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1.
Drug Dev Ind Pharm ; 47(2): 268-279, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33501862

RESUMO

OBJECTIVE: The present work focuses on improving zaleplon (ZAP) performance through nanosizing its insoluble particles which were then delivered intranasally in powder form. SIGNIFICANCE: Since nanopowders have an exceptional ability to cross cell membrane, their absorption is facilitated in the solid form. Hence, delivering insoluble ZAP nanocrystals (NC) through intranasal route improves its bioavailability due to both nanosization and the escape of hepatic metabolism. METHODS: Nanocrystals were prepared by anti-solvent precipitation followed by probe sonication in presence of Soluplus®, Poloxamer-188 (0.25%), sodium lauryl sulfate (0.5%), and mannitol. Physicochemical evaluation of the prepared NC was done by DSC and XRPD. TGA was performed for stability detection. Ex vivo permeation study through isolated cattle nasal mucosal membrane, in addition to an in vivo bioavailability study was performed for assessment of the prepared NC. RESULTS: Nanosization to 200 nm contributed to the enhancement in dissolution ∼100% within 30 min and reduced half-life to 1.63 min. Confirmation of adsorption of polymers over NC' surface was elucidated. TGA confirmed their thermal stability. Ex vivo permeation study showed a 2.7 enhancement ratio in favor of the prepared NC. Both the extent and rate of NC absorption through nasal mucosa of rabbits were significantly higher (p Ë‚ .05) than in case of oral tablets. The relative bioavailability of NC was increased 3.14 times as compared to the Sleep aid® tablets. CONCLUSION: The intranasal delivery of nanoscale ZAP powder proved to be a successful alternative to oral formulations that suffer poor absorption and limited bioavailability.


Assuntos
Acetamidas/farmacologia , Nanopartículas , Pirimidinas/farmacologia , Acetamidas/química , Administração Oral , Animais , Disponibilidade Biológica , Tamanho da Partícula , Pós , Pirimidinas/química , Coelhos , Solubilidade
2.
Biochem Biophys Res Commun ; 537: 71-77, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33387885

RESUMO

The sanitary emergency generated by the pandemic COVID-19, instigates the search for scientific strategies to mitigate the damage caused by the disease to different sectors of society. The disease caused by the coronavirus, SARS-CoV-2, reached 216 countries/territories, where about 20 million people were reported with the infection. Of these, more than 740,000 died. In view of the situation, strategies involving the development of new antiviral molecules are extremely important. The present work evaluated, through molecular docking assays, the interactions of 4'-acetamidechalcones with enzymatic and structural targets of SARS-CoV-2 and with the host's ACE2, which is recognized by the virus, facilitating its entry into cells. Therefore, it was observed that, regarding the interactions of chalcones with Main protease (Mpro), the chalcone N-(4'[(2E)-3-(4-flurophenyl)-1-(phenyl)prop-2-en-1-one]) acetamide (PAAPF) has the potential for coupling in the same region as the natural inhibitor FJC through strong hydrogen bonding. The formation of two strong hydrogen bonds between N-(4[(2E)-3-(phenyl)-1-(phenyl)-prop-2-en-1-one]) acetamide (PAAB) and the NSP16-NSP10 heterodimer methyltransferase was also noted. N-(4[(2E)-3-(4-methoxyphenyl)-1-(phenyl)prop-2-en-1-one]) acetamide (PAAPM) and N-(4-[(2E)-3-(4-ethoxyphenyl)-1-(phenyl)prop-2-en-1-one]) acetamide (PAAPE) chalcones showed at least one strong intensity interaction of the SPIKE protein. N-(4[(2E)-3-(4-dimetilaminophenyl)-1-(phenyl)-prop-2-en-1-one]) acetamide (PAAPA) chalcone had a better affinity with ACE2, with strong hydrogen interactions. Together, our results suggest that 4'-acetamidechalcones inhibit the interaction of the virus with host cells through binding to ACE2 or SPIKE protein, probably generating a steric impediment. In addition, chalcones have an affinity for important enzymes in post-translational processes, interfering with viral replication.


Assuntos
Acetamidas/química , Acetamidas/farmacologia , Antivirais/farmacologia , Chalcona/análogos & derivados , Simulação de Acoplamento Molecular , Glicoproteína da Espícula de Coronavírus/química , /metabolismo , Antivirais/química , Chalcona/química , Chalcona/farmacologia , /metabolismo , Humanos , Testes de Sensibilidade Microbiana , /enzimologia , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/metabolismo , Replicação Viral/efeitos dos fármacos
3.
Spectrochim Acta A Mol Biomol Spectrosc ; 244: 118825, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32866803

RESUMO

Novel antiviral active molecule 2- [(4,6-diaminopyrimidin-2-yl)sulfanyl]-N-(4-fluoro- phenyl)acetamide has been synthesised and characterized by FT-IR and FT-Raman spectra. The equilibrium geometry, natural bond orbital calculations and vibrational assignments have been carried out using density functional B3LYP method with the 6-311G++(d,p) basis set. The complete vibrational assignments for all the vibrational modes have been supported by normal coordinate analysis, force constants and potential energy distributions. A detailed analysis of the intermolecular interactions has been performed based on the Hirshfeld surfaces. Drug likeness has been carried out based on Lipinski's rule and the absorption, distribution, metabolism, excretion and toxicity of the title molecule has been calculated. Antiviral potency of 2- [(4,6-diaminopyrimidin-2-yl)sulfanyl]-N-(4-fluoro-phenyl) acetamide has been investigated by docking against SARS-CoV-2 protein. The optimized geometry shows near-planarity between the phenyl ring and the pyrimidine ring. Differences in the geometries due to the substitution of the most electronegative fluorine atom and intermolecular contacts due to amino pyrimidine were analyzed. NBO analysis reveals the formation of two strong stable hydrogen bonded N-H···N intermolecular interactions and weak intramolecular interactions C-H···O and N-H···O. The Hirshfeld surfaces and consequently the 2D-fingerprint confirm the nature of intermolecular interactions and their quantitative contributions towards the crystal packing. The red shift in N-H stretching frequency exposed from IR substantiate the formation of N-H···N intermolecular hydrogen bond. Drug likeness and absorption, distribution, metabolism, excretion and toxicity properties analysis gives an idea about the pharmacokinetic properties of the title molecule. The binding energy -8.7 kcal/mol of the nonbonding interaction present a clear view that 2- [(4,6-diaminopyrimidin-2-yl)sulfanyl]-N-(4-fluoro- phenyl) acetamide can irreversibly interact with SARS-CoV-2 protease.


Assuntos
Acetamidas/química , Antivirais/química , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pandemias , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/química , Pirimidinas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Acetamidas/farmacocinética , Antivirais/farmacocinética , Betacoronavirus/enzimologia , Cristalografia por Raios X , Cisteína Endopeptidases , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Dinâmica não Linear , Inibidores de Proteases/farmacocinética , Conformação Proteica , Pirimidinas/farmacocinética , Teoria Quântica , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Termodinâmica , Vibração
4.
Environ Monit Assess ; 192(7): 422, 2020 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-32519186

RESUMO

Chlorine dioxide has been reported as very efficiently removing pesticides and other organic compounds from water matrixes. Due to pesticide toxicity and potential toxicity of their degradation products, it is important to monitor these compounds as environmental pollutants in ground and surface waters. Evaluating the effects of chlorine dioxide treatment is necessary, and toxicity studies are used to ascertain the severity of effects of intermediates due to incomplete degradation of the parent compounds. In this paper, for the first time, chlorine dioxide is applied and evaluated for the removal of chloroacetamide herbicides (pethoxamid and metazachlor) from waters (deionized water and Sava River water). The degradation degree of herbicides was measured by high-performance liquid chromatography, the main degradation products were identified using gas chromatography with a triple quadrupole mass detector, and the degree of mineralization was monitored by total organic carbon analysis. Four and two degradation products were identified after pethoxamid and metazachlor degradation, respectively. Total organic carbon analysis showed mineralization occurred, but it was incomplete. The mineralization and the characteristics of the degradation products obtained were tested using Daphnia magna and showed lower toxicity than the parent herbicides. The advantage of the applied treatment was a very high degradation percentage for pethoxamid removal from deionized water and Sava River water (100% and 97%, respectively), with higher mineralization efficiency (65%) than metazachlor. Slightly lower degradation efficiency in the Sava River water was due to chlorine dioxide oxidizing the herbicides and dissolved organic matter simultaneously.


Assuntos
Acetamidas , Compostos Clorados , Óxidos , Poluentes Químicos da Água , Purificação da Água , Acetamidas/análise , Acetamidas/química , Acetamidas/metabolismo , Acetamidas/toxicidade , Animais , Compostos Clorados/química , Daphnia/efeitos dos fármacos , Ecotoxicologia , Óxidos/química , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/química , Poluentes Químicos da Água/metabolismo , Poluentes Químicos da Água/toxicidade , Purificação da Água/métodos
5.
Phys Chem Chem Phys ; 22(24): 13358-13362, 2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32478770

RESUMO

Label-based functional studies of biomolecules in their native environment require labeling reactions inside living cells. In cell spin labeling using alkyne-azide click chemistry with a Gd3+-DOTAM-azide complex is shown to provide high spin label stability and narrow EPR lines for EPR spectroscopic detection of a spin labeled protein in living cells at ambient temperatures.


Assuntos
Escherichia coli/química , Gadolínio/química , Proteínas de Fluorescência Verde/análise , Marcadores de Spin , Acetamidas/química , Alquinos/química , Azidas/química , Química Click , Espectroscopia de Ressonância de Spin Eletrônica , Escherichia coli/citologia , Compostos Heterocíclicos com 1 Anel/química , Estrutura Molecular
6.
Science ; 368(6489)2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32327570

RESUMO

Protein quality control is essential for the proper function of cells and the organisms that they make up. The resulting loss of proteostasis, the processes by which the health of the cell's proteins is monitored and maintained at homeostasis, is associated with a wide range of age-related human diseases. Here, we highlight how the integrated stress response (ISR), a central signaling network that responds to proteostasis defects by tuning protein synthesis rates, impedes the formation of long-term memory. In addition, we address how dysregulated ISR signaling contributes to the pathogenesis of complex diseases, including cognitive disorders, neurodegeneration, cancer, diabetes, and metabolic disorders. The development of tools through which the ISR can be modulated promises to uncover new avenues to diminish pathologies resulting from it for clinical benefit.


Assuntos
Fator de Iniciação 2 em Eucariotos/metabolismo , Proteostase , Estresse Fisiológico , Fatores de Complexo Ternário/metabolismo , Acetamidas/química , Acetamidas/farmacologia , Animais , Cicloexilaminas/química , Cicloexilaminas/farmacologia , Fator de Iniciação 2 em Eucariotos/antagonistas & inibidores , Humanos , Imunidade , Doenças Metabólicas/metabolismo , Camundongos , Neoplasias/metabolismo , Fosfotransferases/metabolismo
7.
Food Chem ; 318: 126413, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32155561

RESUMO

A novel procedure for the rapid isotope analysis of the carbon-bound non-exchangeable (CBNE) hydrogen in mono and disaccharides has been developed to demonstrate the feasibility of detecting undeclared addition of exogenous sugar products in foods and beverages susceptible to economically motivated adulteration. The procedure utilizes a simple one-step reaction, with the derivatising agent N-methyl-bis-trifluoroacetamide, to substitute the exchangeable hydroxyl-hydrogens with trifluoroacetate derivatives that are sufficiently volatile to be separated and measured by a gas chromatograph coupled to an isotope ratio mass spectrometer. The conversion of the derivatised sugars into the measuring gas is achieved using a high temperature chromium-silver reactor that retains carbon, oxygen and fluorine whilst releasing hydrogen gas for stable isotope measurement. The new procedure has advantages over existing methods in terms of ease of use, analysis time and compound-specific information. Sugars from fruit juice and honey have been measured to demonstrate the feasibility of using this technique.


Assuntos
Carboidratos/química , Cromo/química , Deutério/análise , Cromatografia Gasosa-Espectrometria de Massas/métodos , Prata/química , Acetamidas/química , Fluoracetatos/química , Análise de Alimentos , Sucos de Frutas e Vegetais/análise , Espectrometria de Massas/métodos , Oxirredução , Temperatura
8.
Carbohydr Res ; 490: 107963, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32145534

RESUMO

A photoacid catalyzed O-glycosylation of alcohols with glycosyl trichloroacetimidates in the presence of commercially available phenolic photoacids, fluorescein, 4',5'-dibromo-fluorescein, and eosin Y under visible light irradiation by blue LEDs was developed. The method is operationally simple without neutralization and proceeds at room temperature.


Assuntos
Acetamidas/química , Cloroacetatos/química , Amarelo de Eosina-(YS)/química , Catálise , Glicosilação , Luz , Estrutura Molecular
9.
Eur J Med Chem ; 189: 112078, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32004937

RESUMO

For further development of successors of Agomelatine through modulation of its pharmacokinetic properties, we report herein the design, synthesis and pharmacological results of a new family of melatonin receptor ligands. Issued from the introduction of quinazoline and phthalazine scaffolds carrying an ethyl amide lateral chain and a methoxy group as bioisosteric ligands analogues of previously developed Agomelatine. The biological activity of the prepared analogues was compared with that of Agomelatine. Quinazoline and phthalazine rings proved to be a versatile scaffold for easy feasible MT1 and MT2 ligands. Potent agonists with sub-micromolar binding affinity were obtained. However, the presence of two nitrogen atoms resulted in compounds with lower affinity for both MT1 and MT2, in comparison with the parent compound, balanced by the exhibition of good pharmacokinetic properties.


Assuntos
Acetamidas/química , Ftalazinas/química , Quinazolinas/química , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/metabolismo , Acetamidas/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Células HEK293 , Humanos , Ligantes , Ftalazinas/metabolismo , Quinazolinas/metabolismo , Relação Estrutura-Atividade
10.
Chemosphere ; 248: 125915, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32007770

RESUMO

Herbicide-polluted soils have posed a threat to the crop growth and agro-product quality and safety. Even worse, the low-content of residue is still appreciable for a long time in subsurface soils. The soil bioelectrochemical remediation system (BERS) provides an inexhaustible electron acceptor to cause in situ indigenous microorganisms to generate biocurrent and accelerate the removal of metolachlor (ML). As a result of carbon fiber amendment, the highest current density (637 ± 19 mA/m2) to date has been generated in a soil BERS. The ML half-life and complete removal time decreased from 21 to 3 d and from 245 to 109 d, respectively. Importantly, the soil BERS was verified to be an effective treatment method for low-polluted sediments/soils, whether by ML or by its degradates. The quantitative degradates of ML showed that the first step was dechlorination based on the bioelectrochemical degradation pathway. The biocurrent selectively enriched special species, e.g., Geobacter and Thermincola for bioelectricity generation and Ralstonia, Phyllobacterium and Stenotrophomonas for degradation in soils. Meanwhile, Flavisolibacter and Gemmatimonas occupied the core niche in strengthening interspecific relationships by the biocurrent. This study firstly revealed the explicit abundance of Geobacter in agricultural soils and laid a foundation for the function design of mixed bacteria in the sediment/soil BERS.


Assuntos
Acetamidas/química , Recuperação e Remediação Ambiental , Bactérias/metabolismo , Biodegradação Ambiental , Fontes de Energia Bioelétrica/microbiologia , Geobacter/metabolismo , Halogenação , Herbicidas/metabolismo , Cinética , Solo/química , Microbiologia do Solo , Poluentes do Solo/análise
11.
Int J Mol Sci ; 21(2)2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31963423

RESUMO

A series of 2-thio- and 2-seleno-acetamides bearing the benzenesulfonamide moiety were evaluated as Carbonic Anhydrase (CA, EC 4.2.1.1) inhibitors against different pathogenic bacteria such as the Vibrio cholerae (VchCA-α and VchCA-ß), Burkholderia pseudomallei (BpsCA-ß and BpsCA-γ), Mycobacterium tuberculosis (Rv3723-ß) and the Salmonella enterica serovar Typhimurium (StCA2-ß). The molecules represent interesting leads worth developing as innovative antibacterial agents since they possess new mechanism of action and isoform selectivity preferentially against the bacterial expressed CAs. The identification of potent and selective inhibitors of bacterial CAs may lead to tools also useful for deciphering the physiological role(s) of such proteins.


Assuntos
Acetamidas/química , Bactérias/efeitos dos fármacos , Bactérias/patogenicidade , Infecções Bacterianas/tratamento farmacológico , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/química , Sulfonamidas/química , Bactérias/enzimologia , Infecções Bacterianas/microbiologia , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Compostos Organosselênicos/química , Relação Estrutura-Atividade , Compostos de Sulfidrila/química , Sulfonamidas/farmacologia
12.
J Agric Food Chem ; 68(8): 2297-2305, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-31995372

RESUMO

We previously discovered a method to estimate the groundwater mean residence time using the changes in the enantiomeric ratio of metolachlor ethanesulfonic acid (MESA), (2-[(2-ethyl-6-methylphenyl)(2-methoxy-1-methylethyl)amino]-2-oxoethanesulfonic acid), a metabolite of the herbicide metolachlor. However, many grab samples would be needed for each watershed over an extended period, and this is not practical. Thus, we examined the use of a polar organic chemical integrative sampler (POCIS) deployed for 28 days combined with a modified liquid chromatography-mass spectrometry LC-MS/MS method to provide a time-weighted average of the MESA enantiomeric ratio. POCISs equipped with hydrophilic-lipophilic-balanced (HLB) discs were deployed at five sites across the United States where metolachlor was used before and after 1999 and compared the effectiveness of the POCIS to capture MESA versus grab samples. In addition, an in situ POCIS sampling rate (Rs) for MESA was calculated (0.15 L/day), the precision of MESA extraction from stored POCIS discs was determined, and the effectiveness of HLB to extract MESA was examined. Finally, using molecular modeling, the influence of the asymmetric carbon of metolachlor degradation on the MESA enantiomeric ratio was predicted to be negligible. Results of this work will be used in projects to discern the groundwater mean residence times, to evaluate the delivery of nitrate-N from groundwater to surface waters under various soil, agronomic, and land use conditions, and to examine the effectiveness of conservation practices.


Assuntos
Acetamidas/química , Alcanossulfonatos/química , Monitoramento Ambiental/métodos , Água Subterrânea/química , Herbicidas/química , Compostos Orgânicos/química , Poluentes Químicos da Água/química , Cromatografia Líquida de Alta Pressão/métodos , Estereoisomerismo , Espectrometria de Massas em Tandem/métodos
13.
Eur J Med Chem ; 186: 111867, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31757525

RESUMO

Using the principle of bioisosteric replacement, we present a structure-based design approach to obtain new Axl kinase inhibitors with significant activity at the kinase and cellular levels. Through a stepwise structure-activity relationships exploration, a series of 6,7-disubstituted quinoline derivatives, which contain 1,3,4-oxadiazol acetamide moiety as novel Linker, were ultimately synthesized with Axl as the primary target. Most of them exhibited moderate to excellent activity, with IC50 values ranging from 0.032 to 1.54 µM against the tested cell lines. Among them, the most promising compound 47e, as an Axl kinase inhibitor (IC50 = 10 nM), shows remarkable cytotoxicity against A549, HT-29, PC-3, MCF-7, H1975 and MDA-MB-231 cell lines. More importantly, 47e also shows a significant inhibitory effect on EGFR-TKI resistant NSCLC cell lines H1975/gefitinib. Meanwhile, this study provides a novel type of linker for Axl kinase inhibitors, namely 1,3,4-oxadiazol acetamide moiety, which is out of the scope of the "5- atoms role ".


Assuntos
Acetamidas/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Oxidiazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Acetamidas/síntese química , Acetamidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-Atividade
14.
Eur J Med Chem ; 185: 111866, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31734023

RESUMO

Introducing pyrimidine bases, the basic components of nucleic acid, to P2 ligands might enhance the potency of Human Immunodeficiency Virus-1 (HIV-1) protease inhibitors because of the carbonyl and amino groups promoting the formation of extensive hydrogen bonding interactions. In this work, we provide evidence that inhibitor 10e, with N-2-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetamide as the P2 ligand and a 4-methoxylphenylsulfonamide as the P2' ligand, displayed remarkable enzyme inhibitory and antiviral activity, with the IC50 2.53 nM in vitro and a promising inhibition ratio with 68% against wild-type HIV-1 in vivo, with low cytotoxicity. This inhibitor also exhibited appreciable antiviral activity against DRV-resistant HIV-1 variants, which was of great value for further study.


Assuntos
Acetamidas/farmacologia , Aminas/farmacologia , Fármacos Anti-HIV/farmacologia , Protease de HIV/metabolismo , HIV-1/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Pirimidinas/farmacologia , Acetamidas/síntese química , Acetamidas/química , Aminas/síntese química , Aminas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , HIV-1/enzimologia , Humanos , Ligantes , Testes de Sensibilidade Microbiana , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
15.
Eur J Med Chem ; 186: 111861, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31734025

RESUMO

Respiratory syncytial virus (RSV) and influenza A virus (IAV) are two of the most common viruses that cause substantial morbidity and mortality in infants, young children, elderly persons, and immunocompromised individuals worldwide. Currently, there are no licensed vaccines or selective antiviral drugs against RSV infections and most IAV strains become resistant to clinical anti-influenza drug. Here, we described the discovery of a series of 2-((1H-indol-3-yl)thio)-N-phenyl-acetamide as novel and potent RSV and IAV dual inhibitors. Thirty-five derivatives were designed, prepared, and evaluated for their anti-RSV and anti-IAV activities. Among the tested compounds, 14'c, 14'e, 14'f, 14'h, and 14'i exhibited excellent activity against both RSV and IAV, which showed low micromolar to sub-micromolar EC50 values. Further, compounds 14'c and 14'e were identified as the most promising dual inhibitors with lesser cytotoxicity than the clinical drug, ribavirin. These findings may contribute to the development of a lead compound for the treatment of RSV and/or IAV infections.


Assuntos
Acetamidas/farmacologia , Antivirais/farmacologia , Desenho de Fármacos , Influenzavirus A/efeitos dos fármacos , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Acetamidas/síntese química , Acetamidas/química , Antivirais/síntese química , Antivirais/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
16.
Eur J Med Chem ; 185: 111874, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31735575

RESUMO

The fragment hopping approach is widely applied in drug development. A series of diarylpyrimidines (DAPYs) were obtained by hopping the thioacetamide scaffold to novel human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitors (NNRTIs) to address the cytotoxicity issue of Etravirine and Rilpivirine. Although the new compounds (11a-l) in the first-round optimization possessed less potent anti-viral activity, they showed much lower cytotoxicity. Further optimization on the sulfur led to the sulfinylacetamide-DAPYs exhibiting improved anti-viral activity and a higher selectivity index especially toward the K103N mutant strain. The most potent compound 12a displayed EC50 values of 0.0249 µM against WT and 0.0104 µM against the K103N mutant strain, low cytotoxicity (CC50 > 221 µM) and a high selectivity index (SI WT > 8873, SI K103N > 21186). In addition, this compound showed a favorable in vitro microsomal stability across species. Computational study predicted the binding models of these potent compounds with HIV-1 reverse transcriptase thus providing further insights for new developments.


Assuntos
Acetamidas/farmacologia , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Acetamidas/síntese química , Acetamidas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
17.
Ecotoxicol Environ Saf ; 189: 110037, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31812018

RESUMO

As an emerging class of nitrogenous disinfection by-products (N-DBPs), haloacetamides (HAcAms) have been widely detected in drinking water. Limited toxicity studies have shown an inconsistent toxicity of monoHAcAms, including CAcAm, BAcAm and IAcAm. In this study, the developmental toxicity of monoHAcAms was evaluated in embryo-larval stage of zebrafish. Embryos were exposed to one concentration of 2.50, 5.00, 10.0, 20.0, 40.0 and 80.0 mg/L monoHAcAms from 4 h post-fertilization (hpf) to 120 hpf. Multiple endpoints, including hatching rate, morphological abnormalities, mortality as well as locomotor behavior were assessed at specified stages (24, 48, 72, 96 and 120 hpf). Results showed that 80 mg/L CAcAm and 40 mg/L BAcAm significantly decreased the hatching rate, IAcAm decreased the hatching rate and delayed the hatching process in a concentration-dependent manner with an EC50 of 16.37 mg/L at 72 hpf. The frequency and severity order of morphological abnormalities increased with the raised exposure concentrations and prolonged exposure time, and the corresponding EC50 at 96 hpf were 21.10, 9.77 and 16.60 mg/L for CAcAm, BAcAm and IAcAm, respectively. MonoHAcAms exposure resulted in a time- and dose-dependent response in mortality and the calculated LC50 at 72 hpf were 38.44, 17.74 and 28.82 mg/L for CAcAm, BAcAm and IAcAm, respectively. Based on EC50 for morphological abnormalities and LC50, a toxicity rank order of BAcAm > IAcAm > CAcAm was observed. Different degrees of hyperactivity and hypoactivity were observed from locomotor behavior analysis in larvae from ≤10.0 mg/L monoHAcAms exposure groups. The light-dark periodic change was disappeared in larvae of 10.0 mg/L BAcAm exposure group. In summary, our study showed that monoHAcAms were developmentally toxic to zebrafish even at very low concentrations and BAcAm exerted higher toxicity than IAcAm and CAcAm. These results will further our understanding of the toxicity of HAcAms and its potential toxicological impact on human and ecological environment.


Assuntos
Acetamidas/toxicidade , Desinfecção/métodos , Desenvolvimento Embrionário/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Acetamidas/química , Animais , Relação Dose-Resposta a Droga , Embrião não Mamífero/anormalidades , Embrião não Mamífero/efeitos dos fármacos , Dose Letal Mediana , Locomoção/efeitos dos fármacos , Peixe-Zebra
18.
J Chromatogr A ; 1612: 460652, 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-31679710

RESUMO

Haloacetic acids (HAAs) are the second largest class of disinfection by-products (DBPs) by weight in water and are more cytotoxic and genotoxic to mammalian cells than trihalomethanes, the first largest class of DBPs. Gas chromatography (GC) is the most widely used technique for determining HAAs. Due to their polar nature, derivatization prior to GC analysis is required. Typically, derivatization is undertaken with acidic methanol, which converts HAAs to the corresponding methyl ester (haloacetic acid methyl esters, abbreviated as HAAMEs), and HAAs are quantified by measuring HAAMEs. In this study, the interference from two other groups of DBPs, the haloacetonitriles (HANs) and haloacetamides (HAMs), on the determination of HAAs was investigated. HANs and HAMs at a range of concentrations (0, 20, 40, 60, 80, and 100 µg/L) were subjected to the same derivatization and analytical procedures as HAAs. The stability of HANs and HAMs under strongly acidic conditions was assessed and the operative mechanism of interference was investigated. The results showed that HAMs significantly interfered with the determination of the corresponding HAAs and the transformation rates of HAMs (representing the extent of HAMs transforming to corresponding HAAMEs) ranged from 6.5 to 45.7%, while the impact of HANs can be neglected. The stability of HANs and HAMs under strongly acidic conditions indicated that hydrolysis was not the cause of the interference. Instead, it was proposed that HAMs react with methyl alcohol, to generate the same corresponding HAAMEs that was generated when HAAs reacted with methyl alcohol. A method for revising HAA concentrations in the presence of HAMs is suggested.


Assuntos
Acetamidas/química , Acetatos/análise , Cromatografia Gasosa , Acetatos/química , Acetonitrilos/química , Desinfetantes/química , Água Potável/análise
19.
FEBS J ; 287(2): 239-245, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31550413

RESUMO

The integrated stress response (ISR) regulates protein synthesis under conditions of stress. Phosphorylation of translation initiation factor eIF2 by stress-sensing kinases converts eIF2 from substrate to competitive inhibitor of its dedicated nucleotide exchange factor, eIF2B, arresting translation. A drug-like molecule called integrated stress response inhibitor (ISRIB) reverses the effects of eIF2 phosphorylation and restores translation by targeting eIF2B. When administered to mice, ISRIB enhances cognition and limits cognitive decline due to brain injury. To determine ISRIB's mechanism of action, we solved an atomic structure of ISRIB bound to the human eIF2B decamer. We found that ISRIB acts as a molecular staple, pinning together tetrameric subcomplexes of eIF2B along the assembly path to a fully active, decameric enzyme. In this Structural Snapshot, we discuss ISRIB's mechanism, its ability to rescue disease mutations in eIF2B and conservation of the enzyme and ISRIB-binding pocket.


Assuntos
Acetamidas/química , Cicloexilaminas/química , Fator de Iniciação 2B em Eucariotos/antagonistas & inibidores , Memória/efeitos dos fármacos , Fármacos Neuroprotetores/química , Acetamidas/farmacologia , Animais , Sítios de Ligação , Cicloexilaminas/farmacologia , Fator de Iniciação 2B em Eucariotos/metabolismo , Humanos , Fármacos Neuroprotetores/farmacologia , Ligação Proteica
20.
Chemosphere ; 240: 124761, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31546190

RESUMO

The formation and control of haloacetamides (HAcAms) in drinking water have raised high attention due to their high genotoxicity and cytotoxicity, especially the most cytotoxic one, diiodoacetamide (DIAcAm). In this study, the degradation of DIAcAm by UV/chlorination was investigated in terms of degradation kinetics, efficiency, influencing factors, oxidation products and toxicity evaluation. Results revealed that the degradation of DIAcAm by UV/chlorine process followed pseudo-first-order kinetics, and the rate constant between DIAcAm and OH radicals was determined as 2.8 × 109 M-1 s-1. The contribution of Cl to DIAcAm degradation by UV/chlorine oxidation was negligible. Increasing chlorine dosage and decreasing pH significantly promoted the DIAcAm degradation during UV/chlorine oxidation, but the presence of bicarbonate (HCO3-) and natural organic matter (NOM) inhibited it. The mass balance analysis of iodine species was also evaluated during UV/chlorine oxidation of DIAcAm. In this process, with DIAcAm decreasing from 16.0 to 0.8 µM-I in 20 min, IO3-, I- and HOI/I2 increased from 0 to 6.3, 6.1 and 0.5 µM-I, respectively. The increase of CHO cell viability during DIAcAm degradation indicated that the toxicity of DIAcAm could be decreased by chlorination, UV irradiation and UV/chlorine oxidation treatments, in which UV/chlorine oxidation was more effective on toxicity reduction than chlorination and UV irradiation alone.


Assuntos
Acetamidas/química , Poluentes Químicos da Água/química , Cloro/análise , Halogenação , Cinética , Oxirredução , Raios Ultravioleta , Água , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade , Purificação da Água/métodos
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