tyrosine kinase (Syk) has been shown to block GPVI-mediated platelet function. The aim of our study was to investigate if the Syk inhibitor fostamatinib could be repurposed as an antiplatelet drug, either alone or in combination with conventional antiplatelet therapy. The effect of the active metabolite of fostamatinib (R406) was assessed on platelet activation and function induced by atherosclerotic plaque and a range of agonists in the presence and absence of the commonly used antiplatelet agents aspirin and ticagrelor. The effects were determined ex vivo using blood from healthy volunteers and aspirin- and ticagrelor-treated patients with ACS. Fostamatinib was also assessed in murine models of thrombosis. R406 mildly inhibited platelet responses induced by atherosclerotic plaque homogenate, likely due to GPVI inhibition. The anti-GPVI effects of R406 were amplified by the commonly-used antiplatelet medications aspirin and ticagrelor; however, the effects of R406 were concentration-dependent and diminished in the presence of plasma proteins, which may explain why fostamatinib did not significantly inhibit thrombosis in murine models. For the first time, we demonstrate that the Syk inhibitor R406 provides mild inhibition of platelet responses induced by atherosclerotic plaque and that this is mildly amplified by aspirin and ticagrelor.


Assuntos
Placa Aterosclerótica , Trombose , Aminopiridinas , Animais , Aspirina , Fibrinolíticos/farmacologia , Fibrinolíticos/uso terapêutico , Humanos , Camundongos , Morfolinas , Oxazinas/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/uso terapêutico , Piridinas/farmacologia , Pirimidinas , Trombose/tratamento farmacológico , Ticagrelor/farmacologia
19.
J Med Chem ; 65(15): 10419-10440, 2022 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-35862732

RESUMO

Activated factor XI (FXIa) inhibitors are promising novel anticoagulants with low bleeding risk compared with current anticoagulants. The discovery of potent FXIa inhibitors with good oral bioavailability has been challenging. Herein, we describe our discovery effort, utilizing nonclassical interactions to improve potency, cellular permeability, and oral bioavailability by enhancing the binding while reducing polar atoms. Beginning with literature-inspired pyridine N-oxide-based FXIa inhibitor 1, the imidazole linker was first replaced with a pyrazole moiety to establish a polar C-H···water hydrogen-bonding interaction. Then, structure-based drug design was employed to modify lead molecule 2d in the P1' and P2' regions, with substituents interacting with key residues through various nonclassical interactions. As a result, a potent FXIa inhibitor 3f (Ki = 0.17 nM) was discovered. This compound demonstrated oral bioavailability in preclinical species (rat 36.4%, dog 80.5%, and monkey 43.0%) and displayed a dose-dependent antithrombotic effect in a rabbit arteriovenous shunt model of thrombosis.


Assuntos
Fator XIa , Piridinas , Animais , Anticoagulantes/química , Anticoagulantes/farmacologia , Cães , Desenho de Fármacos , Fator XIa/metabolismo , Piridinas/farmacologia , Coelhos , Ratos
20.
Int J Mol Sci ; 23(15)2022 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-35897709

RESUMO

Herpes simplex virus type-1 (HSV-1) infection causes several disorders, and acyclovir is used as a reference compound. However, resistant strains are commonly observed. Herein, we investigate the effects of N-heterocyclic compounds (pyrazolopyridine derivatives), named ARA-04, ARA-05, and AM-57, on HSV-1 in vitro replication. We show that the 50% effective concentration (EC50) values of the compounds ARA-04, ARA-05, and AM-57 were 1.00 ± 0.10, 1.00 ± 0.05, and 0.70 ± 0.10 µM, respectively. These compounds presented high 50% cytotoxic concentration (CC50) values, which resulted in a selective index (SI) of 1000, 1000, and 857.1 for ARA-04, ARA-05, and AM-57, respectively. To gain insight into which step of the HSV-1 replication cycle these molecules would impair, we performed adsorption and penetration inhibition assays and time-of-addition experiments. Our results indicated that ARA-04 and ARA-05 affected viral adsorption, while AM-57 interfered with the virus replication during its α- and γ-phases and decreased ICP27 content during initial and late events of HSV-1 replication. In addition, we also observed that AM-57 caused a strong decrease in viral gD content, which was reinforced by in silico calculations that suggested AM-57 interacts preferentially with the viral complex between a general transcription factor and virion protein (TFIIBc-VP16). In contrast, ARA-04 and ARA-05 interact preferentially in the proteins responsible for the viral adsorption process (nectin-1 and glycoprotein). Thus, our results suggest that the 1H-pyrazolo[3,4-b]pyridine derivatives inhibit the HSV-1 replicative cycle with a novel mechanism of action, and its scaffold can be used as a template for the synthesis of promising new molecules with antiviral effects, including to reinforce the presented data herein for a limited number of molecules.


Assuntos
Herpes Simples , Infecções por Herpesviridae , Herpesvirus Humano 1 , Aciclovir/farmacologia , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Chlorocebus aethiops , Herpes Simples/tratamento farmacológico , Infecções por Herpesviridae/tratamento farmacológico , Herpesvirus Humano 1/fisiologia , Pirazóis , Piridinas/farmacologia , Piridinas/uso terapêutico , Células Vero , Replicação Viral
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...