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1.
Phytochemistry ; 167: 112101, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31473556

RESUMO

In an effort to identify inhibitors of Chikungunya virus (CHIKV) replication, a systematic study of 594 extracts of plant species originating from the French Guiana plateau region was performed in a virus-cell-based assay for CHIKV assay. The extract obtained from the stem bark of Sagotia racemosa was selected for its potent antiviral activity. Using a classical bioassay-guided procedure, three undescribed degraded diterpenoids, i.e. trigohowilols C and D and trigoflavidol D, as well as trigoxyphin K, stictic acid, hyperhomosekikaic acid and five known flavonoids were isolated. The structures of these compounds were elucidated by extensive NMR spectroscopic data analysis. Although trigohowilols C and D were isolated from the most active fraction they didn't show any antiviral activity. By using the Feature-Based Molecular Networking (FBMN) and Network Annotation Propagation (NAP) workflows, it has been shown that the strong anti-CHIKV activity found for this fraction might be due to the presence of analogues of 12-O-tetradecanoylphorbol-13-acetate (TPA), one of the most potent inhibitors of CHIKV replication identified to date.


Assuntos
Antivirais/isolamento & purificação , Antivirais/farmacologia , Vírus Chikungunya/efeitos dos fármacos , Euphorbiaceae/química , Fenantrenos/isolamento & purificação , Fenantrenos/farmacologia , Ésteres de Forbol/química , Antivirais/química , Vírus Chikungunya/fisiologia , Informática , Fenantrenos/química , Replicação Viral/efeitos dos fármacos , Fluxo de Trabalho
2.
Int J Nanomedicine ; 14: 6217-6229, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496682

RESUMO

Background: Viral and microbial infections constitute one of the most important life-threatening problems. The emergence of new viral and bacterial infectious diseases increases the demand for new therapeutic drugs. Purpose: The objective of this study was to use the aqueous and hexane extracts of Lampranthus coccineus and Malephora lutea F. Aizoaceae for the synthesis of silver nanoparticles, and to investigate its possible antiviral activity. In addition to the investigation of the phytochemical composition of the crude methanolic extracts of the two plants through UPLC-MS metabolomic profiling, and it was followed by molecular docking in order to explore the chemical compounds that might contribute to the antiviral potential. Methods: The formation of SNPs was further confirmed using a transmission electron microscope (TEM), UV-Visible spectroscopy and Fourier transform infrared spectroscopy. The antiviral activity of the synthesized nanoparticles was evaluated using MTT assay against HSV-1, HAV-10 virus and Coxsackie B4 virus. Metabolomics profiling was performed using UPLC-MS and molecular docking was performed via Autodock4 and visualization was done using the Discovery studio. Results: The early signs of SNPs synthesis were detected by a color change from yellow to reddish brown color. The TEM analysis of SNPs showed spherical nanoparticles with mean size ranges between 10.12 nm to 27.89 nm, and 8.91 nm 14.48 nm for Lampranthus coccineus and Malephora lutea aqueous and hexane extracts respectively. The UV-Visible spectrophotometric analysis showed an absorption peak at λmax of 417 nm.The green synthesized SNPs of L. coccineus and M. lutea showed remarkable antiviral activity against HSV-1, HAV-10, and CoxB4 virus. Metabolomics profiling of the methanolic extract of L. coccineus and M. lutea resulted in identifying 12 compounds. The docking study predicted the patterns of interactions between the compounds of L. coccineus and M. lutea with herpes simplex thymidine kinase, hepatitis A 3c proteinase, and Coxsackievirus B4 3c protease, which was similar to those of the co-crystal inhibitors and this can provide a supposed explanation for the antiviral activity of the aqueous and nano extracts of L. coccineus and M. lutea. Conclusion: These results highlight that SNPs of L. coccineus and M. lutea could have antiviral activity against HSV-1, HAV-10, and CoxB4 virus.


Assuntos
Aizoaceae/química , Antivirais/farmacologia , Química Verde , Nanopartículas Metálicas/química , Prata/farmacologia , Animais , Antivirais/química , Morte Celular/efeitos dos fármacos , Cercopithecus aethiops , Ligantes , Metabolômica , Nanopartículas Metálicas/ultraestrutura , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Prata/química , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Células Vero
3.
Chem Biodivers ; 16(10): e1900391, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31479201

RESUMO

A series of novel 2-oxoimidazolidine derivatives were synthesized and their antiviral activities against BK human polyomavirus type 1 (BKPyV) were evaluated in vitro. Bioassays showed that the synthesized compounds 1-{[(4E)-5-(dichloromethylidene)-2-oxoimidazolidin-4-ylidene]sulfamoyl}piperidine-4-carboxylic acid (5) and N-Cyclobutyl-N'-[(4E)-5-(dichloromethylidene)-2-oxoimidazolidin-4-ylidene]sulfuric diamide (4) exhibited moderate activities against BKPyV (EC50 =5.4 and 5.5 µm, respectively) that are comparable to the standard drug Cidofovir. Compound 5 exhibited the same cytotoxicity in HFF cells and selectivity index (SI50 ) as Cidofovir. The selectivity index of compound 4 is three times less than that of Cidofovir due to the higher toxicity of this compound. Hence, these compounds may be taken as lead compound for further development of novel ant-BKPyV agents.


Assuntos
Antivirais/farmacologia , Vírus BK/efeitos dos fármacos , Cidofovir/farmacologia , Desenho de Drogas , Imidazolidinas/farmacologia , Antivirais/síntese química , Antivirais/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cidofovir/química , Relação Dose-Resposta a Droga , Humanos , Imidazolidinas/síntese química , Imidazolidinas/química , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
4.
Cell Biochem Biophys ; 77(4): 319-333, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31559538

RESUMO

Influenza virus is known for its intermittent outbreaks affecting billions of people worldwide. Several neuraminidase inhibitors have been used in practice to overcome this situation. However, advent of new resistant mutants has limited its clinical utilization. In the recent years drug repurposing technique has attained the limelight as it is cost effective and reduces the time consumed for drug discovery. Here, we present multi-dimensional repurposing strategy that integrates the results of ligand-, energy-, receptor cavity, and shape-based pharmacophore algorithm to effectively identify novel drug candidate for influenza. The pharmacophore hypotheses were generated by utilizing the PHASE module of Schrödinger. The generated hypotheses such as AADP, AADDD, and DDRRNH, respectively, for ligand-, e-pharmacophore and receptor cavity based approach alongside shape of oseltamivir were successfully utilized to screen the DrugBank database. Subsequently, these models were evaluated for their differentiating ability using Enrichment calculation. Receiver operating curve and enrichment factors from the analysis indicate that the models possess better capability to screen actives from decoy set of molecules. Eventually, the hits retrieved from different hypotheses were subjected to molecular docking using Glide module of Schrödinger Suite. The results of different algorithms were then combined to eliminate false positive hits and to demonstrate reliable prediction performance than existing approaches. Of note, Pearson's correlation coefficients were calculated to examine the extent of correlation between the glide score and IC50 values. Further, the interaction profile, pharmacokinetic, and pharmacodynamics properties were analyzed for the hit compounds. The results from our analysis showed that alprostadil (DB00770) exhibits better binding affinity toward NA protein than the existing drug molecules. The biological activity of the hit was also predicted using PASS algorithm that renders the antiviral activity of the compound. Further, the results were validated using mutation analysis and molecular dynamic simulation studies. Indeed, this integrative filtering is able to exceed accuracy of other state-of-the-art methods for the drug discovery.


Assuntos
Descoberta de Drogas , Reposicionamento de Medicamentos , Algoritmos , Alprostadil/química , Alprostadil/metabolismo , Alprostadil/uso terapêutico , Antivirais/química , Antivirais/metabolismo , Antivirais/uso terapêutico , Sítios de Ligação , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/patologia , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neuraminidase/química , Neuraminidase/genética , Neuraminidase/metabolismo , Oseltamivir/química , Oseltamivir/metabolismo , Ligação Proteica
5.
J Agric Food Chem ; 67(33): 9241-9253, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31369258

RESUMO

Antiviral compounds targeting viral replicative processes have been studied as an alternative for the control of begomoviruses. Previously, we have reported that the peptide AmPep1 has strong affinity binding to the replication origin sequence of tomato yellow leaf curl virus (TYLCV). In this study, we describe the mechanism of action of this peptide as a novel alternative for control of plant-infecting DNA viruses. When AmPep1 was applied exogenously to tomato and Nicotiana benthamiana plants infected with TYLCV, a decrease in the synthesis of the two viral DNA strands (CS and VS) was observed, with a consequent delay in the development of disease progress in treated plants. The chemical mechanism of action of AmPep1 was deduced using Raman spectroscopy and molecular modeling showing the formation of chemical interactions such as H bonds and electrostatic interactions and the formation of π-π interactions between both biomolecules contributing to tampering with the viral replication.


Assuntos
Amaranthus/química , Antivirais/química , Antivirais/farmacologia , Begomovirus/efeitos dos fármacos , Peptídeos/química , Peptídeos/farmacologia , RNA Viral/química , Replicação Viral/efeitos dos fármacos , Begomovirus/química , Begomovirus/genética , Begomovirus/fisiologia , Sequências Repetidas Invertidas/efeitos dos fármacos , Lycopersicon esculentum/virologia , Doenças das Plantas/virologia , Proteínas de Plantas/química , RNA Viral/genética , Tabaco/virologia
6.
J Agric Food Chem ; 67(36): 10000-10009, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31442045

RESUMO

Improving plant resistance against systemic diseases remains a challenging research topic. In this study, we developed a dual-action pesticide-loaded hydrogel with the capacity to significantly induce plant resistance against tobacco mosaic virus (TMV) infection and promote plant growth. We produced an alginate-lentinan-amino-oligosaccharide hydrogel (ALA-hydrogel) by coating the surface of an alginate-lentinan drug-loaded hydrogel (AL-hydrogel) with amino-oligosaccharide using electrostatic action. We determined the formation of the amino-oligosaccharide film using various approaches, including Fourier transform infrared spectrometry, the ζ potential test, scanning electron microscopy, and elemental analysis. It was found that the ALA-hydrogel exhibited stable sustained-release activity, and the release time was significantly longer than that of the AL-hydrogel. In addition, we demonstrated that the ALA-hydrogel was able to continuously and strongly induce plant resistance against TMV and increase the release of calcium ions to promote Nicotiana benthamiana growth. Meanwhile, the ALA-hydrogel maintained an extremely high safety to organisms. Our findings provide an alternative to the traditional approach of applying pesticide for controlling plant viral diseases. In the future, this hydrogel with the simple synthesis method, green synthetic materials, and its efficiency in the induction of plant resistance will attract increasing attention and have good potential to be employed in plant protection and agricultural production.


Assuntos
Antivirais/química , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Lentinano/química , Lentinano/farmacologia , Doenças das Plantas/virologia , Vírus do Mosaico do Tabaco/fisiologia , Tabaco/virologia , Alginatos/química , Antivirais/farmacologia , Preparações de Ação Retardada/química , Resistência à Doença , Hidrogéis/química , Doenças das Plantas/imunologia , Tabaco/imunologia
7.
J Agric Food Chem ; 67(36): 10018-10031, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31448918

RESUMO

Plant diseases seriously endanger plant health, and it is very difficult to control them. A series of nortopsentin analogues were designed, synthesized, and evaluated for their antiviral activities and fungicidal activities. Most of these compounds displayed higher antiviral activities than ribavirin. Compounds 1d, 1e, and 12a, with excellent antiviral activities, emerged as novel antiviral lead compounds, among which 1e was selected for further antiviral mechanism research. The mechanism research results indicated that these compounds may play an antiviral role by aggregating viral particles to prevent their movement in plants. Further fungicidal activity tests revealed that nortopsentin analogues displayed broad-spectrum fungicidal activities. Compounds 2p and 2f displayed higher antifungal activities against Alternaria solani than the commercial fungicides carbendazim and chlorothalonil. Current research has laid a foundation for the application of nortopsentin analogues in plant protection.


Assuntos
Antivirais/farmacologia , Fungicidas Industriais/farmacologia , Oxazóis/farmacologia , Tiazóis/farmacologia , Alternaria/efeitos dos fármacos , Alternaria/crescimento & desenvolvimento , Antivirais/síntese química , Antivirais/química , Desenho de Drogas , Fungicidas Industriais/síntese química , Fungicidas Industriais/química , Oxazóis/química , Relação Estrutura-Atividade , Tiazóis/química , Vírus do Mosaico do Tabaco/efeitos dos fármacos , Vírus do Mosaico do Tabaco/crescimento & desenvolvimento
8.
Inorg Chem ; 58(17): 11782-11792, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31433630

RESUMO

Reproduction of the dominant vector of Zika and dengue diseases, Aedes aegypti mosquito, is controlled by an active heterodimer complex composed of the 20-hydroxyecdysone receptor (EcR) and ultraspiracle protein. Although A. aegypti EcR shares the structural and functional organization with other nuclear receptors, its C-terminus has an additional long F domain (AaFEcR). Recently, we showed that the full length AaFEcR is intrinsically disordered with the ability to specifically bind divalent metal ions. Here, we describe the details of the exhaustive structural and thermodynamic properties of Zn2+- and Cu2+-complexes with the AaFEcR domain, based on peptide models of its two putative metal binding sites (Ac-HGPHPHPHG-NH2 and Ac-QQLTPNQQQHQQQHSQLQQVHANGS-NH2). Unexpectedly, only in the presence of increasing concentrations of Cu2+ ions, the Ac-HGPHPHPHG-NH2 peptide gained a metal ion-induced poly-l-proline type II helical structure, which is unique for members of the family of nuclear receptors.


Assuntos
Aedes/efeitos dos fármacos , Antivirais/farmacologia , Cobre/farmacologia , Compostos Organometálicos/farmacologia , Peptídeos/farmacologia , Receptores de Esteroides/antagonistas & inibidores , Animais , Antivirais/química , Sítios de Ligação/efeitos dos fármacos , Cobre/química , Dengue/tratamento farmacológico , Dengue/metabolismo , Estrutura Molecular , Compostos Organometálicos/química , Peptídeos/química , Receptores de Esteroides/metabolismo , Termodinâmica , Infecção por Zika virus/tratamento farmacológico , Infecção por Zika virus/metabolismo
9.
J Agric Food Chem ; 67(37): 10498-10504, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31452369

RESUMO

Owing to the changing needs of agriculture, the exploration of new pest control agents remains as critical as ever. The analogues 3a-3v of the natural product cerbinal were synthesized from genipin by an efficient and practical method under additive-free conditions. The antiviral and insecticidal effects of cerbinal and these cyclopenta[c]pyridines (3a-3v) were evaluated systematically. Most of the synthesized compounds exhibited higher anti-TMV activities than the lead compound cerbinal. Compound 3s (2-(4-methoxyphenyl)) had the most promising inhibitory activities against TMV (inactivation effect 49.0 ± 0.8%, curative effect 41.2 ± 4.3%, and protection effect 51.5 ± 2.7% at 500 µg/mL). Among the synthesized compounds, only 3v (2-(2-chloro-4-(trifluoromethoxy)phenyl)) reached the activity level of cerbinal against Plutella xylostella. This suggested that the cyclopenta[c]pyridines obtained by modifications of cerbinal at position 2 are very significant for the anti-TMV activity, and yet were exceptionally less active for the insecticidal activities.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Produtos Biológicos/síntese química , Produtos Biológicos/farmacologia , Indenos/química , Indenos/farmacologia , Inseticidas/química , Inseticidas/farmacologia , Animais , Antivirais/química , Produtos Biológicos/química , Descoberta de Drogas , Indenos/síntese química , Inseticidas/síntese química , Iridoides/química , Estrutura Molecular , Mariposas/efeitos dos fármacos , Mariposas/crescimento & desenvolvimento , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Relação Estrutura-Atividade , Vírus do Mosaico do Tabaco/efeitos dos fármacos , Vírus do Mosaico do Tabaco/crescimento & desenvolvimento
10.
Chem Pharm Bull (Tokyo) ; 67(7): 654-665, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257321

RESUMO

Quassinoids, one kind of triterpenoids with multiple bioactivities such as anti-cancer, anti-malarial, anti-oxidative, anti-microbial, anti-diabetic, anti-viral, and anti-inflammatory effects, have drawn much attention in recent years. Between 2004 and 2018, the structural characteristics and plant sources of 190 quassinoids were reported. Herein, the structure-activity relationships (SARs) of quassinoids along with the anti-cancer mechanisms of four representative quassinoids, eurycomanone, bruceine D, dehydrobruceine B, and brusatol are discussed. This review might be useful for further research and development of quassinoids.


Assuntos
Antineoplásicos Fitogênicos/química , Quassinas/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Antiprotozoários/química , Antiprotozoários/isolamento & purificação , Antiprotozoários/farmacologia , Antivirais/química , Antivirais/isolamento & purificação , Antivirais/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Humanos , Plantas/química , Plantas/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Quassinas/isolamento & purificação , Quassinas/farmacologia , Relação Estrutura-Atividade , Vírus do Mosaico do Tabaco/efeitos dos fármacos
11.
J Agric Food Chem ; 67(31): 8468-8475, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31310114

RESUMO

Fermentation of the fungal strain Skeletocutis sp. originating from Mount Elgon Natural Reserve in Kenya, followed by bioassay guided fractionation led to the isolation of 12 previously undescribed metabolites named skeletocutins A-L (1-5 and 7-13) together with the known tyromycin A (6). Their structures were assigned by NMR spectroscopy complemented by HR-ESIMS. Compounds 1-6 and 11-13 exhibited selective activities against Gram-positive bacteria, while compound 10 weakly inhibited the formation of biofilm of Staphylococcus aureus. The isolated metabolites were also evaluated for inhibition of L-leucine aminopeptidase, since tyromycin A had previously been reported to possess such activities but only showed weak effects. Furthermore, all compounds were tested for antiviral activity against Hepatitis C virus (HCV), and compound 6 moderately inhibited HCV infectivity with an IC50 of 6.6 µM.


Assuntos
Antibacterianos/farmacologia , Polyporales/química , Madeira/microbiologia , Antibacterianos/química , Antibacterianos/metabolismo , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Quênia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Polyporales/crescimento & desenvolvimento , Polyporales/isolamento & purificação , Polyporales/metabolismo
12.
J Agric Food Chem ; 67(31): 8459-8467, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31339701

RESUMO

Novel purine nucleoside derivatives containing a sulfonamide moiety were prepared, as well as their antiviral activities against potato virus Y (PVY), cucumber mosaic virus (CMV), and tobacco mosaic virus (TMV) were evaluated. The antiviral mechanisms of the compounds were investigated. Results showed that most of the compounds had good antiviral activities. Compound 5 at 500 µg/mL exhibited excellent curative and protective activities of 52.5% and 60.0% and of 52.0% and 60.2% for PVY and CMV, respectively, which are higher than those of ningnanmycin (48.1%, 49.6%; 45.3%, 47.7%), ribavirin (38.3%, 48.2%; 40.8%, 45.5%), and chitosan oligosaccharide (32.5%, 33.8%; 35.1%, 34.6%). Moreover, compound 5 displayed good inactivating activity against TMV, with an EC50 value of 48.8 µg/mL, which is better than that of ningnanmycin (84.7 µg/mL), ribavirin (150.4 µg/mL), and chitosan oligosaccharide (521.3 µg/mL). The excellent antiviral activity of compound 5 is related to its immune induction effect which can regulate the physiological and biochemical processes in plants, including defense-related enzyme activities, defense-related genes, and photosynthesis-related proteins. These results indicate that purine nucleoside derivatives containing a sulfonamide moiety are worthy of further research and development as new antiviral agents.


Assuntos
Antivirais/química , Antivirais/farmacologia , Nucleosídeos de Purina/química , Nucleosídeos de Purina/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Antivirais/síntese química , Cucumovirus/efeitos dos fármacos , Desenho de Drogas , Estrutura Molecular , Potyvirus/efeitos dos fármacos , Relação Estrutura-Atividade , Vírus do Mosaico do Tabaco/efeitos dos fármacos
13.
Acta Pharm ; 69(2): 261-276, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31259726

RESUMO

In an attempt to produce heterocyclic compounds based on 1,3,4-oxadiazole derivatives with potential antiviral activity, synthesis of compound 1 [2-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)acetonitrile] was performed through the reaction of cyanoacetic acid hydrazide with carbon disulfide in alcoholic potassium hydroxide. Compound 1 has an activating methylene group, so it was directed toward some specific reactions. Thus, aryldiazonium chlorides reacted with compound 1 affording hydrazono derivatives 2a-c. Also, aromatic aldehydes reacted with compound 1 to produce compounds 3a,b. Furthermore, cyclic ketones were subjected to the synthesis of fused thiophene derivatives 4a,b via reaction with compound 1 in the presence of elemental sulfur. In addition, 1,3,4-oxadiazole derivative 1, when reacted with isothiocyanates, salicylaldehyde or 1,3-dicarbonyl compounds, formed thiazole derivatives 5a,b, coumarin derivative 6 and alkenyl derivatives 7a,b resp. Compound 7b underwent cyclization to afford pyridine derivative 8. Arylhydrazono derivatives 9a,b were produced through the reaction of compound 7a with aryldiazonium chlorides. Products 9a,b underwent cyclization to produce pyridazine derivatives 10a,b. Finally, 1,3,4-oxadiazole derivative 1 was directed toward reaction with hydrazine derivatives, bromoacetophenone and ethylchloroacetate affording compounds 11a,b, 12 and 13, resp. Fused thiophene derivatives 14a,b were produced via reaction of compounds 4a,b with a mixture of malononitrile and ethylorthoformate. Antiviral activity of the synthesized products showed that 5-(4-amino-3-ethyl-2-thioxo-2,3-dihydrothiazol-5-yl)-1,3,4-oxadiazole-2(3H)-thione (5a) and 5-(4-amino-3-phenyl-2-thioxo-2,3-dihydrothiazol-5-yl)-1,3,4-oxadiazole-2(3H)-thione (5b) acted as the most active agents against Feline herpes virus, Feline corona virus, Herpes simplex virus-1 and Herpes simplex virus-2, whereas compound 2-(5-(2-phenylhydrazono)-4,5-dihydro-1,3,4-oxadiazol-2-yl)acetonitrile (11b) was the most effective against Vaccinia virus, Herpes simplex virus (TK-KOS-ACVr), Coxsackie virus B4 and Vesicular stomatitis virus.


Assuntos
Antivirais/farmacologia , Oxidiazóis/farmacologia , Vírus/efeitos dos fármacos , Antivirais/síntese química , Antivirais/química , Oxidiazóis/síntese química , Oxidiazóis/química , Relação Estrutura-Atividade
14.
Molecules ; 24(11)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151219

RESUMO

A series of oxime Cyclohexyl (E)-4-(hydroxyimino)-4-phenylbutanoates and their ethers were designed, synthesized, and evaluated for anti-hepatitis B virus (HBV) activities with HepG 2.2.15 cell line in vitro. Most of these compounds possessed anti-HBV activities, and among them, compound 4B-2 showed significant inhibiting effects on the secretion of HBsAg (IC50 = 63.85 ± 6.26 µM, SI = 13.41) and HBeAg (IC50 = 49.39 ± 4.17 µM, SI = 17.34) comparing to lamivudine (3TC) in HBsAg (IC50 = 234.2 ± 17.17 µM, SI = 2.2) and HBeAg (IC50 = 249.9 ± 21.51 µM, SI = 2.07). Docking study of these compounds binding to a protein residue (PDB ID: 3OX8) from HLA-A2 that with the immunodominant HBcAg18-27 epitope (HLA-A2.1- restricted CTL epitope) active site was carried out by using molecular operation environment (MOE) software. Docking results showed that behaviors of these compounds binding to the active site in HLA-A protein residue partly coincided with their behaviors in vitro anti-HBV active screening.


Assuntos
Antivirais/química , Antivirais/farmacologia , Técnicas de Química Sintética , Desenho de Drogas , Vírus da Hepatite B/efeitos dos fármacos , Antivirais/síntese química , Sítios de Ligação , Domínio Catalítico , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Oximas/síntese química , Oximas/química , Oximas/farmacologia , Ligação Proteica , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
15.
Eur J Med Chem ; 178: 606-622, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31226653

RESUMO

The hydrophobic pocket within viral capsid protein 1 is a target to combat the rhino- and enteroviruses (RV and EV) using small molecules. The highly conserved amino acids lining this pocket enable the development of antivirals with broad-spectrum of activity against numerous RVs and EVs. Inhibitor binding blocks: the attachment of the virion to the host cell membrane, viral uncoating, and/or production of infectious virus particles. Syntheses and biological studies of the most well-known antipicornaviral capsid binders have been reviewed and we propose next steps in this research.


Assuntos
Antivirais/farmacologia , Capsídeo/metabolismo , Enterovirus/efeitos dos fármacos , Antivirais/química , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Enterovirus/química , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
16.
Molecules ; 24(11)2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185617

RESUMO

A series of NH2-sulfonyl oseltamivir analogues were designed, synthesized, and their inhibitory activities against neuraminidase from H5N1 subtype evaluated. The results indicated that the IC50 value of compound 4a, an oseltamivir analogue via methyl sulfonylation of C5-NH2, was 3.50 µM. Molecular docking simulations suggested that 4a retained most of the interactions formed by oseltamivir carboxylate moieties and formed an additional hydrogen bond with the methylsulfonyl group. Meanwhile, 4a showed high stability towards human liver microsomes. More importantly, 4a without basic moieties is not a zwitterion as reported on the general structure of neuraminidase inhibitors. This research will provide valuable reference for the research of new types of neuraminidase inhibitors.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Virus da Influenza A Subtipo H5N1/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Oseltamivir/análogos & derivados , Oseltamivir/síntese química , Antivirais/química , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Neuraminidase/metabolismo , Oseltamivir/química , Oseltamivir/farmacologia
17.
Carbohydr Res ; 480: 61-66, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31176191

RESUMO

Herein we describe the synthesis of imidazo[2,1-b][1,3,4]thiadiazoles from carbohydrates with D-ribo and D-xylo configuration. The antiviral activity of these compounds was tested against Junín virus (the etiological agent of Argentine hemorrhagic fever). The p-chlorophenyl derivatives showed antiviral activity in a range of micromolar concentration.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Ribose/química , Tiadiazóis/síntese química , Tiadiazóis/farmacologia , Xilose/química , Antivirais/química , Técnicas de Química Sintética , Vírus Junin/efeitos dos fármacos , Tiadiazóis/química
18.
Eur J Med Chem ; 178: 64-80, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176096

RESUMO

Encouraged by our earlier discovery of neuraminidase inhibitors targeting 150-cavity or 430-cavity, herein, to yield more potent inhibitors, we designed, synthesized, and biologically evaluated a series of novel oseltamivir derivatives via modification of C-1 and C5-NH2 of oseltamivir by exploiting 150-cavity and/or 430-cavity. Among the synthesized compounds, compound 15e, the most potent N1-selective inhibitor targeting 150-cavity, showed 1.5 and 1.8 times greater activity than oseltamivir carboxylate (OSC) against N1 (H5N1) and N1 (H5N1-H274Y). In cellular assays, 15e also exhibited greater potency than OSC against H5N1 with EC50 of 0.66 µM. In addition, 15e demonstrated low cytotoxicity in vitro and low acute toxicity in mice. Molecular docking studies provided insights into the high potency of 15e against N1 and N1-H274Y mutant NA. Overall, we envisioned that the significant breakthrough in the discovery of potent group-1-specific neuraminidase inhibitors may lead to further investigation of more potent anti-influenza agents.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Neuraminidase/antagonistas & inibidores , Oseltamivir/análogos & derivados , Oseltamivir/farmacologia , Proteínas Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/química , Antivirais/toxicidade , Domínio Catalítico , Linhagem Celular , Galinhas , Desenho de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/toxicidade , Feminino , Influenzavirus A/enzimologia , Influenzavirus B/enzimologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Neuraminidase/química , Oseltamivir/síntese química , Oseltamivir/toxicidade , Proteínas Virais/química
19.
Fitoterapia ; 137: 104190, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31163199

RESUMO

The genus Tripterygium belongs to the family Celastraceae, and contains three species, i.e. Tripterygium wilfordii Hook. F, Tripterygium hypoglaucum (Levl.) Hutch. and Tripterygium regelii Sprague et Takeda. All three species are reported to have excellent medicinal properties that help to cure rheumatoid arthritis, nephrotic syndrome, systemic lupus erythematosus and widely used as a folk medicine in China. Phytochemical studies have led to discovering more than 500 secondary metabolites in this genus, including five main types: sesquiterpenoids, diterpenes, triterpenoids, flavonoids, lignans. This work provides structurally grouping statistic of 198 secondary metabolites of Tripterygium species published from 2008 to the present, as well as pharmacological knowledges in the past five years. The information will be helpful for developing the new discoveries of medicinal value related to the genus Tripterygium.


Assuntos
Tripterygium/química , Tripterygium/classificação , Animais , Anti-Inflamatórios/química , Antineoplásicos Fitogênicos/química , Antioxidantes/química , Antivirais/química , Diterpenos/química , Flavonoides/química , Humanos , Imunossupressores/química , Lignanas/química , Estrutura Molecular , Fármacos Neuroprotetores/química , Compostos Fitoquímicos/química , Metabolismo Secundário , Sesquiterpenos/química , Triterpenos/química
20.
Chemotherapy ; 64(1): 1-7, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31234166

RESUMO

Infections with herpes simplex virus type (HSV)-1 and HSV-2 are distributed worldwide. Although standard therapies with acyclovir and other synthetic drugs are available, the safety and efficacy of these drugs are limited due to the development of drug resistance and adverse side effects. The literature on essential oils and isolated compounds was reviewed regarding their antiviral activities against HSV-1 and HSV-2. The present overview aims to review experimental data and clinical trials focusing on the antiviral activity of selected essential oils and isolated oil components. HSV was found to be susceptible to many essential oils and their constituents. Whereas some essential oils and compounds exhibit direct virucidal activity or inhibit intracellular replication, many essential oils and compounds interact with HSV particles thereby inhibiting cell adsorption. Ayclovir-resistant HSV strains are also susceptible to essential oils since their mode of action is different from the synthetic drug. There are numerous publications on the antiherpetic activity of essential oils and their isolated active compounds. This field of research is still growing, and more clinical trials are required to explore the full potential of different essential oils for the topical treatment of herpetic infections.


Assuntos
Herpes Simples/tratamento farmacológico , Óleos Voláteis/uso terapêutico , Antivirais/química , Antivirais/farmacologia , Antivirais/uso terapêutico , Adesão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Humanos , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Simplexvirus/efeitos dos fármacos , Simplexvirus/fisiologia
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