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1.
J Basic Microbiol ; 60(2): 173-184, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31663623

RESUMO

Spent mushroom substrate (SMS), a major byproduct of the mushroom industry, is a lignocellulosic biomass, which contains approximately 57-74.3% of holocellulose fraction. This study was aimed at utilizing SMS of Pleurotus florida for recovery of lignocellulolytic enzymes and sugars and also as a substrate for production of cellulolytic enzymes using different isolates of Trichoderma and Aspergillus under solid-state fermentation (SSF). SMS of P. florida extracts contained significant amounts of laccase (3,015.8 ± 29.5 U/g SMS) and xylanase (1,187.9 ± 12 U/g SMS) activity. Crystallinity pattern and chemical changes in SMS revealed that SMS had a lower crystallinity index (34.2%) as compared with the raw biomass (37.8%), which, in turn, helps in enhancing the accessibility of cellulolytic enzymes to holocellulose. Among the isolates, Trichoderma longibrachiatum A-01 showed maximum activity of endoglucanase (220.4 ± 5.9 U/mg), exoglucanase (78.5 ± 3.2 U/mg) and xylanase (1,550.4 ± 11.6 U/mg) while Aspergillus aculeatus C-08 showed maximum activity of cellobiase (113.9 ± 3.9 U/mg). Extraction with sodium citrate buffer (pH 4.8) showed maximum cellulolytic enzyme activity as compared with other solvents tested. Partial purification of endoglucanase, exoglucanase, xylanase, and cellobiase resulted in 56.3% (1,112.5 U/mg), 48.4% (212.5 U/mg), 44% (4,492.3 U/mg), and 62% (705.0 U/mg) yield with an increase by 5.2-, 4.5-, 4.1-, and 5.0-fold as compared with crude extract. The results reveal that SMS from P. florida could be a potential and cost-effective substrate for production of cellulolytic enzymes from T. longibrachiatum A-01 and A. aculeatus C-08.

2.
Chem Biol Drug Des ; 94(1): 1378-1389, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30903642

RESUMO

In our continued effort to discover novel PTP1B inhibitor with improved in vivo activity, we attempted to optimize our previously discovered lead compound by replacing the sulfonyl group with benzoyl group to yield compound II. Additional structural modifications were performed on compound II to yield a series of 24 aryl phenylthiazolyl phenylcarboxamides as potential PTP1B inhibitors. Of the 24 tested, 6 compounds showed good PTP1B inhibitory activity while compound 38 as the most promising one. The plausible PTP1B-binding site interaction of compound 38 showed favourable binding similar to known PTP1B binders and suggests its selectivity towards PTP1B. Compound 38 also showed promising antihyperglycaemic, antidyslipidaemic and insulin resistant reversal activities in vivo in STZ model and db/db mice model. Altogether, the compound 38 presents an excellent candidate for future PTP1B targeted drug discovery.

3.
Curr Top Med Chem ; 18(26): 2256-2265, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30569857

RESUMO

A series of substituted oxopropanylindole hydrazone derivatives was synthesized and evaluated for anti-oxidant and anti-dyslipidemic activity. Of the 12 tested, 3 compounds (6c, 7b and 7d) showed good anti-oxidant activity, compound 6c attenuated LDL oxidation by 32%. The compounds 6c and 7d also showed good anti-dyslipidemic activity by reducing serum levels of total cholesterol (TC), phospholipids (PL) and triglycerides (TG). These two compounds were further evaluated for antiadipogenic and anti-hyperglycemic activity, where 6c showed 44% reduction in lipid accumulation and 20.5% and 24.3% reduction in blood glucose at 5h and 24h respectively, as compared to standard drug metformin. Thus, compounds 6c and 7d with balanced anti-oxidant and anti-dyslipidimic activities may be excellent candidates for lead optimization and drug development for the treatment of metabolic disorders.


Assuntos
Antioxidantes/uso terapêutico , Hidrazonas/uso terapêutico , Hipoglicemiantes/uso terapêutico , Indóis/uso terapêutico , Lipoproteínas LDL/uso terapêutico , Células 3T3-L1 , Animais , Antioxidantes/síntese química , Antioxidantes/química , Glicemia/efeitos dos fármacos , Células Cultivadas , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Radical Hidroxila/antagonistas & inibidores , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Indóis/síntese química , Indóis/química , Lipoproteínas LDL/química , Masculino , Camundongos , Oxigênio/química , Ratos , Ratos Sprague-Dawley
4.
Molecules ; 23(7)2018 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-29970872

RESUMO

5-LOX inhibition is among the desired characteristics of anti-inflammatory drugs, while 15-LOX has also been considered as a drug target. Similarity in inhibition behavior between soybean LOX-1 and human 5-LOX has been observed and soybean LOX (sLOX) type 1b has been used for the evaluation of LOX inhibition in drug screening for years. After prediction of LOX inhibition by PASS and docking as well as toxicity by PROTOX and ToxPredict sixteen (E)-N-(thiazol-2-yl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enamide derivatives with lengths varying from about 15⁻20 Å were evaluated in vitro for LOX inhibitory action using the soybean lipoxygenase sLOX 1b. Docking analysis was performed using soybean LOX L-1 (1YGE), soybean LOX-3 (1JNQ), human 5-LOX (3O8Y and 3V99) and mammalian 15-LOX (1LOX) structures. Different dimensions of target center and docking boxes and a cavity prediction algorithm were used. The compounds exhibited inhibitory action between 2.5 µΜ and 165 µΜ. Substituents with an electronegative atom at two-bond proximity to position 4 of the thiazole led to enhanced activity. Docking results indicated that the LOX structures 1JNQ, 3V99 and 1LOX can effectively be used for estimation of LOX inhibition and amino acid interactions of these compounds.


Assuntos
Caproatos/farmacologia , Inibidores de Lipoxigenase/farmacologia , Lipoxigenase/química , Ácido Micofenólico/química , Caproatos/química , Desenho de Drogas , Humanos , Inibidores de Lipoxigenase/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas de Plantas/antagonistas & inibidores , Soja/enzimologia , Relação Estrutura-Atividade
5.
Front Microbiol ; 9: 423, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29662469

RESUMO

Salinity stress is one of the serious factors, limiting production of major agricultural crops; especially, in sodic soils. A number of approaches are being applied to mitigate the salt-induced adverse effects in agricultural crops through implying different halotolerant microbes. In this aspect, a halotolerant, Exiguobacterium profundum PHM11 was evaluated under eight different salinity regimes; 100, 250, 500, 1000, 1500, 2000, 2500, and 3000 mM to know its inherent salt tolerance limits and salt-induced consequences affecting its natural metabolism. Based on the stoichiometric growth kinetics; 100 and 1500 mM concentrations were selected as optimal and minimal performance limits for PHM11. To know, how salt stress affects the expression profiles of regulatory genes of its key metabolic pathways, and total production of important metabolites; biomass, carotenoids, beta-carotene production, IAA and proline contents, and expression profiles of key genes affecting the protein folding, structural adaptations, transportation across the cell membrane, stress tolerance, carotenoids, IAA and mannitol production in PHM11 were studied under 100 and 1500 mM salinity. E. profundum PHM11 showed maximum and minimum growth, biomass and metabolite production at 100 and 1500 mM salinity respectively. Salt-induced fine-tuning of expression profiles of key genes of stress pathways was determined in halotolerant bacterium PHM11.

6.
J Nat Med ; 72(4): 837-845, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24677095

RESUMO

The antidyslipidemic effect of the ethanolic extract of Dysoxylum binectariferum stem bark and its major active constituent rohitukine was evaluated in a high fat diet (HFD)-fed dyslipidemic rat model. Chronic feeding of ethanolic extract (200 mg/kg) in HFD-fed rats showed significant lipid lowering activity. The bioassay guided fractionation of ethanolic extract resulted in the identification of known alkaloid rohitukine as major active constituent. Rohitukine (50 mg/kg) significantly decreased the plasma levels of total cholesterol (24 %), phospholipids (25 %), triglycerides (27 %), very low density lipoprotein (27 %) and low density lipoprotein (32 %) accompanied with an increase in high density lipoprotein (21 %). The present study demonstrated that ethanolic extract of Dysoxylum binectariferum stem bark and its major constituent rohitukine both have antidyslipidemic as well as antioxidant potentials. The antidyslipidemic activity of rohitukine can be correlated to its effect on enzymes involved in lipid metabolism.


Assuntos
Cromonas/uso terapêutico , Dislipidemias/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Piperidinas/uso terapêutico , Animais , Antioxidantes , Cromonas/farmacologia , Masculino , Piperidinas/farmacologia , Ratos
7.
Eur J Pharm Sci ; 101: 107-114, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28189817

RESUMO

S002-333 [2-(4-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-b-carboxylic acid amide], a potent antithrombotic agent developed by CSIR-CDRI, is a racemic mixture of two enantiomers (S004-1032 (R)-isomer and S007-1558 (S)-isomer). Despite extensive research, little is known about the pharmacokinetics of S002-333 enantiomers. Given that mouse is an established model for anti-platelet/antithrombotic activity and interspecies differences exists in the direction of stereoselectivity in pharmacokinetic processes, we investigated the pharmacokinetic disposition of S002-333 enantiomers in mice. Whereas the pharmacokinetics of S002-333 was non-stereoselective after intravenous (i.v.) administration, substantial stereoselectivity was observed after oral administration of the racemate. The oral AUC0-∞ of (R)-isomer (1228.21±97.55h∗ng/mL) was higher than that of (S)-isomer (861.55±182.07h∗ng/mL) whereas it was comparable after i.v. administration. The absolute oral bioavailability of (R)-isomer was ~1.7 times higher than that of its antipode. On incubating the racemic mixture or individual isomers with mice liver microsomes, (S)-isomer depleted significantly faster than (R)-isomer. Thus, low absolute oral bioavailability of (S)-isomer in comparison to (R)-isomer could be associated to stereoselective hepatic metabolism of (S)-isomer. Furthermore, no metabolic interaction between the enantiomers was observed. Tissue distribution analysis revealed that the highest amount of the enantiomers was localized in small intestine and liver which could be due to first pass metabolism in these organs. Stereoselectivity in the distribution of S002-333 was observed in liver, kidney, spleen and brain; however no significant differences between the plasma protein binding of the enantiomers were observed. The information revealed in the present work might prove valuable in deciding the development of S002-333 as racemic mixture and/or single enantiomer.


Assuntos
Carbolinas/metabolismo , Fibrinolíticos/metabolismo , Sulfonamidas/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Estereoisomerismo , Distribuição Tecidual/fisiologia
8.
Arch Pharm (Weinheim) ; 350(3-4)2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28207169

RESUMO

A series of substituted 1,2,4-trioxanes were synthesized and evaluated for their antimalarial potential, in silico ADME properties and cytotoxicity on neuronal cell lines. Among the 15 synthesized substituted 1,2,4-trioxanes, two compounds (compound 15, IC50 = 25.71 nM; compound 21, IC50 = 19.6 nM) exhibited promising in vitro antimalarial potential comparable to those of the existing drugs chloroquine and artemisinin. Both of these compounds were found to be nontoxic up to 20 µM concentration in neuronal PC-12 cells. Compound 21 may serve as an optimized lead compound because of its less in vitro toxicity and lower probability to cross the blood brain barrier.


Assuntos
Antimaláricos/farmacologia , Desenho de Drogas , Compostos Heterocíclicos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/síntese química , Antimaláricos/química , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
9.
Chem Biol Drug Des ; 90(2): 254-261, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28102941

RESUMO

Primaquine (PQ) is the only drug used to prevent relapse of malaria due to P. vivax and P. ovale, by eradicating the dormant liver form of the parasite (hypnozoites). The side-effects associated with PQ limits is uses in treatment of malaria. To overcome the premature oxidative deamination and to increase the life span of drug in the biological system, the novel glyco-conjugates of PQ were synthesized by coupling of primaquine with hexoses in phosphate buffer. The saccharide part of the hybrid molecules thought to direct the drug to the liver, where hypnozoites resides. All the synthesized compounds were fully characterized and evaluated for their radical curative activities. The three compounds viz glucoside (15a), galactoside (15b) and mannoside (15c) with high activity were tested for their activity in rhesus monkeys where the most active compound 15b showed twofold activity (100% radical curative activity at 1.92 mmol/kg) than the standard drug PQ diphosphate (3.861 mmol/kg). It is proposed that results from these studies may be advantageous to develop a new potent tissue schizonticide antimalarial compound.


Assuntos
Antimaláricos/química , Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Plasmodium/efeitos dos fármacos , Primaquina/análogos & derivados , Primaquina/uso terapêutico , Animais , Antimaláricos/síntese química , Antimaláricos/farmacologia , Feminino , Glicoconjugados/síntese química , Glicoconjugados/química , Glicoconjugados/farmacologia , Glicoconjugados/uso terapêutico , Macaca mulatta , Malária Vivax/tratamento farmacológico , Masculino , Camundongos , Plasmodium cynomolgi/efeitos dos fármacos , Plasmodium vivax/efeitos dos fármacos , Primaquina/síntese química , Primaquina/farmacologia
10.
J Med Chem ; 60(1): 322-337, 2017 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-27996269

RESUMO

The development of small molecule inhibitors targeting GPVI has promising therapeutic role, as they inhibit arterial thrombosis with limited risk of bleeding. Among the compounds showing in vivo antithrombotic activity, the most active compound 6b (ED50 = 28.36 µmol/kg po in mice) showed improved inhibition for collagen (IC50 = 6.7 µM), CRP-XL (IC50 = 53.5 µM), and convulxin (CVX) (IC50 = 5.7 µM) mediated platelet aggregation as compared to losartan (LOS) (collagen, IC50 = 10.4 µM; CRP-XL, IC50 = 158 µM; CVX, IC50 = 11 µM) than any of its enantiomers S (6c) (collagen, IC50 = 25.3 µM; CRP-XL, IC50 = 181.4 µM; CVX, IC50 = 9 µM) and R (6d) (collagen, IC50 = 126.3 µM; CRP-XL, IC50 > 500 µM; CVX, IC50 = 86.8 µM). Compound 6b also inhibited platelet P-selectin expression and thus may diminish atherosclerosis. The molecular interactions of both enantiomers 6c and 6d at the GPVI receptor have been explained through docking studies.


Assuntos
Antitrombinas/farmacologia , Indóis/química , Indóis/farmacologia , Glicoproteínas da Membrana de Plaquetas/antagonistas & inibidores , Animais , Antitrombinas/química , Humanos , Camundongos , Modelos Moleculares , Agregação Plaquetária/efeitos dos fármacos
11.
Stand Genomic Sci ; 11(1): 54, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27570579

RESUMO

Arthrobacter agilis strain L77, is a plant growth promoting and cold active hydrolytic enzymes producing psychrotrophic bacterium, isolated from Pangong Lake, a subglacial lake in north western Himalayas, India. Genome analysis revealed metabolic versatility with genes involved in metabolism and cold shock adaptation, utilization and biosynthesis of diverse structural and storage polysaccharides such as plant based carbon polymers. The genome of Arthrobacter agilis strain L77 consists of 3,608,439 bp (3.60 Mb) of a circular chromosome. The genome comprises of 3316 protein coding genes and 74 RNA genes, 725 hypothetical proteins, 25 pseudo-genes and 1404 unique genes.

12.
Artigo em Inglês | MEDLINE | ID: mdl-27491065

RESUMO

S002-333 [2-(4-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-b-carboxylic acid amide] is a novel and potent antithrombotic agent developed by CSIR-CDRI, India. The present study was aimed to develop a sensitive LC-MS/MS method for the quantification of S002-333 in mice plasma and tissues. The extraction of S002-333 from relatively small amount of mouse biomatrices (50µL) was accomplished using protein precipitation followed by liquid-liquid extraction and the separation of analytes was achieved on C18 reversed phase column using acetonitrile and triple distilled water (75:25, v/v) as mobile phase at a flow rate of 0.6mL/min. The instrument was operated in the multiple reaction monitoring (MRM) mode using electrospray ionization (ESI) in the positive scan mode. For all the biomatrices, linear relationship was attained over the concentration range of 0.39-200ng/mL with correlation coefficients ≥0.992. The lower limit of quantification for mouse plasma and tissue homogenates was 0.39ng/mL. The bioanalytical method was reproducible and reliable for all the matrices with inter-day and intra-day variability in precision being less than 15% and accuracy within ±15%. The assay was successfully applied to pharmacokinetics and tissue distribution of S002-333 in mice. The pharmacokinetic study revealed adequate gastrointestinal absorption of S002-333 into the systemic circulation of mice with absolute oral bioavailability of 45.8%. Tissue distribution data showed rapid and wide distribution of S002-333 in the following order: small intestine>liver>kidney≈lungs>heart>spleen>brain. The present findings may provide meaningful basis for further clinical development of this new chemical entity.


Assuntos
Antitrombinas/farmacocinética , Carbolinas/farmacocinética , Sulfonamidas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Antitrombinas/sangue , Carbolinas/sangue , Limite de Detecção , Camundongos , Reprodutibilidade dos Testes , Sulfonamidas/sangue , Distribuição Tecidual
13.
Acta Pharm ; 66(3): 353-72, 2016 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-27383885

RESUMO

A series of N-(2-(benzoyl/4-chlorobenzoyl)-benzofuran- 3-yl)-2-(substituted)-acetamide derivatives (4a-l, 5a-l) was synthesized in good yield. All synthesized compounds were in agreement with elemental and spectral data. The anticonvulsant activity of all synthesized compounds was assessed against the maximal electroshock induced seizures (MES) model in mice. Neurotoxicity was evaluated using the rotarod method. The majority of compounds exhibited anticonvulsant activity at a dose of 30 mg kg-1 body mass during 0.5-4 h, indicating their ability to prevent seizure spread at low doses. Relative to phenytoin, [N-(2-(4-chlorobenzoyl)benzofuran-3-yl)-2-(cyclohexyl( methyl) amino)-acetamide] (5i) and [N-(2-(4-chlorobenzoyl)benzofuran-3-yl)-2-(4-methylpiperidin-1- yl)-acetamide] (5c) demonstrated comparable relative anticonvulsant potency of 0.74 and 0.72, respectively, whereas [(N-(2-(4-chlorobenzoyl)benzofuran-3-yl)-2-(4-(furan-2-carbonyl)-piperazin-1-yl)-acetamide] (5f) exhibited the lowest relative potency of 0.16. The ALD50 of tested compounds ranged from 1.604 to 1.675 mmol kg-1 body mass. The ED50 of synthesized compounds ranged from 0.055 to 0.259 mmol kg-1 (~23.4 to 127.6 mg kg-1) body mass. The pharmacophore mapping of the examined compounds on standard drugs (phenobarbital, phenytoin, ralitolin and carbamazepine) strongly suggests that these compounds may exert their anticonvulsant activity via the same established mechanism as that of known drugs.


Assuntos
4-Aminobutirato Transaminase/metabolismo , Anticonvulsivantes/uso terapêutico , Benzofuranos/uso terapêutico , Desenho de Drogas , Modelos Moleculares , Convulsões/prevenção & controle , 4-Aminobutirato Transaminase/química , Acetamidas/efeitos adversos , Acetamidas/química , Acetamidas/metabolismo , Acetamidas/uso terapêutico , Animais , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/química , Anticonvulsivantes/metabolismo , Benzofuranos/efeitos adversos , Benzofuranos/química , Benzofuranos/metabolismo , Sítios de Ligação , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Relação Dose-Resposta a Droga , Agonistas GABAérgicos/efeitos adversos , Agonistas GABAérgicos/química , Agonistas GABAérgicos/metabolismo , Agonistas GABAérgicos/uso terapêutico , Glicina/efeitos adversos , Glicina/análogos & derivados , Glicina/química , Glicina/metabolismo , Glicina/uso terapêutico , Dose Letal Mediana , Masculino , Bulbo/efeitos dos fármacos , Bulbo/metabolismo , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Ratos Wistar , Sus scrofa , Ácido gama-Aminobutírico/química , Ácido gama-Aminobutírico/metabolismo
14.
Chem Biol Interact ; 256: 257-65, 2016 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-27387538

RESUMO

A significant number of new chemical entities (NCEs) fail in drug discovery due to inhibition of Cytochrome P450 (CYP) enzymes. Therefore, to avert costly drug failure at the clinical phase it becomes indispensable to evaluate the CYP inhibition profile of NCEs early in drug discovery. In light of these concerns, we envisioned to investigate the inhibitory effects of S002-333 [2-(4-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-b-carboxylic acid amide], a novel and potent antithrombotic agent, on nine major CYP enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4) of human liver microsomes (HLM). S002-333 exists as racemic mixture of S004-1032 (R-isomer) and S007-1558 (S-isomer), consequently, we further examined the enantioselective differences of S002-333 in the inhibition of human CYP enzymes. Of the CYP enzymes tested, CYP2B6-catalyzed bupropion 6-hydroxylation was inhibited by S002-333 (IC50 âˆ¼ 9.25 ± 2.46 µM) in a stereoselective manner with (S)-isomer showing potent inhibition (IC50 âˆ¼ 5.28 ± 1.25 µM) in contrast to (R)-isomer which showed negligible inhibition on CYP2B6 activity (IC50 > 50 µM). S002-333 and its (S)-isomer inhibited CYP2B6 activity in a non-competitive fashion with estimated Ki values of 10.1 ± 3.4 µM and 5.09 ± 1.05 µM, respectively. No shift in the IC50 value was observed for S002-333 and its isomers when preincubated for 30 min in the presence of NADPH suggesting that neither S002-333 nor its enantiomers are time-dependent inhibitors. Thus, the present findings signified that S002-333 is a potent stereoselective inhibitor of CYP2B6, whereas, inhibition for other CYPs was substantially negligible. These in vitro findings would be useful in deciding the development of S002-333 as a single-enantiomer or as a racemic mixture.


Assuntos
Carbolinas/metabolismo , Inibidores do Citocromo P-450 CYP2B6/metabolismo , Citocromo P-450 CYP2B6/metabolismo , Fibrinolíticos/metabolismo , Sulfonamidas/metabolismo , Carbolinas/química , Inibidores do Citocromo P-450 CYP2B6/química , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Fibrinolíticos/química , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Isoformas de Proteínas/metabolismo , Estereoisomerismo , Sulfonamidas/química
15.
J Basic Microbiol ; 56(9): 1009-20, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27133232

RESUMO

Eisenia foetida and Perionyx excavatus are potent vermicomposting earthworms having immense importance in organic matter recycling under tropical conditions, particularly in India. Comparative assessment of the cultivable gut microbiome of these two epigeic earthworms after growth on lignocellulosic biomass, revealed populations of 3.2-8.3 × 10(9) CFU. Diversity analyses using 16S rDNA sequences revealed that the major dominating classes were Firmicutes (50-60%), followed by Actinobacteria (26.7-33%), and Alphaproteobacteria (5.6-6.7%). Despite exhibiting similar diversity indices and species richness, Betaproteobacteria (6.7%) and Gammaproteobacteria (11.1%) were solely present in E. foetida and P. excavatus, respectively. A set of 33 distinct morphotypes, including 18 from E. foetida and 15 from P. excavatus were selected. Carbohydrate utilization profiles generated using Hi-Carbo™ kits revealed that the isolates from the gut of P. excavatus - Arthrobacter pascens IARI-L13 and Bacillus subtilis IARIC were able to utilize 54 and 51.4% of the carbohydrates tested. Sorbose was not utilized, while unusual carbohydrates - adonitol and methyl-d-mannoside were utilized only by members from the gut of P. excavatus, while melizitose was utilized by those uniquely by E. foetida microbiome. Functional characterization revealed that ß-glucosidase activity was most prevalent in the culturable microbial community. Alkaline and acid phosphatase activity was more widespread in the E. foetida gut microbiome. All the culturable gut bacterial isolates produced ammonia, but IAA was detected only in five cultures. The unique functional attributes of the two culturable microbiomes, grown on a similar diet, reveals the significance of proper selection of earthworm substrate combinations for effective vermicomposting.


Assuntos
Actinobacteria/metabolismo , Amônia/metabolismo , Firmicutes/metabolismo , Microbioma Gastrointestinal , Oligoquetos/microbiologia , Proteobactérias/metabolismo , Fosfatase Ácida/metabolismo , Agricultura , Fosfatase Alcalina/metabolismo , Animais , Metabolismo dos Carboidratos , Ácidos Indolacéticos/metabolismo , Lignina/metabolismo , Microbiologia do Solo , beta-Glucosidase/metabolismo
16.
Eur. j. anat ; 20(2): 131-136, abr. 2016. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-152869

RESUMO

The objective of this study was to examine the effect of Eurycoma longifolia (EL) extract on intima media thickness (IMT) of aorta in Sprague Dawley (SD) rats fed with high-fat diet. Twenty healthy male SD rats were divided into 4 groups of 5 animals each and treated for 12 weeks as follows: Group ND was given only normal diet, Group NDEL was given normal diet and EL, Group HFD was given only high fat diet, Group HFDEL was given HFD and EL extracts. The aortic thicknesses of the intima media were photographed and measured with Dino-Capture® 2.0.In this study, the HFD produced obvious atherosclerotic plaque; treatment with aqueous extract of EL has reduced the size and formation of atherosclerotic plaque. The aortic IMT was more significantly increased in the HFD group than that of ND (p < 0.05); on the other hand, the aortic IMT was more significantly reduced in HFDEL group than that of HFD group (p < 0.05). It is concluded that the aqueous extract of EL significantly attenuated the formation of atherosclerotic plaques in the aorta of rats and preserved the vascular structure


No disponible


Assuntos
Animais , Ratos , Aterosclerose/prevenção & controle , Eurycoma , Extratos Vegetais/farmacocinética , Espessura Intima-Media Carotídea , Substâncias Protetoras/farmacocinética , Dieta Hiperlipídica , Aorta/fisiopatologia
17.
Biopharm Drug Dispos ; 37(4): 185-99, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26477787

RESUMO

OBJECTIVE: The aim of this research work was to characterize the metabolism of S002-333, (2-(4'-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido (3,4-b) indole-3-carboxylic acid amide) and its enantiomers, S004-1032 (R-form) and S007-1558 (S-form) in pooled human liver microsomes (PHLM) and pooled liver microsomes (LM) of rat (RLM), rabbit (RABLM), dog (DLM) and monkey (MLM). Another objective of this study was to identify suitable surrogate species to humans for further development of lead candidates. METHOD: In vitro metabolic stability and metabolite identification of S002-333 and enantiomers were carried out in PHLM and LM of various species. The prediction of surrogate species and in vitro in vivo extrapolation were performed based upon the calculated in vitro intrinsic clearance (CLint ). RESULTS/CONCLUSION: The in vitro CLint values for S002-333, S004-1032 and S007-1558 were 0.027 ± 0.005, 0.025 ± 0.004 and 0.036 ± 0.005 ml/min/mg, respectively, in PHLM, indicating that S007-1558 was the most metabolically unstable of the three. The LM of other species showed similar results. A common surrogate species to humans for S002-333 and enantiomers was predicted as rabbit where the extrapolated hepatic clearance (CLH ) did not show a significant difference to the in vivo CLH values. However, none of the species closely mimic humans with respect to the proportion of major metabolites (M-1-M-4) formed in vitro. Likewise, the CLH values were also predicted in humans for S002-333 and enantiomers using various mathematical models. During analysis, there was no chiral inversion evident among the individual isomers throughout in vitro and in vivo experiments. In conclusion, the in vitro results indicate a prominent role of phase I metabolism in the degradation of S002-333 and enantiomers and predict rabbit as an alternative species to conduct further safety and efficacy studies. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Carbolinas/metabolismo , Fibrinolíticos/metabolismo , Microssomos Hepáticos/metabolismo , Sulfonamidas/metabolismo , Animais , Carbolinas/química , Cães , Feminino , Fibrinolíticos/química , Humanos , Macaca mulatta , Masculino , Metaboloma , Coelhos , Ratos Sprague-Dawley , Especificidade da Espécie , Estereoisomerismo , Sulfonamidas/química
18.
Eur J Med Chem ; 103: 418-28, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26383126

RESUMO

In our continuing search for safe and efficacious antifilarials, a series of novel chalcone-benzothiazole hybrids have been synthesized and evaluated for their Brugia malayi thymidylate kinase (BmTMK) enzyme inhibition activity. Their selectivity towards BmTMK was studied and compared to the human TMK (HsTMK) by an in silico method. Out of seventeen derivatives, compounds 34 and 42 showed higher interactions with the BmTMK active site. MolDock docking model revealed the interactions of these two derivatives and the results corroborated well with their in vitro antifilarial activities. Our studies suggest that these hybrids are selective towards the BmTMK enzyme and may serve as potential therapeutic agents against filariasis.


Assuntos
Benzotiazóis/farmacologia , Brugia Malayi/enzimologia , Chalcona/farmacologia , Desenho de Drogas , Simulação de Acoplamento Molecular , Núcleosídeo-Fosfato Quinase/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Animais , Benzotiazóis/síntese química , Benzotiazóis/química , Brugia Malayi/efeitos dos fármacos , Chalcona/síntese química , Chalcona/química , Relação Dose-Resposta a Droga , Filariose/tratamento farmacológico , Filariose/parasitologia , Estrutura Molecular , Núcleosídeo-Fosfato Quinase/metabolismo , Testes de Sensibilidade Parasitária , Inibidores de Proteínas Quinases/química , Reprodutibilidade dos Testes , Relação Estrutura-Atividade
19.
Curr Comput Aided Drug Des ; 11(1): 72-83, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26126610

RESUMO

Induction of apoptosis by the activation of caspase 3 makes it a promising target for designing anticancer drugs hence an investigation for the essential structural features mandatory for caspase 3 activation has been carried out using a dataset comprising of caspase 3 activator candidate drug Azixa in phase II clinical trial and its analogs using DS2.0. A training set of 40 compounds was selected for the purpose of model generation from 76 molecules with an activity range spanning from 0.002µM to 6.9µM. Among the generated pharmacophore models, the best model Hypo1 constituted by two hydrophobic aliphatic (Hal), two hydrophobic aromatic (Har), and one hydrogen bond acceptor (HBA) features with a correlation coefficient of 0.85, and a cost difference (null cost - total cost) of 46 bits well predicted the test set of 36 compounds (Rpred = 0.8). The key mechanism conferring caspase 3 activation is due to binding of Azixa at ß-tubulin site that is located close to or at same site as colchicine. In the absence of co-crystal structure we have proposed a binding mode of Azixa at the tubulin site by performing docking studies and performed molecular dynamics simulation to ascertain the temporal changes of the protein-ligand complex.


Assuntos
Caspase 3/metabolismo , Ativação Enzimática/efeitos dos fármacos , Quinazolinas/química , Quinazolinas/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Desenho de Drogas , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo
20.
Xenobiotica ; 45(11): 1016-23, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26084373

RESUMO

1. S002-333 [(2-(4'-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido (3,4-b) indole-3-carboxylic acid amide)] is a novel and potent antithrombotic active agent. The present work investigates the pharmacokinetics, bioavailability, dose proportionality and permeability of the racemate, S002-333 in male New Zealand White (NZW) rabbits. 2. Rabbits were administered single intravenous (i.v.) (2 mg/kg) and three oral doses of 10, 20 and 40 mg/kg of S002-333, respectively, at different occasions to evaluate dose proportionality. Serial blood samples were collected and analyzed by a liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Since S002-333 is a racemate consisting of S004-1032 (R) and S007-1558 (S), same samples were analyzed using a chiralcel column so as to evaluate the respective enantiomers. 3. The peak plasma concentration, after oral administration, occurred at ∼10 h post-dose. The clearance (CL) and volume of distribution (Vd) after i.v. dose were found to be 3.05 ± 0.09 l/h/kg and 6.73 ± 1.16 l/kg, respectively. The absolute oral bioavailability of S002-333 was 16.32%, whereas it was 6.62 and 5.90% for R- and S-enantiomers, respectively. The absolute bioavailability of 10, 20 and 40 mg/kg doses were found to be 27.91, 14.39 and 16.91%, respectively. The PAMPA (parallel artificial membrane permeability assay) assay shows that S002-333 has a low-passive permeability at gastric and intestinal environment. 4. In conclusion, S002-333 has low-passive permeability, low CL and large Vd. The R-enantiomer has a "slightly" greater bioavailability than the S-enantiomer.


Assuntos
Carbolinas/farmacologia , Carbolinas/farmacocinética , Sulfonamidas/farmacologia , Sulfonamidas/farmacocinética , Administração Oral , Animais , Relação Dose-Resposta a Droga , Masculino , Permeabilidade , Coelhos
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