RESUMO
Contemporary sources of organohalogens produced as disinfection byproducts (DBPs) are receiving considerable attention as emerging pollutants because of their abundance, persistence, and potential to structurally mimic natural organohalogens produced by bacteria that serve signaling or toxicological functions in marine environments. Here, we tested 34 organohalogens from anthropogenic and marine sources to identify compounds active toward ryanodine receptor (RyR1), known toxicological targets of non-dioxin-like polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). [3H]Ryanodine ([3H]Ry) binding screening (≤2 µM) identified 10 highly active organohalogens. Further analysis indicated that 2,3-dibromoindole (14), tetrabromopyrrole (31), and 2,3,5-tribromopyrrole (34) at 10 µM were the most efficacious at enhancing [3H]Ry binding. Interestingly, these congeners also inhibited microsomal sarcoplasmic/endoplasmic reticulum (SR/ER) Ca2+ ATPase (SERCA1a). Dual SERCA1a inhibition and RyR1 activation triggered Ca2+ efflux from microsomal vesicles with initial rates rank ordered 31 > 34 > 14. Hexabromobipyrroles (25) enhanced [3H]Ry binding moderately with strong SERCA1a inhibition, whereas pyrrole (24), 2,3,4-tribromopyrrole (26), and ethyl-4-bromopyrrole-2-carboxylate (27) were inactive. Of three PBDE derivatives of marine origin active in the [3H]Ry assay, 4'-hydroxy-2,3',4,5',6-pentabromodiphenyl ether (18) was also a highly potent SERCA1a inhibitor. Molecular targets of marine organohalogens that are also DBPs of emerging environmental concern are likely to contribute to their toxicity.
Assuntos
Poluentes Ambientais , Bifenilos Policlorados , Desinfecção , Estresse do Retículo Endoplasmático , Éteres Difenil Halogenados , Canal de Liberação de Cálcio do Receptor de RianodinaRESUMO
Polyhalogenated N-methylbipyrroles of two different structure classes have been detected worldwide in over 100 environmental samples including seawater, bird eggs, fish, dolphin blubber, and in the breast milk of humans that consume seafood. These molecules are concentrated in the fatty tissues in comparable abundance to some of the most important anthropogenic contaminants, such as the halogenated flame-retardants and pesticides. Although the origin of these compounds is still unknown, we present evidence that the production of these materials can involve the direct ozone activated seawater halogenation of N-methylbipyrrole precursors. This observation shows that environmental polyhalogenated bipyrroles can be produced via an abiotic process, and implies that the ozone activated halogenation of a variety of natural and anthropogenic seawater organics may be a significant process occurring in surface ocean waters.
Assuntos
Halogenação , Ozônio , Monitoramento Ambiental , Retardadores de Chama , Água do Mar/química , Poluentes Químicos da ÁguaRESUMO
Acute nerve agent exposure can kill a person within minutes or produce multiple neurotoxic effects and subsequent brain damage with potential long-term adverse outcomes. Recent abuse of nerve-agents on Syrian civilians, during Japan terrorist attacks, and personal assassinations in the UK, and Malaysia indicate their potential threat to world population. Existing nerve agent antidotes offer only incomplete protection especially, if the treatment is delayed. To develop the effective drugs, it is advantageous to elucidate the underlying mechanisms of nerve agent-induced multiple neurological impairments. This study aimed to investigate the molecular basis of neuroinflammation during nerve agent toxicity with focus on inflammasome-associated proteins and neurodegeneration. In rats, NOD-like receptor family pyrin domain containing 3 (NLRP3), and glial fibrillary acidic protein (GFAP) immunoreactivity levels were considerably increased in the hippocampus, piriform cortex, and amygdala areas after single subcutaneous soman exposure (90 µg/kg-1). Western analysis indicated a notable increase in the neuroinflammatory indicator proteins, high mobility group box 1 (HMGB1) and inducible nitric oxide synthase (iNOS) levels. The presence of fluorojade-C-stained degenerating neurons in distinct rat brain areas is indicating the neurodegeneration during nerve agent toxicity. Pre-treatment with galantamine (3 mg/kg, - 30 min) followed by post-treatment of atropine (10 mg/kg, i.m.) and midazolam (5 mg/kg, i.m.), has completely protected animals from death induced by supra-lethal dose of soman (2XLD50) and reduced the neuroinflammatory and neurodegenerative changes. Results highlight that this new prophylactic and therapeutic drug combination might be an effective treatment option for soldiers deployed in conflict areas and first responders dealing with accidental/deliberate release of nerve agents.
RESUMO
BACKGROUND: Ricin is a potential biowarfare agent. It is a phytotoxin isolated from castor seeds. At present there is no antidote available for ricin poisoning, patients only get supportive treatment based on their symptoms. This highlights the importance of early detection to avoid severity of accidents and reduce the risk factor. Considering this, our study aimed to develop a highly sensitive and specific sandwich ELISA for the detection of ricin. METHODS: Ricin was purified from castor seeds. Anti-ricin polyclonal and monoclonal antibodies were generated from rabbit antisera and hybridoma cell (1H6F1) supernatant using a protein A/G column. Antibody titer estimation was done using Indirect ELISA. A streptavidin-biotin-based sandwich ELISA was developed and the limit of detection (LOD), linear range, intra and inter-assay coefficient of variation (CV), and cross-reactivity with other similar toxins were determined. Interference of human plasma samples spiked with ricin was also checked. RESULTS: The LOD of the ELISA was found to be 0.45 ng/ml, with a linear range of 0.90-62 ng/ml, intra and inter-assay CV ranged from 3.34 % to 5 % and 5.17 % to 10.80 % respectively. The assay was not cross-reactive with other similar ribosome-inactivating protein (RIP) toxins. Ricin was detected in spiked plasma samples. CONCLUSION: The developed assay is highly sensitive and specific for detecting ricin and is not cross-reactive with other similar types of toxins. The assay can detect ricin in spiked plasma samples, so it has the potential to be used for the analysis of clinical samples after ricin poisoning.
Assuntos
Biotina , Ensaio de Imunoadsorção Enzimática , Ricina , Estreptavidina , Ricina/imunologia , Ricina/análise , Ensaio de Imunoadsorção Enzimática/métodos , Animais , Humanos , Coelhos , Limite de Detecção , Anticorpos Monoclonais/imunologia , Reações Cruzadas , Ricinus communis/imunologia , Camundongos , Reprodutibilidade dos Testes , Sementes/imunologia , Sementes/químicaRESUMO
A series of 3,6-epoxy [1,5]dioxocines were synthesized and evaluated for their antifilarial activity against adult parasites of human lymphatic filarial parasite Brugia malayi (sub-periodic strain) in vitro. Out of these, six compounds (4a-f) possessed improved in vitro anti-filarial activity and examples 4d and 4f were also found to be active in the in vivo experiments. These results demonstrate that 3,6-epoxy [1,5]dioxocines exhibits potent antifilarial activity and might be developed into a new class of antifilarial drug.
Assuntos
Brugia Malayi/efeitos dos fármacos , Compostos de Epóxi/síntese química , Filaricidas/farmacologia , Oxocinas/síntese química , Animais , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Feminino , Filaricidas/síntese química , Filaricidas/química , Concentração Inibidora 50 , Estrutura Molecular , Oxocinas/química , Oxocinas/farmacologiaRESUMO
First synthesis of novel coumarin-trioxane hybrids is reported. The synthesis was achieved via condensation of ß-hydroxyhydroperoxides with coumarinic-aldehydes in presence of p-toluenesulfonic acid in good yields and the novel hybrids were evaluated for their antimalarial activity both in vitro and in vivo.
Assuntos
Antimaláricos/síntese química , Cumarínicos/química , Compostos Heterocíclicos/química , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Plasmodium yoelii/efeitos dos fármacos , Aldeídos/química , Animais , Antimaláricos/farmacologia , Benzenossulfonatos/química , Cumarínicos/farmacologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/parasitologia , Compostos Heterocíclicos/farmacologia , Humanos , Concentração Inibidora 50 , Malária Falciparum/parasitologia , Camundongos , Peróxidos/química , Plasmodium falciparum/parasitologia , Plasmodium yoelii/parasitologia , Relação Estrutura-AtividadeRESUMO
In an effort to develop potent antithrombotic agents, a series of novel 3-carboxamide-benzocoumarin derivatives were synthesized and screened for their in vivo antithrombotic activity. Among 20 compounds tested, the compound 12b showed the most promising antithrombotic activity which was comparable with clinically used aspirin or warfarin, but, at variance with these standard drugs, 12b did not exhibit the increased bleeding time, suggesting its potential as a novel antithrombotic agent.
Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Cumarínicos/síntese química , Cumarínicos/farmacologia , Fibrinolíticos/síntese química , Fibrinolíticos/farmacologia , Administração Oral , Animais , Aspirina/química , Aspirina/farmacologia , Cumarínicos/química , Fibrinolíticos/química , Camundongos , Estrutura Molecular , Varfarina/química , Varfarina/farmacologiaRESUMO
A series of 3-phenylcoumarins were synthesized and screened for potential antidepressant activity by tail suspension test (TST) in mice. Three compounds (6, 7 and 13) exhibited impressive antidepressant activity, measured in terms of percentage decrease in immobility duration (% DID). In addition, the active antidepressant compounds were subsequently studied at their most effective dose and activity of these compounds were confirmed in forced swimming test (FST) animal model, in which the compounds at a low dose of 0.5 mg/kg significantly decreased the immobility time and exhibited greater efficacy than the reference standards fluoxetine and imipramine. The potent compounds did not show any neurotoxicity in the rotarod test and the preliminary results are promising enough to warrant further studies around this scaffold.
Assuntos
Antidepressivos/química , Antidepressivos/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Descoberta de Drogas , Animais , Antidepressivos/síntese química , Cumarínicos/síntese química , Relação Dose-Resposta a Droga , Masculino , Camundongos , Espectrofotometria Infravermelho , Estresse Fisiológico , NataçãoRESUMO
A series of novel coumarin bisindole heterocycles were synthesized following an uncommon method and evaluated for their antihyperlipidemic activity in hyperlipidemic hamster model. Among 12 compounds tested, the compound 5e showed potent antihyperlipidemic activity and was found to decrease the plasma triglyceride levels (TG) by 55%, total cholesterol (TC) by 20%, accompanied by an increase in HDL-C/TC ratio by 42% in hyperlipidemic rats to a greater degree than some of the reference statins.
Assuntos
Cumarínicos/química , Hipolipemiantes/síntese química , Hipolipemiantes/farmacologia , Animais , Colesterol/sangue , Cricetinae , Hipolipemiantes/química , Relação Estrutura-Atividade , Triglicerídeos/sangueRESUMO
A series of novel benzocoumarin derivatives were synthesized and evaluated for their in vivo antidyslipidemic and in vitro antioxidant activities. Among 11 compounds tested, 2 compounds showed potent antidyslipidemic activity and 3 compounds showed potent antioxidant activity.
Assuntos
Cumarínicos/uso terapêutico , Dislipidemias/tratamento farmacológico , Cumarínicos/química , HumanosRESUMO
A series of coumarin-chalcone hybrids have been synthesized and evaluated for their in vitro cytotoxicity against a panel of four human cancer cell lines and normal fibroblasts (NIH3T3). Among 21 compounds screened, three compounds (23, 25 and 26) showed IC(50) range from 3.59 to 8.12 µM. The most promising compound 26 showed around 30-fold more selectivity towards C33A (cervical carcinoma) cells over normal fibroblast NIH3T3 cells with an IC(50) value of 3.59 µM.
Assuntos
Antineoplásicos/síntese química , Chalconas/química , Cumarínicos/química , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Humanos , Camundongos , Células NIH 3T3 , Neoplasias/tratamento farmacológicoRESUMO
A series of novel benzocoumarin derivatives were synthesized and evaluated for their in vivo anti-dyslipidemic and in vitro antioxidant activities. Preliminary screening indicates compound 4 as potential lead with significant lipid lowering and antioxidant activities. The study revealed that such attempts on benzocoumarin-based pharmacophores which is a biologically important scaffold might result in identification of new lead for anti-dyslipidemia.
Assuntos
Cumarínicos/química , Cumarínicos/síntese química , Hipolipemiantes/síntese química , Animais , Cumarínicos/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/química , Hipolipemiantes/uso terapêutico , Ratos , Relação Estrutura-AtividadeRESUMO
The concept of molecular hybridization led us to discover a novel series of coumarin-dihydropyridine hybrids that have potent osteoblastic bone formation in vitro and that prevent ovariectomy-induced bone loss in vivo. In this context, among all the compounds screened for alkaline phosphatase activity, four compounds 10, 14, 18, and 22 showed significant activity at picomolar concentrations. A series of other in vitro data strongly suggested compound 18 as the most promising bone anabolic agent, which was further evaluated for in vivo studies. From these studies compound 18 proved to be useful, which at low oral dose of 1 (mg/kg)/day body weight increased bone mass density and volume, expression of osteogenic genes (RUNX2, BMP-2, and ColI), bone formation rate (BFR), and mineral apposition rate (MAR), improved the trabecular microarchitecture, and decreased bone turn over markers in an ovariectomized rodent model for postmenopausal osteoporosis.
Assuntos
Anabolizantes/síntese química , Osso e Ossos/efeitos dos fármacos , Cumarínicos/síntese química , Di-Hidropiridinas/síntese química , Quinolonas/síntese química , Administração Oral , Anabolizantes/química , Anabolizantes/farmacologia , Animais , Biomarcadores/metabolismo , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/fisiopatologia , Osso e Ossos/fisiologia , Calcificação Fisiológica/efeitos dos fármacos , Diferenciação Celular , Cumarínicos/química , Cumarínicos/farmacologia , Cristalografia por Raios X , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacologia , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/etiologia , Osteoporose Pós-Menopausa/fisiopatologia , Ovariectomia , Quinolonas/química , Quinolonas/farmacologia , Relação Estrutura-AtividadeRESUMO
Despite extensive research efforts, there is no unanimous approval of any animal model to evaluate the toxicity of sulphur mustard [SM; bis (2-chloroethyl) sulphide] or nitrogen mustard [HN-3; tris-(2-chloroethyl) amine] and screening of various prophylactic and therapeutic agents against them. In this study, differential toxicity of mustard agents in higher animal model that is male rabbit was determined. Protective efficacy of DRDE 07 [S-2(2-aminoethylamino) ethyl phenyl sulphide] and its analogues were also evaluated against SM and HN-3 toxicity. Differential toxicity study of SM and HN-3 reveals that both the compounds were more toxic by percutaneous route as compared to subcutaneous route. Till date, there is no recommended drug to counteract SM induced toxicity or mortality in vivo. However, DRDE 07 (an amifostine analogue) and its analogues are found to be very effective protective agents against percutaneously exposed SM in rabbits. The present experiments also showed that SM does not cause skin injury alone but also can cause systemic toxicity as well. DRDE 07 and many of its analogues may prove as prototype compounds for the development of better prophylactic and therapeutic drugs to counter the toxicity of SM or HN-3. In conclusion, rodents and rabbits can be used for the screening of drugs against the blistering agents.
Assuntos
Amifostina/análogos & derivados , Substâncias para a Guerra Química/toxicidade , Gás de Mostarda/toxicidade , Compostos de Mostarda Nitrogenada/antagonistas & inibidores , Compostos de Mostarda Nitrogenada/toxicidade , Substâncias Protetoras/uso terapêutico , Administração Cutânea , Amifostina/administração & dosagem , Amifostina/uso terapêutico , Animais , Antídotos/administração & dosagem , Antídotos/uso terapêutico , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Injeções Subcutâneas , Dose Letal Mediana , Masculino , Gás de Mostarda/administração & dosagem , Compostos de Mostarda Nitrogenada/administração & dosagem , Substâncias Protetoras/administração & dosagem , Coelhos , Fatores de TempoRESUMO
8-Hydroxyquinoline when subjected to Duff reaction resulted in the formation of unexpected 7-methylaminomethylene-8-oxo-7, 8-dihydroquinoline-5-carbaldehyde 2, which existed in the keto-enamine form, in which the aromaticity of the relevant ring was disrupted, which upon subsequent treatment with various primary amines resulted in its nucleophilic substitution of aliphatic methyl amine. These interesting novel derivatives were evaluated in vitro for their antioxidant and in vivo for their antidyslipidemic and post-heparin lipolytic activities. Compound 6 was found to be most active antidyslipidemic and antioxidative agent in this series, respectively, and thus represent a new class of promising lead.
Assuntos
Aminas/química , Antioxidantes/química , Antioxidantes/farmacologia , Dislipidemias/tratamento farmacológico , Hidroxiquinolinas/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Bases de Schiff/química , Animais , Antioxidantes/uso terapêutico , Dislipidemias/metabolismo , Fluorescência , Heparina/farmacologia , Radical Hidroxila/metabolismo , Hidroxiquinolinas/farmacologia , Masculino , Ratos , Bases de Schiff/farmacologia , Superóxidos/metabolismoRESUMO
In the course of our studies on the isolation of bioactive compounds from the roots of Coleus forskohlii, a traditional herb in India, rare 13-epi-sclareol has been isolated, and its structure determined by extensive 2D NMR. This is the first report of isolation from this plant. The isolated compound showed antiproliferative activity in breast and uterine cancers in vitro. The antiproliferative activity of 13-epi-sclareol is comparable to Tamoxifen in terms of IC50 and also showed concentration dependent increased apoptotic changes in the breast cancer cell line, MCF-7.