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1.
Environ Pollut ; 253: 302-311, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31323613

RESUMO

Fomesafen, a long-lived protoporphyrinogen-oxidase inhibitor, specially developed for post-emergence control of broad-leaf weeds, is used widely in soybean fields in northern China (Dayan and Duke, 2010). The impact of fomesafen on microbial communities in rhizosphere soils, however, is unknown. In this study we examined fomesafen degradation as well as its effects in the rhizosphere of soybean plants grown in a greenhouse. Fomesafen had shorter half-life in rhizosphere soil than previously reported for bulk soil from the same location (87 vs 120 days). The enzyme activity of soil extracts and the microbial community composition of 16S rRNA genes (16S) amplified from soil DNA were also investigated. Although not immediately apparent, both the high (37.5 mg kg-1) and low (18.75 mg kg-1) doses of fomesafen significantly decreased urease and invertase activities in the rhizosphere soil from days 30 and 45 respectively until the end of the experiment (90 days). Analysis of 16S amplicons demonstrated that fomesafen had a dose dependent effect, decreasing alpha diversity and altering beta diversity. Significant phylum level decreases were observed in five of the ten phyla that were most abundant in the control. Proteobacteria was the only phylum whose relative abundance increased in the presence of fomesafen, driven by increases in the genera Methylophilacaea, Dyella, and Sphingomonas. The functional implications of changes in 16S abundance as predicted using PICRUSt suggested that fomesafen enriched for enzymes involved in xenobiotic metabolism and detoxification (cytochrome P450s and glutathione metabolism). Our data suggest that, despite being degraded more rapidly in the rhizosphere than in bulk soil, fomesafen had long-lasting functional impacts on the soil microbial community.


Assuntos
Benzamidas/toxicidade , Inibidores Enzimáticos/toxicidade , Rizosfera , Microbiologia do Solo , Poluentes do Solo/toxicidade , Bactérias/efeitos dos fármacos , China , Microbiota , Proteobactérias/genética , RNA Ribossômico 16S/genética , Solo , Poluentes do Solo/análise , Soja
2.
Environ Sci Pollut Res Int ; 26(25): 26184-26192, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31280445

RESUMO

In the standard ISO soil toxicity test using Collembola, adult survival and juvenile production are the only endpoints that can be attainable. The information on egg production and egg hatching cannot be investigated in the ISO test. To overcome this limitation, in this study, the effects of teflubenzuron on life history parameters of Yuukianura szeptyckii (Collembola) were investigated with a compressed soil test. Teflubenzuron is an insect growth regulator and has a negative effect on egg production, and egg hatching process of arthropods. LC50 decreased with increases in exposure period from 6.97 mg/kg in the third week to 3.60 mg/kg in the fourth week. The EC50 for egg and juvenile production was 0.57 mg/kg and 0.26 mg/kg, respectively. The hatching rate decreased significantly from 46 to 7% as the concentration increased from 0.25 to 1.00 mg/kg, respectively, and the molting frequency was significantly affected only at > 4 mg/kg. The toxic contribution rate (TCR) was defined as the ratio of juvenile production at an exposure concentration compared with the control, and a simple life history model was developed for TCR estimations. At the lower concentrations (< 0.3 mg/kg), the hatching rate reduction was a main contributor to the total toxicity, but the adult mortality and egg production reduction were the main contributors at the higher concentrations (> 2.0 mg/kg). The contribution of egg production reduction remained relatively constant. Since collembolan populations in the soil can be composed of various developmental stages, the differences in the sensitivity to chemicals depending on the developmental stages should be included in the assessment of the toxic impact on soil ecosystems.


Assuntos
Benzamidas/toxicidade , Reprodução/efeitos dos fármacos , Poluentes do Solo/toxicidade , Animais , Artrópodes/efeitos dos fármacos , Benzamidas/química , Ecossistema , Dose Letal Mediana , Solo , Testes de Toxicidade
3.
Eur J Med Chem ; 176: 195-207, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31103900

RESUMO

Previously, we focused on a series of 2-aminobenzamide-based histone deacetylase (HDAC) inhibitors, compound 9 of which displayed potent HDAC inhibitory activity against HDAC1 and HDAC2, and moderate anti-proliferative activity against several cancer cell lines. In the current study, we have designed and synthesized a series of novel HDAC inhibitors based on thioether moiety with 9 as a lead compound. Representative compounds12 g and 12 h showed apparently potent anti-proliferative activities against five solid cancer cell lines: A549, HCT116, Hela, A375 and SMMC7721, and low cytotoxicity against NIH 3T3 normal cells. Especially, 12 g and 12 h also revealed potent HDAC inhibitory activity against HDAC1, 2 and 3. In addition, the two compounds could arrest cell cycle in G2/M phase and promote cell apoptosis. Moreover, they showed extended inhibition of colony formation and effectively blocked cell migration towards A549 cancer cells. Furthermore, 12 g and 12 h possessed better pharmacokinetic properties than the lead compound 9. Benefiting from these results, we also explored 12 g and 12 h in the A549 xenografts model for in vivo antitumor activity. The in vivo experiment indicated that 12 g and 12 h could evidently augment antitumor activity (TGI = 56.9% and 62.7% respectively).


Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Sulfetos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Benzamidas/síntese química , Benzamidas/farmacocinética , Benzamidas/toxicidade , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacocinética , Inibidores de Histona Desacetilases/toxicidade , Humanos , Camundongos , Simulação de Acoplamento Molecular , Células NIH 3T3 , Sulfetos/síntese química , Sulfetos/farmacocinética , Sulfetos/toxicidade , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Eur J Med Chem ; 174: 116-129, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31029943

RESUMO

The discovery of new chemical entities endowed with potent and selective acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE) inhibitory activity is still a relevant subject for Alzheimer's disease therapy. Therefore, a small library of benzoic based amide nitrones (compounds 24 to 42) was synthesized and screened toward cholinesterase enzymes. SAR studies showed that the tert-butyl moiety is the most favourable nitrone pattern. In general, tert-butyl derivatives effectively inhibited AChE, being compound 33 the most potent (IC50 = 8.3 ±â€¯0.3 µM; Ki 5.2 µM). The data pointed to a non-competitive inhibition mechanism of action, which was also observed for the standard donepezil. None of compounds showed BChE inhibitory activity. Molecular modelling studies provided insights into the enzyme-inhibitor interactions and rationalised the experimental data, confirming that the binding mode of nitrones 33 and 38 towards AChE has the most favourable binding free energy. The tert-butylnitrones 33 and 38 were not cytotoxic on different cell lines (SH-SY5Y and HepG2). Moreover, compound 33 was able to prevent t-BHP-induced oxidative stress in SH-SY5Y differentiated cells. Due to its AChE selectivity and promising cytoprotective properties, as well as its appropriate drug-like profile pointing toward blood-brain barrier permeability, compound 33 is proposed as a valid lead for a further optimization step.


Assuntos
Acetilcolinesterase/metabolismo , Benzamidas/farmacologia , Inibidores da Colinesterase/farmacologia , Iminas/farmacologia , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/química , Benzamidas/síntese química , Benzamidas/química , Benzamidas/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/toxicidade , Humanos , Iminas/síntese química , Iminas/química , Iminas/toxicidade , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/toxicidade , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/toxicidade , Relação Estrutura-Atividade
5.
Bioorg Chem ; 85: 431-444, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30685693

RESUMO

In this research paper, a stepwise chemical reaction was conducted to synthesize and develop of a new potent azo-oxazolone, which was used as prototypical molecule for production of two series of azo-benzimide (5a-j) and azo-imidazolone (6a-j). FT-IR, 1H NMR, 13C NMR and CHN analysis were used for the structural elucidation. The high biological efficiency of newly obtained compounds was confirmed by in vitro antioxidant efficacy and in vitro antimicrobial activity against gram-positive and gram-negative bacteria via disc diffusion and tube dilution techniques. In addition, in vivo anti-microbial activity of some of the synthesized compounds was determined by using burnt rats which infected by Staphylococcus aureus. Tested compounds have shown high anti-microbial activity and wound healing in comparison to ucederm as a control. In vivo acute toxicity was carried out by up and down method for the compounds 4, 5d and 6d. The limited test dose was 2000 mg/kg, while the maximum tolerated dose was 5000 mg/kg which has administered no lethality recorded.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Benzamidas/farmacologia , Imidazóis/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/toxicidade , Antioxidantes/síntese química , Antioxidantes/toxicidade , Benzamidas/síntese química , Benzamidas/toxicidade , Escherichia coli/efeitos dos fármacos , Feminino , Imidazóis/síntese química , Imidazóis/toxicidade , Testes de Sensibilidade Microbiana , Ratos Wistar , Staphylococcus aureus/efeitos dos fármacos , Cicatrização/efeitos dos fármacos
6.
Thromb Haemost ; 119(3): 397-406, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30685871

RESUMO

Ibrutinib and acalabrutinib are approved for B cell malignancies and novel Bruton's tyrosine kinase (Btk) inhibitors undergo clinical testing also in B cell-driven autoimmune disorders. Btk in platelets mediates platelet activation via glycoprotein (GP) VI, which is crucial for atherosclerotic plaque-induced platelet thrombus formation. This can be selectively inhibited by Btk inhibitors. Since patients on second-generation Btk inhibitors apparently show less bleeding than patients on ibrutinib, we compared the effects of ibrutinib and four novel irreversible Btk inhibitors on GPVI-dependent platelet aggregation in blood and in vitro bleeding time. Low concentrations of collagen which induced the same low degree of GPVI-mediated platelet aggregation as atherosclerotic plaque material were applied. IC50 values for collagen (0.2-0.5 µg/mL)-induced platelet aggregation after 15-minute pre-incubation were: ibrutinib 0.12 µM, BGB-3111 0.51 µM, acalabrutinib 1.21 µM, ONO/GS-4059 1.20 µM and evobrutinib 5.84 µM. Peak venous plasma concentrations of ibrutinib (0.5 µM), acalabrutinib (2 µM) and ONO/GS-4059 (2 µM) measured after anti-proliferative dosage inhibited collagen-induced platelet aggregation, but did not increase PFA-200 closure time on collagen/epinephrine. Closure times were moderately increased by 2- to 2.5-fold higher concentrations of these inhibitors, but not by BGB-3111 (1 µM) and evobrutinib (10 µM). Prolonging platelet drug exposure to 60 minutes lowered IC50 values of any Btk inhibitor for GPVI-mediated aggregation by several fold, and 5- to 10-fold below anti-proliferative therapeutic drug plasma levels. In conclusion, low blood concentrations of ibrutinib and the novel Btk inhibitors suffice for GPVI selective platelet inhibition relevant for atherothrombosis but do not impair primary haemostasis.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Benzamidas/farmacologia , Plaquetas/efeitos dos fármacos , Imidazóis/farmacologia , Piperidinas/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Glicoproteínas da Membrana de Plaquetas/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Tirosina Quinase da Agamaglobulinemia/sangue , Benzamidas/toxicidade , Plaquetas/metabolismo , Relação Dose-Resposta a Droga , Hemorragia/sangue , Hemorragia/induzido quimicamente , Hemostasia/efeitos dos fármacos , Humanos , Imidazóis/toxicidade , Concentração Inibidora 50 , Piperidinas/toxicidade , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/toxicidade , Glicoproteínas da Membrana de Plaquetas/metabolismo , Pirazinas/toxicidade , Pirazóis/toxicidade , Pirimidinas/toxicidade
7.
Arch Pharm (Weinheim) ; 352(3): e1800278, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30624805

RESUMO

Novel bi-heterocyclic benzamides were synthesized by sequentially converting 4-(1H-indol-3-yl)butanoic acid (1) into ethyl 4-(1H-indol-3-yl)butanoate (2), 4-(1H-indol-3-yl)butanohydrazide (3), and a nucleophilic 5-[3-(1H-indol-3-yl)propyl]-1,3,4-oxadiazole-2-thiol (4). In a parallel series of reactions, various electrophiles were synthesized by reacting substituted anilines (5a-k) with 4-(chloromethyl)benzoylchloride (6) to afford 4-(chloromethyl)-N-(substituted-phenyl)benzamides (7a-k). Finally, the nucleophilic substitution reaction of 4 was carried out with newly synthesized electrophiles, 7a-k, to acquire the targeted bi-heterocyclic benzamides, 8a-k. The structural confirmation of all the synthesized compounds was done by IR, 1 H NMR, 13 C NMR, EI-MS, and CHN analysis data. The inhibitory effects of these bi-heterocyclic benzamides (8a-k) were evaluated against alkaline phosphatase, and all these molecules were identified as potent inhibitors relative to the standard used. The kinetics mechanism was ascribed by evaluating the Lineweaver-Burk plots, which revealed that compound 8b inhibited alkaline phosphatase non-competitively to form an enzyme-inhibitor complex. The inhibition constant Ki calculated from Dixon plots for this compound was 1.15 µM. The computational study was in full agreement with the experimental records and these ligands exhibited good binding energy values. These molecules also exhibited mild cytotoxicity toward red blood cell membranes when analyzed through hemolysis. So, these molecules might be deliberated as nontoxic medicinal scaffolds to render normal calcification of bones and teeth.


Assuntos
Fosfatase Alcalina/antagonistas & inibidores , Benzamidas/síntese química , Inibidores Enzimáticos/síntese química , Animais , Benzamidas/química , Benzamidas/farmacologia , Benzamidas/toxicidade , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/toxicidade , Membrana Eritrocítica/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Cinética , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade
8.
Ecotoxicol Environ Saf ; 171: 75-83, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-30597319

RESUMO

The herbicide "fomesafen" causes phytotoxicity to the rotational wheat crop and may reduce its yield. Considering that biochar may improve remediation and biophysical conditions of the contaminated soil environments to benefit plant growth. Here, we investigated the impacts of three levels of the wheat straw-derived biochar (1%, 2%, and 4% (w/w)) on growth, physiological properties, and rhizosphere microbial communities of the wheat (Triticum aestivum) seedlings under the fomesafen stress using high-throughput sequencing. The results showed that biochar amended into soil significantly reduced the uptake of wheat to fomesafen and thereby eliminate its toxicity to wheat seedlings. Moreover, biochar increased the abundance and diversity of plant beneficial bacterial and fungal taxa in the rhizosphere of wheat seedlings. Compared with the three addition amounts, amendment with 2% of biochar has the best effects to reduce the toxicity of fomesafen on wheat seedlings and maintain the balance of soil microbial community structure in soil contaminated with fomesafen (1.0 mg kg-1). Overall, our results suggest that the level of biochar application influences the structure and diversity of soil microbiome (and mycobiome) and plant performance under abiotic stress conditions.


Assuntos
Benzamidas/toxicidade , Carvão Vegetal , Herbicidas/toxicidade , Desenvolvimento Vegetal , Microbiologia do Solo , Triticum/crescimento & desenvolvimento , Bactérias , Fungos , Microbiota , Rizosfera , Poluentes do Solo/toxicidade , Triticum/efeitos dos fármacos
9.
Environ Sci Pollut Res Int ; 26(4): 3723-3730, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30539393

RESUMO

Triflumuron (TFM) is one of the most widely used insecticides over the world. It is a benzoylphenyl urea that belongs to the class of insect growth regulators. This insecticide acts by inhibiting insect's chitin synthesis and by consequences, making insect more susceptible to pathogens and malformations. TFM effects have been reported in mammalians and crops. However, studies that reveal its toxicity mechanisms are limited. In this line, the current study aimed to determine the implication of oxidative stress in the toxicity induced by TFM and particularly in the perturbation of biochemical parameters in male Balb/C mice. Male Balb/C mice were divided into three groups receiving TFM at doses of 250, 350, and 500 mg/kg bw respectively. The occurrence of oxidative stress in both kidney and liver tissues was monitored by measuring of oxidative stress markers. TFM caused an increase as protein carbonyls generation, malondialdehyde induction (MDA) and catalase (CAT), superoxide dismutase (SOD), glutathion peroxidase (Gpx), as well as glutathion S transferase (GST) activities. In the same conditions, we have evaluated the effect of TFM treatment on biochemical parameters. In response to the three TFM doses, we showed significant dose dependent inductions in all tested oxidative stress markers. However, TFM caused an increase in the liver enzyme activities as aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), g-glutamyltranspeptidase (GTT), and total bilirubin (BILT) in a dose-dependent manner. Equally, renal markers as urea, uric acid, albumin, and creatinine were increased in the same manner. We can conclude that oxidative damage seems to be a key determinant of TFM-induced toxicity in both liver and kidney of male Balb/C mice. Moreover, the oxidative stress is more pronounced in the liver than in the kidney. Thus, TFM may be considered as a hepatotoxic insecticide.


Assuntos
Benzamidas/toxicidade , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Alanina Transaminase/metabolismo , Animais , Antioxidantes/metabolismo , Aspartato Aminotransferases/metabolismo , Benzamidas/administração & dosagem , Biomarcadores/metabolismo , Catalase/metabolismo , Creatinina/metabolismo , Glutationa Peroxidase/metabolismo , Inseticidas/administração & dosagem , Inseticidas/toxicidade , Rim/metabolismo , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos BALB C , Estresse Oxidativo/fisiologia , Superóxido Dismutase/metabolismo , Testes de Toxicidade Aguda
10.
Toxicol Sci ; 167(2): 509-523, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30329129

RESUMO

Chlorantraniliprole (CP) and flubendiamide (FD) are widely used in agriculture globally to control lepidopteran pests. Both insecticides target ryanodine receptors (RyRs) and promote Ca2+ leak from sarcoplasmic reticulum (SR) within insect skeletal muscle yet are purportedly devoid of activity toward mammalian RyR1 and muscle. RyRs are ion channels that regulate intracellular Ca2+ release from SR during physiological excitation-contraction coupling. Mutations in RYR1 genes confer malignant hyperthermia susceptibility (MHS), a potentially lethal pharmacogenetic disorder in humans and animals. Compared with vehicle control, CP (10 µM) triggers a 65-fold higher rate of Ca2+ efflux from Ca2+-loaded mammalian WT-RyR1 SR vesicles, whereas FD (10 µM) produces negligible influence on Ca2+ leak. We, therefore, compared whether CP or FD differentially influence patterns of high-affinity [3H]ryanodine ([3H]Ry) binding to RyR1 isolated from muscle SR membranes prepared from adult C57BL/6J mice expressing WT, homozygous C-terminal MHS mutation T4826I, or heterozygous N-terminal MHS mutation R163C. Basal [3H]Ry binding differed among genotypes with rank order T4826I ≫R163C∼WT, regardless of [Ca2+] in the assay medium. Both CP and FD (0.01-100 µM) elicited concentration-dependent increase in [3H]Ry binding, although CP showed greater efficacy regardless of genotype or [Ca2+]. Exposure to CP (500 mg/kg; p.o) failed to shift intolerance to heat stress (38°C) characteristic of R163C and T4826I MHS mice, nor cause lethality in WT mice. Although nM-µM of either diamide is capable of differentially altering WT and MHS RyR1 conformation in vitro, human RyR1 mutations within putative diamide N- and C-terminal interaction domains do not alter heat stress intolerance (HSI) in vivo.


Assuntos
Benzamidas/toxicidade , Cálcio/metabolismo , Resposta ao Choque Térmico/efeitos dos fármacos , Hipertermia Maligna/metabolismo , Músculo Esquelético/efeitos dos fármacos , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Sulfonas/toxicidade , ortoaminobenzoatos/toxicidade , Animais , Relação Dose-Resposta a Droga , Resposta ao Choque Térmico/genética , Heterozigoto , Homozigoto , Masculino , Hipertermia Maligna/genética , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Mutação , Ligação Proteica , Coelhos , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Retículo Sarcoplasmático/efeitos dos fármacos , Retículo Sarcoplasmático/metabolismo
11.
Bioorg Chem ; 83: 569-579, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30471579

RESUMO

Treatment of nosocomial and community acquired Staphylococcus aureus infections has become more challenging due to the egression of multi-drug resistance. This has spurred the need for rapid development of new therapeutic agents which can effectively negate the resistance mechanisms. In our current work, several new 4-oxoquinazolin-3(4H)-yl)benzoic acid and benzamide derivatives were synthesized and examined for their antimicrobial activity against ESKAP pathogen panel and pathogenic mycobacteria. In the primary screening, compounds 4a, 4b, 6'a, 6'b, 6'h, 6'i and 6'j were found to demonstrate selective and potent inhibitory activity against Staphylococcus aureus (MICs = 0.25-0.5 µg/mL). When tested against Vero cells, all the compounds were found to be non toxic possessing favourable selectivity index (SI > 10), which encouraged us for carrying out further studies. Compound 6'a (SI > 40) was tested against a number of multiple clinical strains of multi-drug resistant S. aureus and was found to exhibit potent activity, irrespective of the resistant status of the strain. Besides, compound 6'a also exhibited concentration dependent bactericidal activity and synergized with the FDA approved drugs tested. The interesting results obtained suggest the potential utility of the newly synthesized compounds for treatment of multidrug resistant S. aureus infections.


Assuntos
Antibacterianos/farmacologia , Benzamidas/farmacologia , Benzoatos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Quinazolinonas/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/toxicidade , Benzamidas/síntese química , Benzamidas/química , Benzamidas/toxicidade , Benzoatos/síntese química , Benzoatos/química , Benzoatos/toxicidade , Sinergismo Farmacológico , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinazolinonas/síntese química , Quinazolinonas/química , Quinazolinonas/toxicidade , Relação Estrutura-Atividade , Células Vero
12.
Bioorg Chem ; 83: 367-379, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30408649

RESUMO

Based on some common structural features of known compounds interfering with p53 pathways and our previously synthesized benzamides, we synthesized new ethyl 5-(4-substituted benzamido)-1-phenyl-1H-pyrazole-4-carboxylates 26a-c, ethyl 5-(4-substituted benzamido)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylates 27a-c and N-(1H-indazol-6-yl)-4-substituted benzamides 31a,b bearing in the 4 position of the benzamido moiety the 2-phenylpropanamido or 2-phenoxyacetamido or cinnamamido groups. A preliminary test to evaluate the antiproliferative activity against human lung carcinoma H292 cells highlighted how compound 26c showed the best activity. This last was therefore selected for further studies with the aim to find the mechanism of action. Compound 26c induces intrinsic apoptotic pathway by activating p53 and is also able to activate TRAIL-inducing death pathway by promoting increase of DR4 and DR5 death receptors, downregulation of c-FLIPL and caspase-8 activation.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Indazóis/farmacologia , Pirazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Benzamidas/síntese química , Benzamidas/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indazóis/síntese química , Indazóis/toxicidade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pirazóis/síntese química , Pirazóis/toxicidade
13.
Environ Toxicol Chem ; 38(2): 396-411, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30365191

RESUMO

In the present study we performed a microcosm experiment to assess the effects of the insecticide lufenuron on zooplankton communities exposed to increased temperature and drought in (semi-)arid regions. The experiment consisted of 3 environmental scenarios, assessed in 2 parts. Firstly, we assessed how water temperature (20 and 28 °C) affects the sensitivity and resilience of the zooplankton community to lufenuron. Secondly, we investigated the influence of drought on the structure of the zooplankton community at a high water temperature (28 °C) and evaluated its possible interaction with lufenuron. The results show that the community exposed to lufenuron at 28 °C had a faster lufenuron-related response and recovery than the community at 20 °C. The combined effects of lufenuron and temperature resulted in a synergistic effect on some taxa (Daphnia sp., Cyclopoida, and Copepoda nauplii). The tested zooplankton community had a high resilience to drought, although some particular taxa were severely affected after desiccation (Calanoida). Interactions between drought and lufenuron were not statistically significant. However, rewetting after desiccation contributed to lufenuron remobilization from sediments and resulted in a slight Cyclopoida population decline at high exposure concentrations. The study shows how environmental conditions related to global change in (semi-)arid regions may influence chemical fate and the vulnerability of zooplankton communities to chemical stress. Environ Toxicol Chem 2019;38:396-411. © 2018 SETAC.


Assuntos
Benzamidas/toxicidade , Secas , Temperatura Alta , Inseticidas/toxicidade , Poluentes Químicos da Água/toxicidade , Zooplâncton/efeitos dos fármacos , Animais , Copépodes/efeitos dos fármacos , Daphnia/efeitos dos fármacos , Água Doce/química
14.
Acta Pharmacol Sin ; 40(7): 895-907, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30573812

RESUMO

The manipulation of bile acid (BA) homeostasis by blocking the ileal apical Na+-dependent bile salt transporter (ASBT/SLC10A2) may have therapeutic effects in nonalcoholic fatty liver disease. We developed a novel ASBT inhibitor, an N-(3,4-o-dichlorophenyl)-2-(3-trifluoromethoxy) benzamide derivative referred to as IMB17-15, and investigated its therapeutic effects and the molecular mechanisms underlying the effects. Syrian golden hamsters were challenged with high-fat diet (HFD) to induce NAFLD and were subsequently administered 400 mg/kg IMB17-15 by gavage daily for 21 days. Serum, liver, and fecal samples were collected for further analysis. Plasma concentration-time profiles of IMB17-15 were also constructed. The human hepatocyte cell line HL-7702 was treated with Oleic acid (OA) with or without IMB17-15. Western blotting and real-time PCR were used to study the molecular mechanisms of IMB17-15. We found that IMB17-15 inhibited ASBT and subsequently suppressed ileal farnesoid X receptor (FXR) and FXR-activated fibroblast growth factor15/19 (FGF15/19) expression, which reduced the hepatic phosphorylated extracellular regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) levels and upregulated the cholesterol 7α-hydroxylase (CYP7A1) activity. Additionally, IMB17-15 stimulated adenosine monophosphate (AMP)-activated protein kinase (AMPKα) phosphorylation and enhanced peroxisome proliferator activated receptor α (PPARα) expression and thus promoted triglyceride (TG) oxidation and high-density lipoprotein cholesterol (HDL-c) metabolism through an ASBT-independent mechanism. In conclusion, a novel ASBT inhibitor known as IMB17-15 protected hamsters against HFD-induced NFALD by manipulating BA and lipid homeostasis. IMB17-15 also reduced lipid deposition in human hepatic cell lines, indicating that it may be useful as a therapy for NAFLD patients.


Assuntos
Benzamidas/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Simportadores/antagonistas & inibidores , Animais , Benzamidas/farmacocinética , Benzamidas/toxicidade , Linhagem Celular , Citocinas/metabolismo , Dieta Hiperlipídica , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fígado/patologia , Masculino , Mesocricetus , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Sulfonamidas/farmacocinética , Sulfonamidas/toxicidade
15.
Drug Dev Res ; 79(7): 315-323, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30291750

RESUMO

Renal ischemia-reperfusion injury (IRI) induces the production of aldehydes which are detoxified by aldehyde dehydrogenases (ALDHs). Alda-1 is a selective ALDH2 agonist and its protective effect was demonstrated in several conditions. The effect of Alda-1 on the kidney or on renal IRI was not investigated. We investigated the effect of Alda-1 on the renal dysfunction following IRI. Wistar rats underwent left IRI for 40 min. Group-Alda (n = 11) received Alda-1 starting 24 h before IRI and continued for 7 days thereafter when renal functions were measured. Group-Vx (n = 11) underwent similar protocol but received the dissolvent. Alda-1 did not affect renal blood flow or glomerular filtration rate in the left ischemic kidney in Group-Alda compared to Group-Vx (3.05 ± 0.50 vs. 3.53 ± 0.70, and 0.40 ± 0.06 vs. 0.51 ± 0.08, respectively, p > .05 for both). However, left renal fractional sodium excretion was higher in Group-Alda (2.80 ± 0.43 vs. 1.37 ± 0.36, p = .02). Alda-1 also adversely affected the gene expressions of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin (217 ± 38 vs. 99 ± 13 and 49 ± 13 vs. 20 ± 5, respectively, p < .05 for both) and the alterations in tumor necrosis factor-α, transforming growth factor-ß1, plasminogen activator inhibitor-1, fibronectin 1 and p53 (4.4 ± 0.9 vs. 2.1 ± 0.3, 1.5 ± 0.1 vs. 1.1 ± 0.1, 30.0 ± 2.7 vs. 11.7 ± 2.3, 3.6 ± 0.4 vs. 2.1 ± 0.2 and 1.3 ± 0.1 vs. 0.9 ± 0.07, respectively, p ≤ .05 for all). This was associated with intratubular crystal deposition suggestive of crystalline nephropathy. Alda-1 exacerbated the IRI-induced renal tubular dysfunction and alterations in markers of acute kidney injury, biomarkers of inflammation, fibrosis and apoptosis and this was associated with intratubular crystal deposition suggestive of crystalline nephropathy.


Assuntos
Aldeído-Desidrogenase Mitocondrial/metabolismo , Benzamidas/toxicidade , Benzodioxóis/toxicidade , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Cristalinas/metabolismo , Nefropatias/patologia , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Traumatismo por Reperfusão/patologia
16.
Ecotoxicol Environ Saf ; 166: 78-85, 2018 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-30248564

RESUMO

The application of foliar fungicides to horticultural crops has raised public concerns worldwide. In fact, it has been demonstrated that such fungicides have an impact on non-target microorganisms in the rhizosphere. Fluopyram, triadimenol and penthiopyrad are three broad-spectrum fungicides recommended to control foliar diseases. In our experiment, these fungicides were applied to a cucumber crop to mainly control downy mildew caused by Pseudoperonospora cubensis and grey mold caused by Botrytis cinerea. At the same time, we found that these treatments also controlled other fungal pathogens affecting cucumber crops, particularly penthiopyrad, which was more effective. Once the fungicide application period was over, the effect decreased, although fungicide traces remained in the soil. Furthermore, microbial soil community analysis indicated that both fungicide treatments affect fungal communities to a greater extent than bacterial communities.


Assuntos
Produtos Agrícolas , Cucumis sativus , Fungicidas Industriais/toxicidade , Microbiota/efeitos dos fármacos , Microbiologia do Solo , Benzamidas/toxicidade , Doenças das Plantas/microbiologia , Pirazóis/toxicidade , Piridinas/toxicidade , Solo , Tiofenos/toxicidade , Triazóis/toxicidade
17.
J Toxicol Sci ; 43(9): 557-563, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30185696

RESUMO

There is sometimes controversy over whether or not statistically significant responses produced in carcinogenicity studies have biologically significance. Ambiguous results from our previous two-year oral carcinogenicity study on acotiamide hydrochloride hydrate (acotiamide-HH), a prokinetic drug for functional dyspepsia, in rats made it unclear whether the drug may exhibit uterine carcinogenicity. To check this finding, we performed a second long-term carcinogenicity study using two identical control groups to more accurately evaluate uterine carcinogenesis by considering the incidence of spontaneous neoplasms. Female Fischer 344 rats were divided into three groups: the two control groups (control 1 and 2) were administered vehicle (0.5% w/v methylcellulose) and the acotiamide-HH-treated group was administered 2,000 mg/kg/day of acotiamide-HH by oral gavage for two years. Among all groups, the incidence of endometrial adenocarcinoma (EmA) was highest in the control 2 group, followed by the acotiamide-HH-treated group and the control 1 group. Moreover, acotiamide-HH did not affect the incidence of precursor lesions of EmA. In cases where an ambiguous difference is observed, the use of two control groups allows for a more informed interpretation of the findings in the drug-treated groups. The outcomes in this study strongly support the hypothesis that the increase in EmA in rats treated with acotiamide-HH in our previous study is unrelated to administration of the drug.


Assuntos
Adenocarcinoma/induzido quimicamente , Benzamidas/toxicidade , Testes de Carcinogenicidade/métodos , Grupos Controle , Neoplasias do Endométrio/induzido quimicamente , Tiazóis/toxicidade , Administração Oral , Animais , Benzamidas/administração & dosagem , Reações Falso-Positivas , Feminino , Ratos Endogâmicos F344 , Tiazóis/administração & dosagem , Fatores de Tempo
18.
ChemMedChem ; 13(19): 2080-2089, 2018 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-30134015

RESUMO

The introduction of fluorine into bioactive molecules is a matter of importance in medicinal chemistry. In this study, representatives of various chemical entities of fluoroaromatic compounds were synthesized. Depending on the reaction conditions, either tetrafluorophthalimides or ammonium tetrafluorophthalamates are accessible from tetrafluorophthalic anhydride and primary amines. Tetrafluorophthalamic acids undergo thermal decarboxylation to yield tetrafluorobenzamides. These could be successfully converted upon treatment with primary amines, in the course of an aromatic nucleophilic substitution, to 2,3,5-trifluorobenzamides with respective amino substituents at the 4-position. The five structure types were characterized by means of spectroscopic and crystallographic methods. The synthesized compounds were evaluated as inhibitors of angiogenesis by measuring microvessel outgrowth in a rat aortic ring assay. The biological activity was maintained throughout these different polyfluorinated chemotypes.


Assuntos
Inibidores da Angiogênese/farmacologia , Benzamidas/farmacologia , Fluorcarbonetos/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/toxicidade , Animais , Aorta/efeitos dos fármacos , Benzamidas/síntese química , Benzamidas/química , Benzamidas/toxicidade , Fluorcarbonetos/síntese química , Fluorcarbonetos/química , Fluorcarbonetos/toxicidade , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Microvasos/efeitos dos fármacos , Estrutura Molecular , Ftalimidas/síntese química , Ftalimidas/química , Ftalimidas/farmacologia , Ftalimidas/toxicidade , Ratos Sprague-Dawley , para-Aminobenzoatos/síntese química , para-Aminobenzoatos/química , para-Aminobenzoatos/farmacologia , para-Aminobenzoatos/toxicidade
19.
Bioorg Chem ; 81: 191-202, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30138907

RESUMO

A series of N-(2-(3,4,5-trimethoxybenzyl)-benzoxazole-5-yl)benzamide derivatives (3a-3n) was synthesized and evaluated for its in vitro inhibitory activity against COX-1 and COX-2. The compounds with considerable in vitro activity (IC50 < 1 µM), were evaluated in vivo for their anti-inflammatory and ulcerogenic potential. Out of the fourteen newly synthesized compounds; 3b, 3d, 3e, 3h, 3l and 3m were found to be most potent COX-2 inhibitors in in vitro enzymatic assay with IC50 in the range of 0.14-0.69 µM. In vivo anti-inflammatory activity of these six compounds (3b, 3d, 3e, 3h, 3l and 3m) was assessed by carrageenan induced rat paw edema method. The compound 3b (79.54%), 3l (75.00%), 3m (72.72%) and 3d (68.18%) exhibited significant anti-inflammatory activity than standard drug ibuprofen (65.90%). Ulcerogenic activity with histopathological studies was performed, and the screened compounds demonstrated significant gastric tolerance than ibuprofen. Molecular Docking study was also performed with resolved crystal structure of COX-2 to understand the interacting mechanisms of newly synthesized inhibitors with the active site of COX-2 enzyme and the results were found to be in line with the biological evaluation studies of the compounds.


Assuntos
Anti-Inflamatórios/uso terapêutico , Benzamidas/uso terapêutico , Benzoxazóis/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Inflamação/tratamento farmacológico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/toxicidade , Antiulcerosos/síntese química , Antiulcerosos/farmacocinética , Antiulcerosos/uso terapêutico , Antiulcerosos/toxicidade , Benzamidas/síntese química , Benzamidas/farmacocinética , Benzamidas/toxicidade , Benzoxazóis/síntese química , Benzoxazóis/farmacocinética , Benzoxazóis/toxicidade , Carragenina , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Inibidores de Ciclo-Oxigenase 2/toxicidade , Ensaios Enzimáticos , Feminino , Humanos , Ibuprofeno , Inflamação/induzido quimicamente , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos Wistar , Ovinos , Estômago/patologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Relação Estrutura-Atividade
20.
Environ Sci Pollut Res Int ; 25(27): 27594-27605, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30054838

RESUMO

The persistence of chlorpyrifos, fluopyram, and tebuconazole was estimated in green pods, matured seeds, and soil of French beans using dispersive QuEChERS. Three foliar applications each of chlorpyrifos and a combination fungicide fluopyram + tebuconazole (Luna experience, 400 SC) were applied at 600 and 125 + 125 as a standard dose and 1200 and 250 + 250 g a.i. ha-1 as a double dose, respectively, were applied at an interval of 10 days and treated pods were picked up at regular intervals. Dried mature seeds and soil were also monitored at harvest. The initial deposits of chlorpyrifos on bean pods were 3.083 and 6.017 mg kg-1 with a half-life of 1.86 and 2.29 days, at respective doses. Foliar application of a combi product Luna experience yielded 3.396 and 5.772 mg kg-1 residues of fluopyram and 3.613 and 5.887 mg kg-1 of tebuconazole in green pods at standard and double dose with almost same half-lives of 3.4 and 3.8-3.9 days. Residues declined below the limit of quantitation (LOQ) of 0.05 mg kg-1 in green beans after 15 and 25 days after the application of double dose of chlorpyrifos and Luna experience, respectively. However, the residues in dry bean seeds and soil reached below the LOQ of 0.05 mg kg-1 at the time of harvest. A pre-harvest interval of 5, 10, and 7 days has been proposed for chlorpyrifos, fluopyram, and tebuconazole, respectively, in beans. HQ < 1 and TMDI < MPI in all test chemicals. Hence, it was concluded that a waiting period of 5 days for chlorpyrifos and 7-10 days in Luna experience will be safer to consumers. This data generated will be useful for regulatory agency for fixing MRLs.


Assuntos
Benzamidas/análise , Clorpirifos/análise , Fungicidas Industriais/análise , Resíduos de Praguicidas/análise , Phaseolus/crescimento & desenvolvimento , Piridinas/análise , Poluentes do Solo/análise , Triazóis/análise , Benzamidas/toxicidade , Clorpirifos/toxicidade , Fungicidas Industriais/toxicidade , Meia-Vida , Índia , Resíduos de Praguicidas/toxicidade , Phaseolus/química , Piridinas/toxicidade , Medição de Risco , Solo/química , Poluentes do Solo/toxicidade , Triazóis/toxicidade
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