当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY期刊下所有文献 > Synthesis and in vitro binding of N,N-dialkyl-2-phenylindol-3-yl-glyoxylamides for the peripheral benzodiazepine binding sites.

Synthesis and in vitro binding of N,N-dialkyl-2-phenylindol-3-yl-glyoxylamides for the peripheral benzodiazepine binding sites.

Abstract：

:A series of N,N-dialkyl-2-phenylindol-3-ylglyoxylamides bearing the halogens iodine and bromine were synthesised and their binding affinity for the peripheral benzodiazepine binding sites (PBBS) in rat kidney mitochondrial membranes was evaluated using [(3)H]PK11195. Central benzodiazepine receptor (CBR) affinities were also evaluated in rat cortices using [(3)H]flumazenil to determine their selectivity for PBBS over CBR. The tested compounds had PBBS binding affinities (IC(50)) ranging from 7.86 to 618 nM, with all compounds showing high selectivity over the CBR (CBR IC(50) > 5000 nM). Among the 12 compounds tested, those with a diethylamide group were the most potent. The highest affinity iodinated PBBS ligand, N,N-diethyl-[5-chloro-2-(4-iodophenyl)indol-3-yl]glyoxylamide, was radiolabelled with iodine-123. This high affinity and selective radioligand may be useful for imaging neurodegeneration, inflammation and tumours using single photon emission computed tomography.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Homes TP,Mattner F,Keller PA,Katsifis A

doi

10.1016/j.bmc.2006.01.039

subject

Has Abstract

pub_date

2006-06-01 00:00:00

pages

3938-46

issue

11

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(06)00077-0

journal_volume

14

pub_type

杂志文章

相关文献

BIOORGANIC & MEDICINAL CHEMISTRY文献大全
  • 3-D-QSAR analysis of N-(3-acyloxy-2-benzylpropyl)-N'-dihydroxytetrahydrobenzazepine and tetrahydroisoquinoline and N-(3-acyloxy-2-benzylpropyl)-N'-(4-hydroxy-3-methoxybenzyl) thioureas analogues as potent vanilloid receptor ligands.

    abstract：:3-D-Quantitative structure--activity relationships of N-(3-acyloxy-2-benzylpropyl)-N'-dihydroxytetrahydro-benzazepine and tetrahydroisoquinoline and N-(3-acyloxy-2-benzylpropyl)-N'-(4-hydroxy-3-methoxybenzyl) thiourea analogues as potent vanilloid receptor ligands were investigated using the CoMFA and the COMSIA metho...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(01)00404-7

    authors： Kim KH

    更新日期：2002-05-01 00:00:00

  • The role of dicarbonyl compounds in non-enzymatic crosslinking: a structure-activity study.

    abstract：:The Maillard reaction is a complex network of reactions that has been shown to result in the non-enzymatic crosslinking of proteins. Recent attention has focussed on the role of alpha-dicarbonyl compounds as important in vivo contributors to protein crosslinking but, despite extensive research, the molecular mechanism...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(02)00564-3

    authors： Meade SJ,Miller AG,Gerrard JA

    更新日期：2003-03-20 00:00:00

  • Carbonic anhydrases of anaerobic microbes.

    abstract：:Carbonic anhydrases (CAs) catalyze the reversible hydration of carbon dioxide to bicarbonate and are abundantly distributed in prokaryotes and eukaryotes. There are five classes (α,β,γ,δ,ζ) with no significant sequence or structural identity among them, a remarkable example of convergent evolution. The β and γ classes...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2012.12.005

    authors： Ferry JG

    更新日期：2013-03-15 00:00:00

  • Discovery of an 8-methoxytetrahydroisoquinoline derivative as an orally active N-type calcium channel blocker for neuropathic pain without CYP inhibition liability.

    abstract：:In lead optimization efforts starting from the tetrahydroisoquinoline (S)-1, we identified 2-{[(2R)-2-hydroxypropyl]amino}-1-[(1S)-8-methoxy-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone ((1S)-8t) as a novel orally active small-molecule N-type calcium channel blocker without CYP inhibition liability. CYP3A4 inhibi...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2015.05.053

    authors： Ogiyama T,Yonezawa K,Inoue M,Katayama N,Watanabe T,Yoshimura S,Gotoh T,Kiso T,Koakutsu A,Kakimoto S,Shishikura JI

    更新日期：2015-08-01 00:00:00

  • Slow reversible inhibitions of rabbit muscle aldolase with substrate analogues: synthesis, enzymatic kinetics and UV difference spectroscopy studies.

    abstract：:Various dihydroxyacetone-phosphate (DHAP) analogues bearing an aromatic ring or beta-dicarbonyl structures were synthesized. Their capacity to form a stabilized iminium ion or conjugated enamine in the reaction catalyzed by rabbit muscle aldolase (EC 4.1.2.13) were investigated by enzymatic kinetics and UV difference ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(96)00221-0

    authors： Gefflaut T,Blonski C,Périé J

    更新日期：1996-12-01 00:00:00

  • Synthesis of novel 7-oxo and 7-hydroxy trifluoroallocolchicinoids with cytotoxic effect.

    abstract：:The synthesis of 7-oxo and 7-hydroxy trifluoroallocolchicinoids was achieved through the intramolecular cyclization of o-phenyl-β-phenylalanines. The resulting compounds were evaluated for their cytotoxic activity against KB cells and their inhibitory effect towards the polymerization of tubulin. The results yielded s...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2012.02.043

    authors： Chosson E,Santoro F,Rochais C,Santos JS,Legay R,Thoret S,Cresteil T,Sinicropi MS,Besson T,Dallemagne P

    更新日期：2012-04-15 00:00:00

  • One-pot enzymatic glycan remodeling of a therapeutic monoclonal antibody by endoglycosidase S (Endo-S) from Streptococcus pyogenes.

    abstract：:A facile, one-pot enzymatic glycan remodeling of antibody rituximab to produce homogeneous high-mannose and hybrid type antibody glycoforms is described. This method was based on the unique substrate specificity of the endoglycosidase S (Endo-S) from Streptococcus pyogenes. While Endo-S efficiently hydrolyzes the bi-a...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2017.07.053

    authors： Tong X,Li T,Orwenyo J,Toonstra C,Wang LX

    更新日期：2018-04-01 00:00:00

  • Hemi-synthesis and biological activity of new analogues of podophyllotoxin.

    abstract：:Various 4-analogues of podophyllotoxin and epipodophyllotoxin were obtained via the formation of the corresponding 4-keto derivatives. Methyloximation of podophyllotoxone, followed by subsequent catalytic hydrogenation, gave stereoselective access to 4-alpha-amino-4-deoxypodophyllotoxin and from there, to the correspo...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(02)00255-9

    authors： Roulland E,Magiatis P,Arimondo P,Bertounesque E,Monneret C

    更新日期：2002-11-01 00:00:00

  • Synthesis and antiproliferative activity of sulfonamide-based peptidomimetic calpain inhibitors.

    abstract：:The calpains are a conserved family of cysteine proteases that includes several isoforms of which µ-calpain and m-calpain are the most widely distributed in mammalian cells. Calpains have been implicated in normal physiological processes as well as cellular abnormalities such as neurodegenerative disorders, cataract, ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2020.115433

    authors： Donkor IO,Xu J,Liu J,Cameron K

    更新日期：2020-05-01 00:00:00

  • Lead identification and optimization of bacterial glutamate racemase inhibitors.

    abstract：:Mycobacterium tuberculosis glutamate racemase is an essential enzyme involved in peptidoglycan synthesis and conserved in most bacteria. Small molecule inhibitors were reported on other bacterial species whereas in M. tuberculosis it wasn't explored much. In this study we have screened in house compound library using ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2017.11.031

    authors： Malapati P,Siva Krishna V,Nallangi R,Meda N,Reshma Srilakshmi R,Sriram D

    更新日期：2018-01-01 00:00:00

  • Pharmacophore identification of a chemokine receptor (CXCR4) antagonist, T22 ([Tyr(5,12),Lys7]-polyphemusin II), which specifically blocks T cell-line-tropic HIV-1 infection.

    abstract：:We have previously found that T22 ([Tyr(5,12), Lys7]-polyphemusin II) has strong anti-human immunodeficiency virus (HIV) activity, and that T22 inhibits T cell-line-tropic HIV-1 infection mediated by CXCR4/fusin. T22 is an 18-residue peptide amide, which takes an antiparallel beta-sheet structure that is maintained by...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(98)00061-3

    authors： Tamamura H,Imai M,Ishihara T,Masuda M,Funakoshi H,Oyake H,Murakami T,Arakaki R,Nakashima H,Otaka A,Ibuka T,Waki M,Matsumoto A,Yamamoto N,Fujii N

    更新日期：1998-07-01 00:00:00

  • The hemA gene encoding glutamyl-tRNA reductase from the archaeon Methanobacterium thermoautotrophicum strain Marburg.

    abstract：:In archaea the first general tetrapyrrole precursor 5-aminolevulinic acid (ALA) is formed via the tRNA-dependent five-carbon pathway from glutamate. We have cloned the hemA gene encoding the central enzyme of the pathway glutamyl-tRNA reductase from the methanogenic archaeon Methanobacterium thermoautotrophicum by com...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/0968-0896(96)00098-3

    authors： Hungerer C,Weiss DS,Thauer RK,Jahn D

    更新日期：1996-07-01 00:00:00

  • Selective activity against Mycobacteriumtuberculosis of new quinoxaline 1,4-di-N-oxides.

    abstract：:New series of 3-phenylquinoxaline 1,4-di-N-oxide with selective activity against Mycobacterium tuberculosis have been prepared and evaluated. Thirty-four of the seventy tested compounds showed an MIC value less than 0.2 microg/mL, a value on the order of the MIC of rifampicin. Furthermore, 45% of the evaluated derivat...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2008.10.086

    authors： Vicente E,Pérez-Silanes S,Lima LM,Ancizu S,Burguete A,Solano B,Villar R,Aldana I,Monge A

    更新日期：2009-01-01 00:00:00

  • Synthesis and biological evaluation of 4'-[(benzimidazole-1-yl)methyl]biphenyl-2-sulfonamide derivatives as dual angiotensin II/endothelin A receptor antagonists.

    abstract：:A series of 4'-[(benzimidazole-1-yl)methyl]biphenyl-2-sulfonamide derivatives (Ia-Il) were synthesized and biologically evaluated. It was found that Ig, the most active compound, antagonized both Ang II AT(1) and endothelin ET(A) receptors (AT(1) IC(50)=8.5, ET(A) IC(50)=8.9 nM), and was more potent than losartan in R...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2012.06.011

    authors： Bai R,Wei Z,Liu J,Xie W,Yao H,Wu X,Jiang J,Wang Q,Xu J

    更新日期：2012-08-01 00:00:00

  • Structure-activity relationship studies of manzamine A: amidation of positions 6 and 8 of the beta-carboline moiety.

    abstract：:Twenty manzamine amides were synthesized and evaluated for in vitro antimalarial and antimicrobial activities. The amides of manzamine A (1) showed significantly reduced cytotoxicity against Vero cells, although were less active than 1. The structure-activity analysis showed that linear, short alkyl groups adjacent to...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2009.09.026

    authors： Wahba AE,Peng J,Kudrimoti S,Tekwani BL,Hamann MT

    更新日期：2009-11-15 00:00:00

  • Identification of topoisomerases as molecular targets of cytosporolide C and its analog.

    abstract：:Cytosporolide (Cytos) A-C, isolated from the fungus Cytospora sp., have anti-microbial activity, but their molecular targets in mammalian cells are unknown. We have previously reported the total synthesis of Cytos A by biomimetic hetero-Diels-Alder reaction. In this study, to examine the novel bioactivity of Cytos, we...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2019.06.014

    authors： Otake K,Yamada K,Miura K,Sasazawa Y,Miyazaki S,Niwa Y,Ogura A,Takao KI,Simizu S

    更新日期：2019-08-01 00:00:00

  • New, stronger nucleophiles for nucleic acid-templated chemistry: Synthesis and application in fluorescence detection of cellular RNA.

    abstract：:Nucleic acid-templated chemistry is a promising strategy for imaging genetic sequences in living cells. Here we describe the synthesis of two new nucleophiles for use in templated nucleophilic displacements with DNA probes. The nucleophilic groups are phosphorodithioate and phosphorotrithioate; we report on synthetic ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2007.04.051

    authors： Miller GP,Silverman AP,Kool ET

    更新日期：2008-01-01 00:00:00

  • Bromo-deaza-SAH: a potent and selective DOT1L inhibitor.

    abstract：:Chemical inhibition of proteins involved in chromatin-mediated signaling is an emerging strategy to control chromatin compaction with the aim to reprogram expression networks to alter disease states. Protein methyltransferases constitute one of the protein families that participate in epigenetic control of gene expres...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2013.01.049

    authors： Yu W,Smil D,Li F,Tempel W,Fedorov O,Nguyen KT,Bolshan Y,Al-Awar R,Knapp S,Arrowsmith CH,Vedadi M,Brown PJ,Schapira M

    更新日期：2013-04-01 00:00:00

  • A new and efficient synthesis of substituted 6-[(2'-dialkylamino)ethyl] pyrimidine and 4-N,N-dialkyl-6-vinyl-cytosine derivatives and evaluation of their anti-rubella activity.

    abstract：:New 6-[(2'-dialkylamino)ethyl]-4(3H)-pyrimidinones were prepared by a multistep procedure starting from acetone dicarboxylic acid diethyl ester and urea derivatives. These compounds were used as starting materials to obtain 4-N,N-dialkyl-6-vinyl-pyrimidine derivatives by an unprecedented tandem C-6 side chain Hofmann-...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(02)00077-9

    authors： Saladino R,Ciambecchini U,Maga G,Mastromarino P,Conti C,Botta M

    更新日期：2002-07-01 00:00:00

  • Time-dependent slowly-reversible inhibition of monoamine oxidase A by N-substituted 1,2,3,6-tetrahydropyridines.

    abstract：:A novel class of N-substituted tetrahydropyridine derivatives was found to have multiple kinetic mechanisms of monoamine oxidase A inhibition. Eleven structurally similar tetrahydropyridine derivatives were synthesized and evaluated as inhibitors of MAO-A and MAO-B. The most potent MAO-A inhibitor in the series, 2,4-d...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2011.10.038

    authors： Wichitnithad W,O'Callaghan JP,Miller DB,Train BC,Callery PS

    更新日期：2011-12-15 00:00:00

  • Structure-affinity relationships and pharmacological characterization of new alkyl-resorcinol cannabinoid receptor ligands: Identification of a dual cannabinoid receptor/TRPA1 channel agonist.

    abstract：:In our ongoing program aimed at deeply investigating the endocannabinoid system (ES), a set of new alkyl-resorcinol derivatives was prepared focusing on the nature and the importance of the carboxamide functionality. Binding studies on CB1 and CB2 receptors, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolas...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2014.07.006

    authors： Brizzi A,Aiello F,Marini P,Cascio MG,Corelli F,Brizzi V,De Petrocellis L,Ligresti A,Luongo L,Lamponi S,Maione S,Pertwee RG,Di Marzo V

    更新日期：2014-09-01 00:00:00

  • Carbonic anhydrase inhibitors: inhibition of the human transmembrane isozyme XIV with a library of aromatic/heterocyclic sulfonamides.

    abstract：:The first inhibition study of the transmembrane carbonic anhydrase (CA, EC 4.2.1.1) isozymes hCA XIV with a library of aromatic and heteroaromatic sulfonamides synthesized earlier is reported. Most of the inhibitors were sulfanilamide, homosulfanilamide and 4-aminoethyl-benzenesulfonamide derivatives, to which tails t...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2005.06.022

    authors： Ozensoy O,Nishimori I,Vullo D,Puccetti L,Scozzafava A,Supuran CT

    更新日期：2005-11-15 00:00:00

  • Structural interrogation of benzosuberene-based inhibitors of tubulin polymerization.

    abstract：:The discovery of 3-methoxy-9-(30,40,50-trimethoxyphenyl)-6,7-dihydro-5H-benzo[7]annulen-4-ol (a benzosuberene-based analogue referred to as KGP18) was originally inspired by the natural products colchicine and combretastatin A-4 (CA4). The relative structural simplicity and ease of synthesis of KGP18, coupled with its...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2015.10.012

    authors： Herdman CA,Devkota L,Lin CM,Niu H,Strecker TE,Lopez R,Liu L,George CS,Tanpure RP,Hamel E,Chaplin DJ,Mason RP,Trawick ML,Pinney KG

    更新日期：2015-12-15 00:00:00

  • Synthesis of benzopolycyclic cage amines: NMDA receptor antagonist, trypanocidal and antiviral activities.

    abstract：:The synthesis of several 6,7,8,9,10,11-hexahydro-9-methyl-5,7:9,11-dimethano-5H-benzocyclononen-7-amines is reported. Several of them display low micromolar NMDA receptor antagonist and/or trypanocidal activities. Two compounds are endowed with micromolar anti vesicular stomatitis virus activity, while only one compou...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2011.11.050

    authors： Torres E,Duque MD,López-Querol M,Taylor MC,Naesens L,Ma C,Pinto LH,Sureda FX,Kelly JM,Vázquez S

    更新日期：2012-01-15 00:00:00

  • Efficient synthesis of fluorothiosparfosic acid analogues with potential antitumoral activity.

    abstract：:In this paper, we describe a short synthesis of N-(phosphonoacetyl)-L-aspartate (PALA) analogues. The mono- and difluorinated thioacetamide precursors were prepared in one step from methyl (diethoxyphosphono)di- and monofluoromethyldithioacetates 8 and 11 as starting materials. Antiproliferating properties on a L1210 ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2005.05.026

    authors： Pfund E,Lequeux T,Masson S,Vazeux M,Cordi A,Pierre A,Serre V,Hervé G

    更新日期：2005-08-15 00:00:00

  • Design, synthesis, and docking studies of quinazoline analogues bearing aryl semicarbazone scaffolds as potent EGFR inhibitors.

    abstract：:Two series of quinazoline derivatives bearing aryl semicarbazone scaffolds (9a-o and 10a-o) were designed, synthesized and evaluated for the IC50 values against four cancer cell lines (A549, HepG2, MCF-7 and PC-3). The selected compound 9o was further evaluated for the inhibitory activity against EGFR kinases. Four of...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2017.04.001

    authors： Tu Y,Wang C,Xu S,Lan Z,Li W,Han J,Zhou Y,Zheng P,Zhu W

    更新日期：2017-06-15 00:00:00

  • Cholinesterase inhibitors: SAR and enzyme inhibitory activity of 3-[omega-(benzylmethylamino)alkoxy]xanthen-9-ones.

    abstract：:In this work, we further investigated a previously introduced class of cholinesterase inhibitors. The removal of the carbamic function from the lead compound xanthostigmine led to a reversible cholinesterase inhibitors 3. Some new 3-[omega-(benzylmethylamino)alkoxy]xanthen-9-one analogs were designed, synthesized, and...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2006.09.026

    authors： Piazzi L,Belluti F,Bisi A,Gobbi S,Rizzo S,Bartolini M,Andrisano V,Recanatini M,Rampa A

    更新日期：2007-01-01 00:00:00

  • NMR determination of Electrophorus electricus acetylcholinesterase inhibition and reactivation by neutral oximes.

    abstract：:Neurotoxic organophosphorus compounds (OPs), which are used as pesticides and chemical warfare agents lead to more than 700,000 intoxications worldwide every year. The main target of OPs is the inhibition of acetylcholinesterase (AChE), an enzyme necessary for the control of the neurotransmitter acetylcholine (ACh). T...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2013.05.063

    authors： da Cunha Xavier Soares SF,Vieira AA,Delfino RT,Figueroa-Villar JD

    更新日期：2013-09-15 00:00:00

  • Synthesis of phenserine analogues and evaluation of their cholinesterase inhibitory activities.

    abstract：:Phenserine is a potentially attractive drug for Alzheimer's disease. In order to further expand SAR study for inhibitions of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), the methyl group at the 3a-position of phenserine was replaced with an alkyl or alkenyl group, and its phenylcarbamoyl moiety was s...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2012.06.048

    authors： Shinada M,Narumi F,Osada Y,Matsumoto K,Yoshida T,Higuchi K,Kawasaki T,Tanaka H,Satoh M

    更新日期：2012-08-15 00:00:00

  • Application of descriptors based on Lipinski's rules in the QSPR study of aqueous solubilities.

    abstract：:We complement new physically interpretable descriptors inspired by the Lipinski's rules of drug bioavailability with others obtained from the Dragon 3.0 software, in order to find the best QSPR relationship for aqueous solubilities of 100 structurally heterogeneous organic, drug-like compounds. The simultaneous linear...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2007.03.044

    authors： Duchowicz PR,Talevi A,Bellera C,Bruno-Blanch LE,Castro EA

    更新日期：2007-06-01 00:00:00