当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY LETTERS期刊下所有文献 > Synthesis, characterization and activity of new phosphonate dipeptides as potential inhibitors of VanX.

Synthesis, characterization and activity of new phosphonate dipeptides as potential inhibitors of VanX.

Abstract：

:VanX, a Zn(II)-dependent D-ala-D-ala dipeptidase, is essential for vancomycin resistance in Enterococcus faecium. The enzymatic activity of VanX was previously found to be inhibited competitively by 2-{[(1-aminoethyl) (hydroxy) phosphoryl]oxy} propanoic acid (1B). Here we report the synthesis and characterization of seven phosphonate dipeptide analogs of D-ala-D-ala with various substituent, the activity evaluation indicated that six of these phosphonate analogs inhibit VanX with IC(50) of 0.48-8.21mM. These data revealed a structure-activity relationship which is that the large substituent group on β-carbon resulted in low binding affinity of the phonphonate analog to VanX. This information will be helpful to guide the design and synthesis of the tightly-binding inhibitors for VanX.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Jia C,Yang KW,Liu CC,Feng L,Xiao JM,Zhou LS,Zhang YL

doi

10.1016/j.bmcl.2011.10.094

subject

Has Abstract

pub_date

2012-01-01 00:00:00

pages

482-4

issue

1

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(11)01501-0

journal_volume

22

pub_type

杂志文章

相关文献

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS文献大全
  • Polycyclic aromatic compounds as anticancer agents: synthesis and biological evaluation of some chrysene derivatives.

    abstract：:Synthesis and biological evaluation of new chrysene derivatives aimed at the development of anticancer agents were carried out. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(98)00520-4

    authors： Becker FF,Banik BK

    更新日期：1998-10-20 00:00:00

  • Alpha-keto amides as inhibitors of histone deacetylase.

    abstract：:Alpha-keto ester and amides were found to be potent inhibitors of histone deacetylase. Nanomolar inhibitors against the isolated enzyme and sub-micromolar inhibitors of cellular proliferation were obtained. The alpha-keto amide 30 also exhibited significant anti-tumor effects in an in vivo tumor model. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(03)00685-1

    authors： Wada CK,Frey RR,Ji Z,Curtin ML,Garland RB,Holms JH,Li J,Pease LJ,Guo J,Glaser KB,Marcotte PA,Richardson PL,Murphy SS,Bouska JJ,Tapang P,Magoc TJ,Albert DH,Davidsen SK,Michaelides MR

    更新日期：2003-10-06 00:00:00

  • Hydrolysis of linear DNA duplex catalyzed by Co(III) complex of cyclen attached to polystyrene.

    abstract：:To design artificial restriction enzymes, synthetic catalytic centers that effectively hydrolyze linear double-stranded polydeoxyribonucleotides are needed. The Co(III) complex of cyclen (CoCyc) attached to polystyrene derivatives hydrolyzes linearized pUC18 DNA with half-lives as short as 30 min at 25 degrees C. The ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(01)00615-1

    authors： Jeung CS,Song JB,Kim YH,Suh J

    更新日期：2001-12-03 00:00:00

  • Discovery of highly potent and selective benzyloxybenzyl-based peroxisome proliferator-activator receptor (PPAR) delta agonists.

    abstract：:A series of 1,4-benzyloxybenzylsulfanylaryl carboxylic acids were prepared and their activities for PPAR receptor subtypes (alpha, delta, and gamma) with potential indications for the treatment of dyslipidemia were investigated. Analog 13a displayed the greatest binding affinity (IC(50)=10nM) and selectivity (120-fold...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2007.04.046

    authors： Bratton LD,Filzen GF,Geyer A,Hoffman JK,Lu G,Pulaski J,Trivedi BK,Unangst PC,Xu X

    更新日期：2007-07-01 00:00:00

  • Synthesis and anti-Candida activity of novel 2-hydrazino-1,3-thiazole derivatives.

    abstract：:Eighteen new hydrazino-1,3-thiazole derivatives were evaluated against 8 strains of multi-resistant Candida spp. Introduction of an indolyl moiety linked to the hydrazone function enhanced the in vitro anti-Candida activity, with an activity spectrum towards Candida albicans strains. Introduction of a (S)-2-aminoethyl...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2013.01.039

    authors： Maillard LT,Bertout S,Quinonéro O,Akalin G,Turan-Zitouni G,Fulcrand P,Demirci F,Martinez J,Masurier N

    更新日期：2013-03-15 00:00:00

  • Benzothiazole-based N-(phenylsulfonyl)amides as a novel family of PPARα antagonists.

    abstract：:The discovery of PPAR antagonists is emerging as an useful tool for elucidating the biological role of the receptor. Here we report the identification of N-(phenylsulfonyl)amides containing the benzothiazole scaffold, a novel class of potent PPARα antagonists obtained from chemical modification of carboxylic acid agon...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2011.06.028

    authors： Ammazzalorso A,Giancristofaro A,D'Angelo A,Filippis BD,Fantacuzzi M,Giampietro L,Maccallini C,Amoroso R

    更新日期：2011-08-15 00:00:00

  • Protection of a single-cysteine redox switch from oxidative destruction: On the functional role of sulfenyl amide formation in the redox-regulated enzyme PTP1B.

    abstract：:Model reactions offer a chemical mechanism by which formation of a sulfenyl amide residue at the active site of the redox-regulated protein tyrosine phosphatase PTP1B protects the cysteine redox switch in this enzyme against irreversible oxidative destruction. The results suggest that 'overoxidation' of the sulfenyl a...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.12.001

    authors： Sivaramakrishnan S,Cummings AH,Gates KS

    更新日期：2010-01-15 00:00:00

  • In vitro characterization of the Gd complex of [2,6-pyridinediylbis(methylene nitrilo)] tetraacetic acid (PMN-tetraacetic acid) and of its Eu analogue, suitable bimodal contrast agents for MRI and optical imaging.

    abstract：:Gd and Eu complexes of PMN-tetraacetic acid show interesting properties either for MRI or for optical imaging; that is, for the Gd-complex, a high proton relaxivity with favorable water residence time; for the Eu-complex, a luminescence lifetime of 400 micros at room temperature compatible with the use of time-resolve...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2007.09.027

    authors： Laurent S,Vander Elst L,Wautier M,Galaup C,Muller RN,Picard C

    更新日期：2007-11-15 00:00:00

  • Conversion of A3 adenosine receptor agonists into selective antagonists by modification of the 5'-ribofuran-uronamide moiety.

    abstract：:The highly selective agonists of the A(3) adenosine receptor (AR), Cl-IB-MECA (2-chloro-N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine), and its 4'-thio analogue, were successfully converted into selective antagonists simply by appending a second N-methyl group on the 5'-uronamide position. The 2-chloro-5'-(N,N-d...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2005.10.054

    authors： Gao ZG,Joshi BV,Klutz AM,Kim SK,Lee HW,Kim HO,Jeong LS,Jacobson KA

    更新日期：2006-02-01 00:00:00

  • Evaluation of licorice flavonoids as protein tyrosine phosphatase 1B inhibitors.

    abstract：:Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator in insulin- and leptin-signaling cascades as well as a positive regulator in tumorigenesis, and much attention has been paid to PTP1B inhibitors as potential therapies for diabetes, obesity, and cancer. In the present study, the screening of a compo...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2013.08.102

    authors： Li W,Li S,Higai K,Sasaki T,Asada Y,Ohshima S,Koike K

    更新日期：2013-11-01 00:00:00

  • Austalides V and W, new meroterpenoids from the fungus Aspergillus ustus and their antitumor activities.

    abstract：:Two new austalide meroterpenoids, named austalides V and W (1 and 2), were isolated from the fungus Aspergillus ustus VKM F-4692. Their structures were elucidated by extensive spectroscopic analysis and by comparison with related known compounds. The main structural feature of both compounds is a tetrahydrofuranyl rin...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2019.126708

    authors： Antipova TV,Zaitsev KV,Oprunenko YF,Ya Zherebker A,Rystsov GK,Zemskova MY,Zhelifonova VP,Ivanushkina NE,Kozlovsky AG

    更新日期：2019-11-15 00:00:00

  • Synthesis of sub-micromolar inhibitors of MraY by exploring the region originally occupied by the diazepanone ring in the liposidomycin structure.

    abstract：:The synthesis and inhibitory activity against MraY of a series of simplified analogues of liposidomycins are described. These compounds were mainly obtained by performing parallel synthesis in the 6'-position of a scaffold that gathers key features found necessary for the binding to MraY. Thus, inhibitory activity was...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(02)00109-9

    authors： Dini C,Didier-Laurent S,Drochon N,Feteanu S,Guillot JC,Monti F,Uridat E,Zhang J,Aszodi J

    更新日期：2002-04-22 00:00:00

  • An inhibitor-like binding mode of a carbonic anhydrase activator within the active site of isoform II.

    abstract：:The 2,4,6-trimethylpyridinium derivative of histamine is an effective activator of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). However, unlike other CA activators, which bind at the entrance of the active site cavity, an X-ray crystal structure of hCA II in complex with the 1-[2-(1H-imidazol-4-yl)-ethyl]-2,4,...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2010.10.045

    authors： Dave K,Ilies MA,Scozzafava A,Temperini C,Vullo D,Supuran CT

    更新日期：2011-05-01 00:00:00

  • Synthesis and evaluation of novel phosphoramidate prodrugs of 2'-methyl cytidine as inhibitors of hepatitis C virus NS5B polymerase.

    abstract：:A variety of new prodrugs of 2'-methyl cytidine based on acyloxy ethylamino phosphoramidates have been synthesized and tested in vitro and in vivo for their biological activity. Compared with the parent drug a 10- to 20-fold increase in formation of nucleotide triphosphate in rat and human hepatocytes could be achieve...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.01.035

    authors： Donghi M,Attenni B,Gardelli C,Marco AD,Fiore F,Giuliano C,Laufer R,Leone JF,Pucci V,Rowley M,Narjes F

    更新日期：2009-03-01 00:00:00

  • Development of indole/indazole-aminopyrimidines as inhibitors of c-Jun N-terminal kinase (JNK): optimization for JNK potency and physicochemical properties.

    abstract：:A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 信件

    doi：10.1016/j.bmcl.2013.04.029

    authors： Gong L,Han X,Silva T,Tan YC,Goyal B,Tivitmahaisoon P,Trejo A,Palmer W,Hogg H,Jahagir A,Alam M,Wagner P,Stein K,Filonova L,Loe B,Makra F,Rotstein D,Rapatova L,Dunn J,Zuo F,Dal Porto J,Wong B,Jin S,Chang A,T

    更新日期：2013-06-15 00:00:00

  • Discovery of potent transient receptor potential vanilloid 1 antagonists: design and synthesis of phenoxyacetamide derivatives.

    abstract：:We aimed to discover a novel type of transient receptor potential vanilloid 1 (TRPV1) antagonist because such antagonists are possible drug candidates for treating various disorders. We modified the structure of hit compound 7 (human TRPV1 IC50=411 nM) and converted its pyrrolidino group to a (hydroxyethyl)methylamino...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2013.04.016

    authors： Takahashi E,Hirano N,Nagahara T,Yoshikawa S,Momen S,Yokokawa H,Hayashi R

    更新日期：2013-06-01 00:00:00

  • Synthesis and biological evaluation of benzazepine oxazolidinone antibacterials.

    abstract：:Novel benzazepine oxazolidinone antibacterials were synthesized and evaluated against clinically relevant susceptible and resistant organisms. The effect of ring nitrogen position and N-substitution on antibacterial activity is examined. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2003.07.017

    authors： Johnson PD,Aristoff PA,Zurenko GE,Schaadt RD,Yagi BH,Ford CW,Hamel JC,Stapert D,Moerman JK

    更新日期：2003-12-01 00:00:00

  • Antibody-mediated delivery of chimeric protein degraders which target estrogen receptor alpha (ERα).

    abstract：:Chimeric molecules which effect intracellular degradation of target proteins via E3 ligase-mediated ubiquitination (e.g., PROTACs) are currently of high interest in medicinal chemistry. However, these entities are relatively large compounds that often possess molecular characteristics which may compromise oral bioavai...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2019.126907

    authors： Dragovich PS,Adhikari P,Blake RA,Blaquiere N,Chen J,Cheng YX,den Besten W,Han J,Hartman SJ,He J,He M,Rei Ingalla E,Kamath AV,Kleinheinz T,Lai T,Leipold DD,Li CS,Liu Q,Lu J,Lu Y,Meng F,Meng L,Ng C,Peng K,Le

    更新日期：2020-02-15 00:00:00

  • The synthesis of amino-acid functionalized beta-carbolines as topoisomerase II inhibitors.

    abstract：:The synthesis and biological activity of amino acid functionalized beta-carboline derivatives, which are structurally related to azatoxin and the tryprostatins, are reported. These compounds were assayed for their growth inhibition properties in H520 and PC3 cell lines and were examined for their abilities to inhibit ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(01)00136-6

    authors： Deveau AM,Labroli MA,Dieckhaus CM,Barthen MT,Smith KS,Macdonald TL

    更新日期：2001-05-21 00:00:00

  • Synthesis and evaluation of novel prenylated chalcone derivatives as anti-leishmanial and anti-trypanosomal compounds.

    abstract：:Chalcones form a class of compounds that belong to the flavonoid family and are widely distributed in plants. Their simple structure and the ease of preparation make chalcones attractive scaffolds for the synthesis of a large number of derivatives enabling the evaluation of the effects of different functional groups o...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2015.05.072

    authors： Passalacqua TG,Dutra LA,de Almeida L,Velásquez AM,Torres FA,Yamasaki PR,dos Santos MB,Regasini LO,Michels PA,Bolzani Vda S,Graminha MA

    更新日期：2015-08-15 00:00:00

  • Design and synthesis of a beta-amino phosphotyrosyl mimetic suitably protected for peptide synthesis.

    abstract：:Mimetics of phosphotyrosine (pTyr) such as phosphonomethylphenylalanine (Pmp) have traditionally retained alpha-amino functionality. However, beta-amino acids represent isomeric variants, which may exhibit properties that are distinct from the parent. Reported herein is the first beta-amino pTyr mimetic (Pmp(beta)) be...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(02)00783-7

    authors： Lee K,Zhang M,Yang D,Burke TR Jr

    更新日期：2002-12-02 00:00:00

  • 2,3,4,5-Tetrahydro-1H-pyrido[2,3-b and e][1,4]diazepines as inhibitors of the bacterial enoyl ACP reductase, FabI.

    abstract：:In the search for new antibacterial agents, the enzyme FabI has been identified as an attractive target. Employing a structure guided approach, the previously reported ene-amide series of FabI inhibitors were expanded to include 2,3,4,5-tetrahydro-1H-pyrido[2,3-b and e][1,4]diazepines. These novel series incorporate a...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.07.094

    authors： Ramnauth J,Surman MD,Sampson PB,Forrest B,Wilson J,Freeman E,Manning DD,Martin F,Toro A,Domagala M,Awrey DE,Bardouniotis E,Kaplan N,Berman J,Pauls HW

    更新日期：2009-09-15 00:00:00

  • Structure-activity relationship studies of a bisbenzimidazole-based, Zn(2+)-dependent inhibitor of HCV NS3 serine protease.

    abstract：:A survey of isosteric replacements of the phosphonoalanine side chain coupled with a process of conformational constraint of a bisbenzimidazole-based, Zn(2+)-dependent inhibitor of hepatitis C virus (HCV) NS3 serine protease resulted in the identification of novel series of active compounds with extended side chains. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(01)00457-7

    authors： Yeung KS,Meanwell NA,Qiu Z,Hernandez D,Zhang S,McPhee F,Weinheimer S,Clark JM,Janc JW

    更新日期：2001-09-03 00:00:00

  • Anti-HBV active constituents from Piper longum.

    abstract：:In the screening search for Hepatitis B virus inhibitory agents from medicinal plants, the ethanol extract of Piper longum Linn. was found to possess superior anti-HBV activity in vitro. Bioassay-guided fractionation coupled with repeated purification resulted in the isolation of four new compounds, involving two new ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2013.01.118

    authors： Jiang ZY,Liu WF,Zhang XM,Luo J,Ma YB,Chen JJ

    更新日期：2013-04-01 00:00:00

  • Conversion of human-selective PPARalpha agonists to human/mouse dual agonists: a molecular modeling analysis.

    abstract：:To understand the species selectivity in a series of alpha-methyl-alpha-phenoxy carboxylic acid PPARalpha/gamma dual agonists (1-11), structure-based molecular modeling was carried out in the ligand binding pockets of both human and mouse PPARalpha. This study suggested that interaction of both 4-phenoxy and phenyloxa...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2004.09.031

    authors： Wang M,Winneroski LL,Ardecky RJ,Babine RE,Brooks DA,Etgen GJ,Hutchison DR,Kauffman RF,Kunkel A,Mais DE,Montrose-Rafizadeh C,Ogilvie KM,Oldham BA,Peters MK,Rito CJ,Rungta DK,Tripp AE,Wilson SB,Xu Y,Zink RW,McCarthy

    更新日期：2004-12-20 00:00:00

  • 2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a new class of cannabinoid receptor agonists. Part 3: Synthesis and activity of isosteric analogs.

    abstract：:Structure-activity relationships and efforts to optimize the pharmacokinetic profile of isosteric analogs of 2-arylimino-5,6-dihydro-4H-1,3-thiazines as cannabinoid receptor agonists are described. Among those examined, compound 25 showed potent affinity for cannabinoid receptor 1 (CB1) and receptor 2 (CB2). This comp...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2008.10.070

    authors： Kai H,Morioka Y,Koriyama Y,Okamoto K,Hasegawa Y,Hattori M,Koike K,Chiba H,Shinohara S,Iwamoto Y,Takahashi K,Tanimoto N

    更新日期：2008-12-15 00:00:00

  • Discovery of pyrrolidine-based β-secretase inhibitors: lead advancement through conformational design for maintenance of ligand binding efficiency.

    abstract：:We have developed a novel series of pyrrolidine derived BACE-1 inhibitors. The potency of the weak initial lead structure was enhanced using library-based SAR methods. The series was then further advanced by rational design while maintaining a minimal ligand binding efficiency threshold. Ultimately, the co-crystal str...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2011.11.024

    authors： Stachel SJ,Steele TG,Petrocchi A,Haugabook SJ,McGaughey G,Katharine Holloway M,Allison T,Munshi S,Zuck P,Colussi D,Tugasheva K,Wolfe A,Graham SL,Vacca JP

    更新日期：2012-01-01 00:00:00

  • Novel BK channel openers containing dehydroabietic acid skeleton: structure-activity relationship for peripheral substituents on ring C.

    abstract：:A series of dehydroabietic acid (DHAA, 2) derivatives was synthesized and evaluated as BK channel openers in an assay system of CHO-K1 cells expressing hBKalpha channels. Systematic modifications of the peripheral functionality of ring C of DHAA showed that the introduction of a nitro or (thio)urea group in ring C gre...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2008.08.078

    authors： Cui YM,Yasutomi E,Otani Y,Yoshinaga T,Ido K,Sawada K,Ohwada T

    更新日期：2008-10-01 00:00:00

  • Neomycin-phenolic conjugates: polycationic amphiphiles with broad-spectrum antibacterial activity, low hemolytic activity and weak serum protein binding.

    abstract：:Here we present a proof-of-concept study, combining two known antimicrobial agents into a hybrid structure in order to develop an emergent cationic detergent-like interaction with the bacterial membrane. Six amphiphilic conjugates were prepared by copper (I)-catalyzed 1,3-dipolar cycloaddition between a neomycin B-der...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2012.01.025

    authors： Findlay B,Zhanel GG,Schweizer F

    更新日期：2012-02-15 00:00:00

  • Synthesis, in vitro, and in vivo antibacterial activity of nocathiacin I thiol-Michael adducts.

    abstract：:The synthesis and antibacterial activity of a series of nocathiacin I derivatives (4-20) containing polar water solubilizing groups is described. Thiol-Michael adducts containing acidic polar groups have reduced antibacterial activity whereas those with basic polar groups have retained very good antibacterial activity...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2005.02.046

    authors： Naidu BN,Sorenson ME,Bronson JJ,Pucci MJ,Clark JM,Ueda Y

    更新日期：2005-04-15 00:00:00