Towards new antibiotics targeting bacterial transglycosylase: Synthesis of a Lipid II analog as stable transition-state mimic inhibitor.

Abstract:

:Described here is the asymmetric synthesis of iminosugar 2b, a Lipid II analog, designed to mimic the transition state of transglycosylation catalyzed by the bacterial transglycosylase. The high density of functional groups, together with a rich stereochemistry, represents an extraordinary challenge for chemical synthesis. The key 2,6-anti- stereochemistry of the iminosugar ring was established through an iridium-catalyzed asymmetric allylic amination. The developed synthetic route is suitable for the synthesis of focused libraries to enable the structure-activity relationship study and late-stage modification of iminosugar scaffold with variable lipid, peptide and sugar substituents. Compound 2b showed 70% inhibition of transglycosylase from Acinetobacter baumannii, providing a basis for further improvement.

journal_name

Bioorg Med Chem Lett

authors

Wang X,Krasnova L,Wu KB,Wu WS,Cheng TJ,Wong CH

doi

10.1016/j.bmcl.2018.03.035

subject

Has Abstract

pub_date

2018-09-01 00:00:00

pages

2708-2712

issue

16

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(18)30228-2

journal_volume

28

pub_type

杂志文章
  • Synthesis and acrosin inhibitory activities of substituted ethyl 5-(4-aminophenyl)-1H-pyrazole-3-carboxylate derivatives.

    abstract::A series of novel ethyl 5-(4-aminophenyl)-1H-pyrazole-3-carboxylate derivatives were designed and synthesized and their in vitro acrosin inhibitory activities were evaluated. Most of the compounds exhibited acrosin inhibitory activities. Among them, three compounds (5l, 5n, and 5v) were more potent than that of the co...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2011.07.110

    authors: Qi J,Zhu J,Liu X,Ding L,Zheng C,Han G,Lv J,Zhou Y

    更新日期:2011-10-01 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

  • Substrate and inhibitor specificity of kynurenine monooxygenase from Cytophaga hutchinsonii.

    abstract::Kynurenine monooxygenase (KMO) is a potential drug target for treatment of neurodegenerative disorders such as Huntington's and Alzheimer's diseases. We have evaluated substituted kynurenines as substrates or inhibitors of KMO from Cytophaga hutchinsonii. Kynurenines substituted with a halogen at the 5-position are ex...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2017.02.080

    authors: Phillips RS,Anderson AD,Gentry HG,Güner OF,Bowen JP

    更新日期:2017-04-15 00:00:00

  • Structure-activity relationship in two series of aminoalkyl substituted coumarin inhibitors of gyrase B.

    abstract::Two series of aminosubstituted coumarins were synthesised and evaluated in vitro as inhibitors of DNA gyrase and as potential antibacterials. Novel novobiocin-like coumarins, 4-(dialkylamino)methylcoumarins and 4-((2-alkylamino)ethoxy)coumarins, were discovered as gyrase B inhibitors with promising antibacterial activ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(99)00492-8

    authors: Laurin P,Ferroud D,Schio L,Klich M,Dupuis-Hamelin C,Mauvais P,Lassaigne P,Bonnefoy A,Musicki B

    更新日期:1999-10-04 00:00:00

  • Synthesis of H-bonding probes of alpha7 nAChR agonist selectivity.

    abstract::The alpha7 subtype of the nicotinic acetylcholine receptor (nAChR) is the target of studies aimed at identifying features that will lead to the development of selective therapeutics. Five arylidine anabaseines, three with pyridine rings and two with the pyrrole rings, were synthesized in 35-65% yield via aldol condens...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2008.11.044

    authors: Wang J,Papke RL,Horenstein NA

    更新日期:2009-01-15 00:00:00

  • trans-3,4-Disubstituted pyrrolidines as inhibitors of the human aspartyl protease renin. Part II: prime site exploration using an oxygen linker.

    abstract::Inhibition of the aspartyl protease renin is considered as an efficient approach for treating hypertension. Lately, we described the discovery of a novel class of direct renin inhibitors which comprised a pyrrolidine scaffold (e.g., 2). Based on the X-ray structure of the lead compound 2 bound to renin we predicted th...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2015.02.040

    authors: Sellner H,Cottens S,Cumin F,Ehrhardt C,Kosaka T,Lorthiois E,Ostermann N,Webb RL,Rigel DF,Wagner T,Maibaum J

    更新日期:2015-04-15 00:00:00

  • Synthesis and biological study of medicinally important Mannich bases derived from 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a pentahydroxy naphthacene carboxamide.

    abstract::The paper describes synthesis and antibacterial study of biologically active Mannich bases of carboxamide derivative employing Mannich reaction of 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a pentahydroxy naphthacene carboxamide with various sulfonamides/secondary amines . They were analysed by eleme...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2006.11.001

    authors: Joshi S,Manikpuri AD,Tiwari P

    更新日期:2007-02-01 00:00:00

  • The binding of cocaine to cyclodextrins.

    abstract::Cocaine binds into beta-cyclodextrin, but not detectably into alpha- or gamma-cyclodextrin, in water solution. NMR studies indicate the geometry of the complex, which is confirmed by molecular mechanics calculations and binding studies on cocaine analogues and cyclodextrin dimers. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(00)00371-1

    authors: Nesna N,Lou J,Breslow R

    更新日期:2000-09-04 00:00:00

  • Synthesis of β-boswellic acid derivatives as cytotoxic and apoptotic agents.

    abstract::A series of β-boswellic acid derivatives were synthesized and evaluated for anticancer activity. One of the lead analog 4f displayed significant anticancer activity against a panel of cancer cells as well as substantially inhibited colony formation in HCT-116 cells. Furthermore, 4f was found to be a potent inducer of ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2015.11.027

    authors: Kumar A,Qayum A,Sharma PR,Singh SK,Shah BA

    更新日期:2016-01-01 00:00:00

  • Crystal structure of the most catalytically effective carbonic anhydrase enzyme known, SazCA from the thermophilic bacterium Sulfurihydrogenibium azorense.

    abstract::Two thermostable α-carbonic anhydrases (α-CAs) isolated from thermophilic Sulfurihydrogenibium spp., namely SspCA (from S. yellowstonensis) and SazCA (from S. azorense), were shown in a previous work to possess interesting complementary properties. SspCA was shown to have an exceptional thermal stability, whereas SazC...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2015.02.068

    authors: De Simone G,Monti SM,Alterio V,Buonanno M,De Luca V,Rossi M,Carginale V,Supuran CT,Capasso C,Di Fiore A

    更新日期:2015-05-01 00:00:00

  • Targeting TRAIL.

    abstract::Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), also known as Apo2L, has been investigated in the past decade for its promising anticancer activity due to its ability to selectively induce apoptosis in tumoral cells by binding to TRAIL receptors (TRAIL-R). Macromolecules such as agonistic monoclonal a...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章,评审

    doi:10.1016/j.bmcl.2019.07.053

    authors: Ion GND,Nitulescu GM,Popescu CI

    更新日期:2019-09-15 00:00:00

  • Fluorescent metal ion indicators based on benzoannelated crown systems: a green fluorescent indicator for intracellular sodium ions.

    abstract::The synthesis and metal binding properties of cation-sensitive fluorescent indicators intended for biological applications are described. The increase of the crown ether ring size enhances the affinity for larger cations, but weakens the fluorescent response and selectivity. A compound having a 15-crown-5 chelator dir...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2005.02.017

    authors: Martin VV,Rothe A,Gee KR

    更新日期:2005-04-01 00:00:00

  • Respiratory syncytial virus fusion inhibitors. Part 5: Optimization of benzimidazole substitution patterns towards derivatives with improved activity.

    abstract::Extensive SAR studies and optimization of ADME properties of benzimidazol-2-one derivatives led to the identification of BMS-433771 (3) as an orally active RSV fusion inhibitor. In order to extend the structure-activity relationships for this compound series, substitution of the benzimidazole ring was examined with a ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2007.05.102

    authors: Wang XA,Cianci CW,Yu KL,Combrink KD,Thuring JW,Zhang Y,Civiello RL,Kadow KF,Roach J,Li Z,Langley DR,Krystal M,Meanwell NA

    更新日期:2007-08-15 00:00:00

  • Design, synthesis and bioactivity of catechin/epicatechin and 2-azetidinone derived chimeric molecules.

    abstract::A new class of chimeric molecules have been developed. These are based on polyphenols like catechin and epicatechin and monocyclic beta-lactams. The two units are joined via a triazole linker using the 'Click Chemistry' conditions. The compounds showed good to weak antibacterial activity against Escherichia coli as we...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2009.04.084

    authors: Roy B,Chakraborty A,Ghosh SK,Basak A

    更新日期:2009-12-15 00:00:00

  • In vitro antitubercular and antimicrobial activities of 1-substituted quinoxaline-2,3(1H,4H)-diones.

    abstract::1-((Substituted)methyl)quinoxaline-2,3(1H,4H)-dione (2a-e) and 1-((substituted)acryloyl)quinoxaline-2,3(1H,4H)-dione (4a-c) were synthesized from quinoxaline-2,3(1H,4H)-dione 1 and evaluated for their antimicrobial activities. Results of the antitubercular screening against Mycobacterium tuberculosis H(37)Rv showed th...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2009.10.026

    authors: Ramalingam P,Ganapaty S,Rao ChB

    更新日期:2010-01-01 00:00:00

  • Discovery of aryl ureas and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (part I).

    abstract::A series of structurally novel aryl ureas was derived from optimization of the HTS lead as selective histamine H3 receptor (H3R) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b,...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2013.03.080

    authors: Gao Z,Hurst WJ,Guillot E,Czechtizky W,Lukasczyk U,Nagorny R,Pruniaux MP,Schwink L,Sanchez JA,Stengelin S,Tang L,Winkler I,Hendrix JA,George PG

    更新日期:2013-06-01 00:00:00

  • A new quinoline derivative with cytotoxic activity from Streptomyces sp. neau50.

    abstract::A new quinoline derivative, methyl 8-(3-methoxy-3-methylbutyl)-2-methylquinoline-4-carboxylate (1), was isolated from the endophytic strain Streptomyces sp. neau50, and the structure was elucidated by extensive spectroscopic analysis. Compound 1 showed cytotoxicity against human lung adenocarcinoma cell line A549 with...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2011.02.095

    authors: Wang XJ,Gong DL,Wang JD,Zhang J,Liu CX,Xiang WS

    更新日期:2011-04-15 00:00:00

  • Potent covalent inhibitors of bacterial urease identified by activity-reactivity profiling.

    abstract::Covalent enzyme inhibitors constitute a highly important group of biologically active compounds, with numerous drugs available on the market. Although the discovery of inhibitors of urease, a urea hydrolyzing enzyme crucial for the survival of some human pathogens, is a field of medicinal chemistry that has grown in r...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2017.02.022

    authors: Macegoniuk K,Kowalczyk R,Rudzińska A,Psurski M,Wietrzyk J,Berlicki Ł

    更新日期:2017-03-15 00:00:00

  • Diversification of edaravone via palladium-catalyzed hydrazine cross-coupling: Applications against protein misfolding and oligomerization of beta-amyloid.

    abstract::N-Aryl derivatives of edaravone were identified as potentially effective small molecule inhibitors of tau and beta-amyloid aggregation in the context of developing disease-modifying therapeutics for Alzheimer's disease (AD). Palladium-catalyzed hydrazine monoarylation protocols were then employed as an expedient means...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2015.11.022

    authors: MacLean MA,Diez-Cecilia E,Lavery CB,Reed MA,Wang Y,Weaver DF,Stradiotto M

    更新日期:2016-01-01 00:00:00

  • 3,4-Dihydro-1-isoquinolinamines: a novel class of nitric oxide synthase inhibitors with a range of isoform selectivity and potency.

    abstract::3-Phenyl-3.4-dihydro-1-isoquinolinamine is a weak inhibitor of iNOS and nNOS. Structural variation of 5a results in inhibitors with a range of potency and selectivity for the NOS enzymes, including a potent and very selective iNOS inhibitor 5j. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(01)00119-6

    authors: Beaton H,Hamley P,Nicholls DJ,Tinker AC,Wallace AV

    更新日期:2001-04-23 00:00:00

  • Design, synthesis and biological evaluation of 2-indolinone derivatives as PAK1 inhibitors in MDA-MB-231 cells.

    abstract::P21-activated kinase 1 (PAK1) plays a vital role in the proliferation, survival and migration of cancer cells, which has emerged as a promising drug target for cancer therapy. In this study, a series of 2-indolinone derivatives were designed and synthesized through a structure-based strategy. A potent PAK1 inhibitor (...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2020.127355

    authors: Yao D,Ruhan A,Jiang J,Huang J,Wang J,Han W

    更新日期:2020-09-01 00:00:00

  • Synthesis and antihormonal properties of novel 11β-benzoxazole-substituted steroids.

    abstract::Early studies led to the identification of 11β-aryl-4',5'-dihydrospiro[estra-4,9-diene-17β,4'-oxazole] analogs with potent and more selective antiprogestational activity compared to antiglucocorticoid activity than mifepristone. In the present study, we replaced the 4'-dimethylaminophenyl group of mifepristone with th...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2011.12.110

    authors: Jin C,Fix SE,Kepler JA,Cook CE

    更新日期:2012-02-15 00:00:00

  • An aminopyridazine-based inhibitor of a pro-apoptotic protein kinase attenuates hypoxia-ischemia induced acute brain injury.

    abstract::Death associated protein kinase (DAPK) is a calcium and calmodulin regulated enzyme that functions early in eukaryotic programmed cell death, or apoptosis. To validate DAPK as a potential drug discovery target for acute brain injury, the first small molecule DAPK inhibitor was synthesized and tested in vivo. A single ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(03)00733-9

    authors: Velentza AV,Wainwright MS,Zasadzki M,Mirzoeva S,Schumacher AM,Haiech J,Focia PJ,Egli M,Watterson DM

    更新日期:2003-10-20 00:00:00

  • Bis-azaaromatic quaternary ammonium salts as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release: An investigation of binding conformation.

    abstract::A series of conformationally restricted bis-azaaromatic quaternary ammonium salts (3 and 4) have been designed and synthesized in order to investigate the possible binding conformations of N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB; 2), a compound which potently inhibits neuronal nicotinic acetylcholin...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2007.10.052

    authors: Zheng G,Zhang Z,Pivavarchyk M,Deaciuc AG,Dwoskin LP,Crooks PA

    更新日期:2007-12-15 00:00:00

  • Diaminopyrimidine and diaminopyridine 5-HT7 ligands.

    abstract::The present studies have identified a series of diaminopyrimidines and diaminopyridines as novel 5-HT(7) receptor ligands. Three regiosiomeric classes of pyrimidines and four regioisomeric classes of pyridines were synthesized and analyzed for binding to the 5-HT(7) receptor. The 5-HT(7) binding affinities of differen...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2004.06.007

    authors: Denhart DJ,Purandare AV,Catt JD,King HD,Gao A,Deskus JA,Poss MA,Stark AD,Torrente JR,Johnson G,Mattson RJ

    更新日期:2004-08-16 00:00:00

  • Structure-based design and synthesis of potent benzothiazole inhibitors of interleukin-2 inducible T cell kinase (ITK).

    abstract::Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cel...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2013.09.069

    authors: MacKinnon CH,Lau K,Burch JD,Chen Y,Dines J,Ding X,Eigenbrot C,Heifetz A,Jaochico A,Johnson A,Kraemer J,Kruger S,Krülle TM,Liimatta M,Ly J,Maghames R,Montalbetti CA,Ortwine DF,Pérez-Fuertes Y,Shia S,Stein DB,Tran

    更新日期:2013-12-01 00:00:00

  • Novel antibacterial active quinolone-fluoroquinolone conjugates and 2D-QSAR studies.

    abstract::Novel, quinolone-fluoroquinolone conjugates 10a-f, 11a-f, 13a-f and 14a-f with amino acid linkers were synthesized in good yields utilizing benzotriazole chemistry. Antibacterial bioassay showed the synthesized bis-conjugates exhibit anti-bacterial properties comparable with the parent drugs. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2015.07.077

    authors: Panda SS,Liaqat S,Girgis AS,Samir A,Hall CD,Katritzky AR

    更新日期:2015-09-15 00:00:00

  • Dopamine/serotonin receptor ligands. Part 15: Oxygenation of the benz-indolo-azecine LE 300 leads to novel subnanomolar dopamine D1/D5 antagonists.

    abstract::Relying on the high affinities of the benz-indolo-azecine LE 300 (1) and the hydroxylated dibenz-azecine LE 404 (2b) for the D1/D5 receptor subtypes, we synthesized methoxylated, hydroxylated and an indole-N methylated derivatives of 1 (Fig. 1). Hydroxylation of azecine derivatives is beneficial with regard to the aff...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2006.11.093

    authors: Enzensperger C,Kilian S,Ackermann M,Koch A,Kelch K,Lehmann J

    更新日期:2007-03-01 00:00:00

  • First hydroxamate inhibitors for carboxypeptidase A. N-acyl-N-hydroxy-beta-phenylalanines.

    abstract::A series of N-acyl-N-hydroxy-beta-Phe were designed, synthesized, and shown to have potent inhibitory activity for carboxypeptidase A (CPA). They are the first examples of CPA inhibitors having a hydroxamate functionality. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(99)00055-4

    authors: Kim DH,Jin Y

    更新日期:1999-03-08 00:00:00

  • Recent advances in natural antifungal flavonoids and their derivatives.

    abstract::The resistance of pathogenic fungi and failure of drug therapy increased dramatically. Numerous studies have reported the individual or synergistic antifungal potency of natural and synthesized flavonoids, especially against drug-resistant fungi. This brief review summarizes the structure and individual or synergistic...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章,评审

    doi:10.1016/j.bmcl.2019.07.048

    authors: Jin YS

    更新日期:2019-10-01 00:00:00