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1.
J Enzyme Inhib Med Chem ; 36(1): 1996-2009, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34525898

RESUMO

Microtubule dynamics are crucial for multiple cell functions, and cancer cells are particularly sensitive to microtubule-modulating agents. Here, we describe the design and synthesis of a series of (Z)-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl)-N-phenylacetamide derivatives and evaluation of their microtubule-modulating and anticancer activities in vitro. Proliferation assays identified I20 as the most potent of the antiproliferative compounds, with 50% inhibitory concentrations ranging from 7.0 to 20.3 µM with A549, PC-3, and HepG2 human cancer cell lines. Compound I20 also disrupted cancer A549 cell migration in a concentration-dependent manner. Immunofluorescence microscopy, transmission electron microscopy, and tubulin polymerisation assays suggested that compound I20 promoted protofilament assembly. In support of this possibility, computational docking studies revealed a strong interaction between compound I20 and tubulin Arg ß369, which is also the binding site for the anticancer drug Taxol. Our results suggest that (Z)-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl)-N-phenylacetamide derivatives could have utility for the development of microtubule-stabilising therapeutic agents.


Assuntos
Acetatos/farmacologia , Amidas/farmacologia , Antineoplásicos/farmacologia , Descoberta de Drogas , Microtúbulos/efeitos dos fármacos , Rodanina/farmacologia , Moduladores de Tubulina/farmacologia , Células A549 , Acetatos/síntese química , Acetatos/química , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Microtúbulos/metabolismo , Estrutura Molecular , Polimerização/efeitos dos fármacos , Rodanina/análogos & derivados , Rodanina/química , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
2.
J Agric Food Chem ; 69(38): 11470-11484, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34543010

RESUMO

The development of new green fungicides based on the structural optimization of natural products can effectively solve the problems of low safety and high pathogen resistance of traditional fungicides. In this paper, based on pyrazole amide compound h-I-9 with excellent fungicidal activity discovered in the previous work, a series of l-serine-derived pyrazole amide and waltherione alkaloid-derived pyrazole ester derivatives were synthesized. The structures were successively identified by 1H NMR, 13C NMR, high-resolution mass spectrometry, and X-ray single-crystal diffraction. The in vitro and in vivo fungicidal activity screening demonstrated that compound II-5 showed a good inhibition rate against Physalospora piricola. A transmission electron microscope and fluorescence microscope observation further revealed that compound II-5 may cause damage to the cell membranes and vacuoles, and the hyphae treated with II-5 could produce obvious and easily observed blue fluorescence. The succinate dehydrogenase (SDH) enzymatic activity and molecular docking simulation indicated that compounds I-3 and I-4 may be potential SDH inhibitors against Alternaria sp.


Assuntos
Alcaloides , Produtos Biológicos , Fungicidas Industriais , Alcaloides/farmacologia , Amidas/farmacologia , Produtos Biológicos/farmacologia , Ésteres , Fungicidas Industriais/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/farmacologia , Serina , Relação Estrutura-Atividade , Succinato Desidrogenase/metabolismo
3.
J Agric Food Chem ; 69(35): 10082-10092, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34432441

RESUMO

Thirty-eight novel ferulic amide 1-aminocyclohexane carboxylic acid (Ac6c) derivatives D1-D19 and E1-E19 were designed and synthesized, and their antibacterial, antifungal, and insecticidal activities were tested. Most of the synthesized compounds displayed excellent activity againstXanthomonas oryzae pv. oryzae (Xoo), with EC50 values ranging from 11.6 to 83.1 µg/mL better than that of commercial bismerthiazol (BMT, EC50 = 84.3 µg/mL), as well as much better performance compared to that of thiediazole copper (TDC, EC50 = 137.8 µg/mL). D6 (EC50 = 17.3 µg/mL), D19 (EC50 = 29.4 µg/mL), E3 (EC50 = 29.7 µg/mL), E9 (EC50 = 27.0 µg/mL), E10 (EC50 = 18.6 µg/mL), and E18 (EC50 = 20.8 µg/mL) showed much higher activity on Xanthomonas oryzae pv. oryzicola compared with BMT (EC50 = 80.1 µg/mL) and TDC (EC50 = 124.7 µg/mL). In relation to controlling the fungus, Rhizoctonia solani, E1, E10, and E13 had much lower EC50 values of 0.005, 0.140, and 0.159 µg/mL compared to hymexazol at 74.8 µg/mL. Further in vivo experiments demonstrated that E6 and E12 controlled rice bacterial leaf blight disease better than BMT and TDC did. Scanning electron microscopy (SEM) studies revealed that E12 induced the Xoo cell membrane collapse. Moreover, D13 (73.7%), E5 (80.6%), and E10 (73.4%) also showed moderate activity against Plutella xylostella. These results indicated that the synthesized ferulic amide Ac6c derivatives showed promise as candidates for treating crop diseases.


Assuntos
Oryza , Xanthomonas , Amidas/farmacologia , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana , Oxidiazóis , Doenças das Plantas , Rhizoctonia
4.
ACS Infect Dis ; 7(9): 2650-2665, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34379382

RESUMO

Antibiotic resistance poses an immediate and growing threat to human health. Multidrug efflux pumps are promising targets for overcoming antibiotic resistance with small-molecule therapeutics. Previously, we identified a diaminoquinoline acrylamide, NSC-33353, as a potent inhibitor of the AcrAB-TolC efflux pump in Escherichia coli. This inhibitor potentiates the antibacterial activities of novobiocin and erythromycin upon binding to the membrane fusion protein AcrA. It is also a substrate for efflux and lacks appreciable intrinsic antibacterial activity of its own in wild-type cells. Here, we have modified the substituents of the cinnamoyl group of NSC-33353, giving rise to analogs that retain the ability to inhibit efflux, lost the features of the efflux substrates, and gained antibacterial activity in wild-type cells. The replacement of the cinnamoyl group with naphthyl isosteres generated compounds that lack antibacterial activity but are both excellent efflux pump inhibitors and substrates. Surprisingly, these inhibitors potentiate the antibacterial activity of novobiocin but not erythromycin. Surface plasmon resonance experiments and molecular docking suggest that the replacement of the cinnamoyl group with naphthyl shifts the affinity of the compounds away from AcrA to the AcrB transporter, making them better efflux substrates and changing their mechanism of inhibition. These results provide new insights into the duality of efflux substrate/inhibitor features in chemical scaffolds that will facilitate the development of new efflux pump inhibitors.


Assuntos
Proteínas de Escherichia coli , Amidas/farmacologia , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Humanos , Simulação de Acoplamento Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética
5.
Int J Mol Sci ; 22(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34445417

RESUMO

This study aimed to assess the neuro-regenerative properties of co-ultramicronized PEALut (Glialia®), composed of palmitoylethanolamide (PEA) and the flavonoid luteolin (Lut), in an in vivo model of traumatic brain injury (TBI) and patients affected by moderate TBI. An increase in neurogenesis was seen in the mice at 72 h and 7 d after TBI. The co-ultra PEALut treatment helped the neuronal reconstitution process to restore the basal level of both novel and mature neurons; moreover, it induced a significant upregulation of the neurotrophic factors, which ultimately led to progress in terms of memory recall during behavioral testing. Moreover, our preliminary findings in a clinical trial suggested that Glialia® treatment facilitated neural recovery on working memory. Thus, co-ultra PEALut (Glialia®) could represent a valuable therapeutic agent for intensifying the endogenous repair response in order to better treat TBI.


Assuntos
Amidas/administração & dosagem , Lesões Encefálicas Traumáticas/tratamento farmacológico , Etanolaminas/administração & dosagem , Luteolina/administração & dosagem , Neurogênese/efeitos dos fármacos , Ácidos Palmíticos/administração & dosagem , Administração Oral , Adulto , Idoso , Amidas/farmacologia , Animais , Lesões Encefálicas Traumáticas/etiologia , Lesões Encefálicas Traumáticas/psicologia , Modelos Animais de Doenças , Quimioterapia Combinada , Etanolaminas/farmacologia , Feminino , Humanos , Luteolina/farmacologia , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Pessoa de Meia-Idade , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Ácidos Palmíticos/farmacologia , Distribuição Aleatória , Aprendizagem Espacial/efeitos dos fármacos , Resultado do Tratamento
6.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361792

RESUMO

Glycogen phosphorylase (GP) is a key enzyme in the glycogenolysis pathway and a potential therapeutic target in the management of type 2 diabetes. It catalyzes a reversible reaction: the release of the terminal glucosyl residue from glycogen as glucose 1-phosphate; or the transfer of glucose from glucose 1-phosphate to glycogen. A colorimetric method to follow in vitro the activity of GP with usefulness in structure-activity relationship studies and high-throughput screening capability is herein described. The obtained results allowed the choice of the optimal concentration of enzyme of 0.38 U/mL, 0.25 mM glucose 1-phosphate, 0.25 mg/mL glycogen, and temperature of 37 °C. Three known GP inhibitors, CP-91149, a synthetic inhibitor, caffeine, an alkaloid, and ellagic acid, a polyphenol, were used to validate the method, CP-91149 being the most active inhibitor. The effect of glucose on the IC50 value of CP-91149 was also investigated, which decreased when the concentration of glucose increased. The assay parameters for a high-throughput screening method for discovery of new potential GP inhibitors were optimized and standardized, which is desirable for the reproducibility and comparison of results in the literature. The optimized method can be applied to the study of a panel of synthetic and/or natural compounds, such as polyphenols.


Assuntos
Glucose/química , Glucofosfatos/química , Glicogênio Fosforilase/química , Glicogênio/química , Amidas/farmacologia , Animais , Cafeína/farmacologia , Ácido Elágico/farmacologia , Ensaios Enzimáticos , Glicogênio Fosforilase/antagonistas & inibidores , Glicogênio Fosforilase/isolamento & purificação , Ensaios de Triagem em Larga Escala , Indóis/farmacologia , Cinética , Coelhos , Soluções , Relação Estrutura-Atividade
7.
FEBS Lett ; 595(18): 2366-2382, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34409597

RESUMO

Favipiravir is a broad-spectrum inhibitor of viral RNA-dependent RNA polymerase (RdRp) currently being used to manage COVID-19. Accumulation of mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RdRp may facilitate antigenic drift, generating favipiravir resistance. Focussing on the chain-termination mechanism utilized by favipiravir, we used high-throughput interface-based protein design to generate > 100 000 designs of the favipiravir-binding site of RdRp and identify mutational hotspots. We identified several single-point mutants and designs having a sequence identity of 97%-98% with wild-type RdRp, suggesting that SARS-CoV-2 can develop favipiravir resistance with few mutations. Out of 134 mutations documented in the CoV-GLUE database, 63 specific mutations were already predicted as resistant in our calculations, thus attaining ˜ 47% correlation with the sequencing data. These findings improve our understanding of the potential signatures of adaptation in SARS-CoV-2 against favipiravir.


Assuntos
Amidas/farmacologia , Antivirais/farmacologia , Pirazinas/farmacologia , RNA Viral/genética , RNA Polimerase Dependente de RNA/genética , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética , Farmacorresistência Viral/genética , Mutação/genética , Mutação Puntual/genética
8.
Nat Prod Res ; 35(16): 2655-2659, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34414848

RESUMO

Two novel amide glycosides, named oleraciamide E (1) and oleraciamide F (2), were isolated from the Portulaca oleracea L. Their structures were determined by means of 1D and 2D NMR spectroscopic and UHPLC-ESI-TOF-MS methods. Oleraciamide E (1) exhibited anticholinesterase activity with IC50 values of 52.43 ± 0.33 µM, and presented scavenging activity in 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical quenching assay, with the IC50 values of 24.64 ± 0.33 µM.


Assuntos
Amidas , Sequestradores de Radicais Livres , Glicosídeos , Portulaca , Amidas/isolamento & purificação , Amidas/farmacologia , Sequestradores de Radicais Livres/isolamento & purificação , Sequestradores de Radicais Livres/farmacologia , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Portulaca/química , Espectrometria de Massas por Ionização por Electrospray
9.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202585

RESUMO

Cultured keratinocytes are desirable models for biological and medical studies. However, primary keratinocytes are difficult to maintain, and there has been little research on lingual keratinocyte culture. Here, we investigated the effect of Y-27632, a Rho kinase (ROCK) inhibitor, on the immortalization and characterization of cultured rat lingual keratinocyte (RLKs). Three Y-27632-supplemented media were screened for the cultivation of RLKs isolated from Sprague-Dawley rats. Phalloidin staining and TUNEL assay were applied to visualize cytoskeleton dynamics and cell apoptosis following Y-27632 removal. Label-free proteomics, RT-PCR, calcium imaging, and cytogenetic studies were conducted to characterize the cultured cells. Results showed that RLKs could be conditionally immortalized in a high-calcium medium in the absence of feeder cells, although they did not exhibit normal karyotypes. The removal of Y-27632 from the culture medium led to reversible cytoskeletal reorganization and nuclear enlargement without triggering apoptosis, and a total of 239 differentially expressed proteins were identified by proteomic analysis. Notably, RLKs derived from the non-taste epithelium expressed some molecular markers characteristic of taste bud cells, yet calcium imaging revealed that they rarely responded to tastants. Collectively, we established a high-calcium and feeder-free culture method for the long-term maintenance of RLKs. Our results shed some new light on the immortalization and differentiation of lingual keratinocytes.


Assuntos
Amidas/farmacologia , Cálcio/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Animais , Técnicas de Cultura de Células , Células Cultivadas , Ratos
10.
J Gen Virol ; 102(7)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34242156

RESUMO

Bactrian camel hepatitis E virus (HEV) is a novel HEV belonging to genotype 8 (HEV-8) in the Orthohepevirus A species of the genus Hepevirus in the family Hepeviridae. HEV-8 cross-transmits to cynomolgus monkeys and has a potential risk for zoonotic infection. Until now, neither a cell-culture system to grow the virus nor a reverse genetics system to generate the virus has been developed. To generate replication-competent HEV-8 and to establish a cell-culture system, we synthesized capped genomic HEV-8 RNAs by in vitro transcription and used them to transfect into PLC/PRF/5 cells. A HEV-8 strain, HEV-8M2, was recovered from the capped HEV-8 RNA-transfected cell-culture supernatants and subsequently passaged in the cells, demonstrating that PLC/PRF/5 cells were capable of supporting the replication of the HEV-8, and that a cell-culture system for HEV-8 was successfully established. In addition to PLC/PRF/5 cells, A549 and Caco-2 cells appeared to be competent for the replication, but HepG2 C3/A, Vero, Hela S3, HEp-2C, 293T and GL37 cells were incompetent. The HEV-8M2 strain was capable of infecting cynomolgus monkeys by an intravenous inoculation, indicating that HEV-8 was infectious and again carried a risk for zoonotic infection. In contrast, HEV-8 did not infect nude rats and BALB/c nude mice, suggesting that the reservoir of HEV-8 was limited. In addition, the replication of the HEV-8M2 strain was efficiently abrogated by ribavirin but not by favipiravir, suggesting that ribavirin is a drug candidate for therapeutic treatment of HEV-8-induced hepatitis. The infectious HEV-8 produced by a reverse genetics system would be useful to elucidate the mechanisms of HEV replication and the pathogenesis of type E hepatitis.


Assuntos
Vírus da Hepatite E/genética , Vírus da Hepatite E/fisiologia , Hepatite E/virologia , Genética Reversa , Amidas/farmacologia , Animais , Antivirais/farmacologia , Proteínas do Capsídeo/análise , Linhagem Celular , Feminino , Genoma Viral , Vírus da Hepatite E/efeitos dos fármacos , Vírus da Hepatite E/patogenicidade , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Nus , Pirazinas/farmacologia , RNA Viral/genética , Ratos , Ribavirina/farmacologia , Transfecção , Replicação Viral/efeitos dos fármacos
11.
Biochem Biophys Res Commun ; 571: 26-31, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34303192

RESUMO

The pandemic of SARS-CoV-2 has necessitated expedited research efforts towards finding potential antiviral targets and drug development measures. While new drug discovery is time consuming, drug repurposing has been a promising area for elaborate virtual screening and identification of existing FDA approved drugs that could possibly be used for targeting against functions of various proteins of SARS-CoV-2 virus. RNA dependent RNA polymerase (RdRp) is an important enzyme for the virus that mediates replication of the viral RNA. Inhibition of RdRp could inhibit viral RNA replication and thus new virus particle production. Here, we screened non-nucleoside antivirals and found three out of them to be strongest in binding to RdRp out of which two retained binding even using molecular dynamic simulations. We propose these two drugs as potential RdRp inhibitors which need further in-depth testing.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , RNA-Polimerase RNA-Dependente de Coronavírus/antagonistas & inibidores , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Amidas/farmacologia , Antivirais/química , Benzimidazóis/farmacologia , COVID-19/virologia , Carbamatos/farmacologia , Domínio Catalítico , Simulação por Computador , RNA-Polimerase RNA-Dependente de Coronavírus/química , Ciclopropanos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Fluorenos/farmacologia , Humanos , Lactamas Macrocíclicas/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Prolina/análogos & derivados , Prolina/farmacologia , Conformação Proteica , Quinoxalinas/farmacologia , Sulfonamidas/farmacologia
12.
Eur J Med Chem ; 223: 113668, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198149

RESUMO

Based on successful antitubercular isoniazid scaffold we have designed its "mee-too" analogues by a combination of this drug linked with substituted anilines through pyruvic acid as a bridge. Lipophilicity important for passive diffusion through impenetrable mycobacterial cell wall was increased by halogen substitution on the aniline. We prepared twenty new 2-(2-isonicotinoylhydrazineylidene)propanamides that were assayed against susceptible Mycobacterium tuberculosis H37Rv, nontuberculous mycobacteria, and also multidrug-resistant tuberculous strains (MDR-TB). All the compounds showed excellent activity not only against Mtb. (minimum inhibitory concentrations, MIC, from ≤0.03 µM), but also against M. kansasii (MIC ≥2 µM). The most active molecules have CF3 and OCF3 substituent in the position 4 on the aniline ring. MIC against MDR-TB were from 8 µM. The most effective derivatives were used for the mechanism of action investigation. The treatment of Mtb. H37Ra with tested compounds led to decreased production of mycolic acids and the strains overproducing InhA were more resistant to them. These results confirm that studied compounds inhibit the enoyl-acyl carrier protein reductase (InhA) in mycobacteria. The compounds did not show any cytotoxic and cytostatic activity for HepG2 cells. The amides can be considered as a promising scaffold for antitubercular drug discovery having better antimicrobial properties than original isoniazid together with a significantly improved pharmaco-toxicological profile.


Assuntos
Amidas/química , Antituberculosos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Desenho de Fármacos , Oxirredutases/antagonistas & inibidores , Amidas/metabolismo , Amidas/farmacologia , Amidas/uso terapêutico , Compostos de Anilina/química , Antituberculosos/metabolismo , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Proteínas de Bactérias/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/metabolismo , Oxirredutases/metabolismo , Ácido Pirúvico/química , Relação Estrutura-Atividade , Tuberculose/tratamento farmacológico
13.
Nat Protoc ; 16(8): 3954-3980, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34215863

RESUMO

Naive human pluripotent stem cells (hPSCs) can be used to generate mature human cells of all three germ layers in mouse-human chimeric embryos. Here, we describe a protocol for generating mouse-human chimeric embryos by injecting naive hPSCs converted from the primed state. Primed hPSCs are treated with a mammalian target of rapamycin inhibitor (Torin1) for 3 h and dissociated to single cells, which are plated on mouse embryonic fibroblasts in 2iLI medium, a condition essentially the same for culturing mouse embryonic stem cells. After 3-4 d, bright, dome-shaped colonies with mouse embryonic stem cell morphology are passaged in 2iLI medium. Established naive hPSCs are injected into mouse blastocysts, which produce E17.5 mouse embryos containing 0.1-4.0% human cells as quantified by next-generation sequencing of 18S ribosomal DNA amplicons. The protocol is suitable for studying the development of hPSCs in mouse embryos and may facilitate the generation of human cells, tissues and organs in animals.


Assuntos
Quimera/embriologia , Embrião de Mamíferos/fisiologia , Células-Tronco Embrionárias/fisiologia , Fibroblastos/fisiologia , Células-Tronco Pluripotentes/fisiologia , Amidas/farmacologia , Animais , Embrião de Mamíferos/citologia , Células-Tronco Embrionárias/efeitos dos fármacos , Feminino , Humanos , Camundongos , Naftiridinas/farmacologia , Células-Tronco Pluripotentes/efeitos dos fármacos , Piridinas/farmacologia
14.
Fitoterapia ; 154: 104999, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34302918

RESUMO

Five unreported alkaloids including four amide alkaloids (1a, 2a, 3a, and 3b) and one carbazole alkaloid (4) with two known compounds (1b, 2b) were obtained from the stems of Clausena lansium. Their structures were demonstrated by spectroscopic experiments. And the absolute configurations of compounds 1a, 1b, 2b, and 3b were determined by single X-ray diffraction analysis. The neuroprotection assay showed that compound 4 had moderate inhibition effect on PC12 cells induced by serum withdrawal at the concentration of 10 µM. And compounds 1a and 4 had weak protective effects on primary neurons against oxygen glucose deprivation injury at the concentration of 10 µM.


Assuntos
Alcaloides/farmacologia , Amidas/farmacologia , Carbazóis/farmacologia , Clausena/química , Fármacos Neuroprotetores/farmacologia , Alcaloides/isolamento & purificação , Amidas/isolamento & purificação , Animais , Carbazóis/isolamento & purificação , China , Estrutura Molecular , Fármacos Neuroprotetores/isolamento & purificação , Células PC12 , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Caules de Planta/química , Ratos
15.
J Med Chem ; 64(14): 10139-10154, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34236190

RESUMO

A new series of propionamide derivatives was developed as dual µ-opioid receptor agonists and σ1 receptor antagonists. Modification of a high-throughput screening hit originated a series of piperazinylcycloalkylmethyl propionamides, which were explored to overcome the challenge of achieving balanced dual activity and convenient drug-like properties. The lead compound identified, 18g, showed good analgesic effects in several animal models of both acute (paw pressure) and chronic (partial sciatic nerve ligation) pain, with reduced gastrointestinal effects in comparison with oxycodone.


Assuntos
Amidas/farmacologia , Analgésicos Opioides/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor/tratamento farmacológico , Receptores Opioides mu/agonistas , Receptores sigma/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Animais , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Antagonistas de Entorpecentes/síntese química , Antagonistas de Entorpecentes/química , Relação Estrutura-Atividade
16.
Eur J Med Chem ; 222: 113560, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34111828

RESUMO

HTS campaign of the corporate compound collection resulted in a novel, oxalic acid diamide scaffold of α7 nACh receptor positive allosteric modulators. During the hit expansion, several derivatives, such as 4, 11, 17 demonstrated not only high in vitro potency, but also in vivo efficacy in the mouse place recognition test. The advanced hit molecule 11 was further optimized by the elimination of the putatively mutagenic aromatic-amine building block that resulted in a novel, aminomethylindole compound family. The most balanced physico-chemical and pharmacological profile was found in case of compound 55. Docking study revealed an intersubunit binding site to be the most probable for our compounds. 55 demonstrated favorable cognitive enhancing profile not only in scopolamine-induced amnesia (place recognition test in mice) but also in natural forgetting (novel object recognition test in rats). Compound 55 was, furthermore, active in a cognitive paradigm of high translational value, namely in the rat touch screen visual discrimination test. Therefore, 55 was selected as a lead compound for further optimization. Based on the obtained favorable results, the invented aminomethylindole cluster may provide a viable approach for cognitive enhancement through positive allosteric modulation of α7 nAChRs.


Assuntos
Amidas/farmacologia , Descoberta de Drogas , Ensaios de Triagem em Larga Escala , Ácido Oxálico/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Regulação Alostérica/efeitos dos fármacos , Amidas/síntese química , Amidas/química , Animais , Relação Dose-Resposta a Droga , Humanos , Masculino , Estrutura Molecular , Ácido Oxálico/síntese química , Ácido Oxálico/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 222: 113603, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34126456

RESUMO

We reported three distinct series of novel benzothiopyranones, derived from an active metabolite (M-1) of anti-TB agent 6b. These small molecules were evaluated for their biological activities against a range of Mycobacterium tuberculosis (M. tuberculosis) strains. Preliminary druggability evaluation demonstrated that M-1 showed good aqueous solubility and hepatocyte stability. Benzothiopyranones with acyl, sulfonyl and phosphoryl groups exhibited potent in vitro inhibitory activity against M. tuberculosis H37Rv and low cytotoxicity. In particular, compound 3d, containing a benzoate fragment, displayed marked metabolic stability and potent in vitro activity against drug-resistant tuberculosis clinical strains. Further druggability evaluation based on the identified compounds 3d, 4e and 5b is ongoing for the discovery of promising anti-TB agents.


Assuntos
Amidas/farmacologia , Antituberculosos/farmacologia , Benzopiranos/farmacologia , Ésteres/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Amidas/química , Amidas/metabolismo , Antituberculosos/química , Antituberculosos/metabolismo , Benzopiranos/química , Benzopiranos/metabolismo , Relação Dose-Resposta a Droga , Ésteres/química , Ésteres/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
18.
Molecules ; 26(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062818

RESUMO

Salivary gland stem cells (SGSCs) are potential cell sources for the treatment of salivary gland diseases. The control of cell survival is an essential factor for applying stem cells to regenerative medicine or stem cell-based research. The purpose of this study was to investigate the effects of the ROCK inhibitor Y-27632 on the survival of SGSCs and its underlying mechanisms. SGSCs were isolated from mouse submandibular glands and cultured in suspension. Treatment with Y-27632 restored the viability of SGSCs that was significantly decreased during isolation and the subsequent culture. Y-27632 upregulated the expression of anti-apoptotic protein BCL-2 in SGSCs and, in the apoptosis assay, significantly reduced apoptotic and necrotic cell populations. Matrigel was used to mimic the extracellular environment of an intact salivary gland. The expression of genes regulating apoptosis and the ROCK signaling pathway was significantly reduced when SGSCs were embedded in Matrigel. SGSCs cultured in Matrigel and treated with Y-27632 showed no difference in the total numbers of spheroids and expression levels of apoptosis-regulating genes. Matrigel-embedded SGSCs treated with Y-27632 increased the number of spheroids with budding structures and the expression of acinar cell-specific marker AQP5. We demonstrate the protective effects of Y-27632 against dissociation-induced apoptosis of SGSCs during their culture in vitro.


Assuntos
Amidas/farmacologia , Piridinas/farmacologia , Glândulas Salivares/efeitos dos fármacos , Quinases Associadas a rho/antagonistas & inibidores , Animais , Apoptose , Morte Celular , Sobrevivência Celular , Células Cultivadas , Colágeno/química , Combinação de Medicamentos , Matriz Extracelular/metabolismo , Feminino , Laminina/química , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Necrose , Proteoglicanas/química , Esferoides Celulares , Células-Tronco/citologia , Glândula Submandibular/efeitos dos fármacos
19.
Nat Commun ; 12(1): 3962, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172723

RESUMO

Missense mutations in p53 are severely deleterious and occur in over 50% of all human cancers. The majority of these mutations are located in the inherently unstable DNA-binding domain (DBD), many of which destabilize the domain further and expose its aggregation-prone hydrophobic core, prompting self-assembly of mutant p53 into inactive cytosolic amyloid-like aggregates. Screening an oligopyridylamide library, previously shown to inhibit amyloid formation associated with Alzheimer's disease and type II diabetes, identified a tripyridylamide, ADH-6, that abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD. Moreover, ADH-6 targets and dissociates mutant p53 aggregates in human cancer cells, which restores p53's transcriptional activity, leading to cell cycle arrest and apoptosis. Notably, ADH-6 treatment effectively shrinks xenografts harboring mutant p53, while exhibiting no toxicity to healthy tissue, thereby substantially prolonging survival. This study demonstrates the successful application of a bona fide small-molecule amyloid inhibitor as a potent anticancer agent.


Assuntos
Amiloide/antagonistas & inibidores , Antineoplásicos/farmacologia , Agregação Patológica de Proteínas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Amidas/química , Amidas/farmacologia , Amidas/uso terapêutico , Amiloide/química , Amiloide/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Camundongos , Mutação , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Agregação Patológica de Proteínas/tratamento farmacológico , Domínios Proteicos , Piridinas/química , Piridinas/farmacologia , Piridinas/uso terapêutico , Transcrição Genética/efeitos dos fármacos , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/genética
20.
Inorg Chem ; 60(13): 9880-9898, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34130457

RESUMO

In the search for potential new metal-based antitumor agents, two series of nonclassical palladium(II) pincer complexes based on functionalized amides with S-modified cysteine and homocysteine residues have been prepared and fully characterized by 1D and 2D NMR (1H, 13C, COSY, HMQC or HSQC, 1H-13C, and 1H-15N HMBC) and IR spectroscopy and, in some cases, X-ray diffraction. Most of the resulting complexes exhibit a high level of cytotoxic activity against several human cancer cell lines, including colon (HCT116), breast (MCF7), and prostate (PC3) cancers. Some of the compounds under consideration are also efficient in both native and doxorubicin-resistant transformed breast cells HBL100, suggesting the prospects for the creation of therapeutic agents based on the related compounds that would be able to overcome drug resistance. An analysis of different aspects of their biological effects on living cells has revealed a remarkable ability of the S-modified derivatives to induce cell apoptosis and efficient cellular uptake of their fluorescein-conjugated counterpart, confirming the high anticancer potential of Pd(II) pincer complexes derived from functionalized amides with S-donor amino acid pendant arms.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Cisteína/farmacologia , Paládio/farmacologia , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cisteína/análogos & derivados , Cisteína/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Paládio/química
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