Abstract：
:Pseudomonas aeruginosa is a causative agent of chronic infections in immunocompromised patients. Disruption of quorum sensing circuits is an attractive strategy for treating diseases associated with P. aeruginosa infection. In this study, we designed and synthesized a series of gingerol analogs targeting LasR, a master regulator of quorum sensing networks in P. aeruginosa. Structure-activity relationship studies showed that a hydrogen-bonding interaction in the head section, stereochemistry and rotational rigidity in the middle section, and optimal alkyl chain length in the tail section are important factors for the enhancement of LasR-binding affinity and for the inhibition of biofilm formation. The most potent compound 41, an analog of (R)-8-gingerol with restricted rotation, showed stronger LasR-binding affinity and inhibition of biofilm formation than the known LasR antagonist (S)-6-gingerol. This new LasR antagonist can be used as an early lead compound for the development of anti-biofilm agents to treat P. aeruginosa infections.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Choi H,Ham SY,Cha E,Shin Y,Kim HS,Bang JK,Son SH,Park HD,Byun Ydoi
10.1021/acs.jmedchem.7b01426subject
Has Abstractpub_date
2017-12-14 00:00:00pages
9821-9837issue
23eissn
0022-2623issn
1520-4804journal_volume
60pub_type
杂志文章abstract：:Indirubins have been identified as potent ATP-competitive protein kinase inhibitors. Structural modifications in the 5- and 3'-position have been extensively investigated, but the impact of substituents in 5'-position is not equally well-studied. Here, we report the synthesis of new indirubin 3'- and 5'-derivatives in...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00324
更新日期：2017-06-22 00:00:00
abstract：:Monosubstituted derivatives of adenosine 5'-phosphate (AMP) with substituents of 1-3 atoms or group replacements at any of 11 positions have been synthesized and examined as substrates and inhibitors of the rat muscle adenylate kinase isozyme (AK-M), and the rat AK II and III isozymes predominant in poorly differentia...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00349a008
更新日期：1982-07-01 00:00:00
abstract：:Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD) characterized by liver steatosis, inflammation, and hepatocellular damage. NASH is a serious condition that can progress to cirrhosis, liver failure, and hepatocellular carcinoma. The association of NASH with obesity, type...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.9b01701
更新日期：2020-05-28 00:00:00
abstract：:Previous work has shown that incorporation of either 1-aminocyclohexanecarboxylic acid (Ac6c) or alpha-methyl-p-phosphonophenylalanine ((alpha-Me)Ppp) in the phosphotyrosyl (pTyr) C-proximal position (pY + 1 residue) of Grb2 SH2 domain binding peptides confers high affinity. The tetralin-based (S)-2-amino-6-phosphonot...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0492709
更新日期：2005-02-10 00:00:00
abstract：:We report herein further insight into the biological activities displayed by a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs). Substitution of the N-hydroxyimide two-metal binding pharmacophore at position 4 by carboxamido side chains was previously shown by us to be fruitful for this scaffold, since strong ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm500109z
更新日期：2014-06-12 00:00:00
abstract：:Histone deacetylase 6 (HDAC6) is an emerging target for the treatment of cancer, neurodegenerative diseases, inflammation, and other diseases. Here, we present the multicomponent synthesis and structure-activity relationship of a series of tetrazole-based HDAC6 inhibitors. We discovered the hit compound NR-160 by inve...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01888
更新日期：2020-09-24 00:00:00
abstract：:Inhibitor of secreted frizzled related protein-1 (sFRP-1) would be a novel potential osteogenic agent, since loss of sFRP-1 affects osteoblast proliferation, differentiation, and activity, resulting in improved bone mineral density, quality, and strength. We have identified small molecule diarylsulfone sulfonamide der...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm801069w
更新日期：2008-12-25 00:00:00
abstract：:The design, synthesis, and activity of a novel series of 2,5-substituted tryptamine derivatives at vascular 5HT1B-like receptors is described. Several important auxiliary binding sites of the 5HT1B-like receptor have been proposed following various modifications to the 2-substituent and especially to the methylene- or...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9605849
更新日期：1997-07-18 00:00:00
abstract：:Several 1,2-dihydro-5-(substituted phenyl)-2(1H)-pyridinones were synthesized and evaluated for inotropic activity. 1,2-Dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3- pyridinecarbonitrile (5a) and the corresponding unsubstituted analogue 14a were the most potent positive inotropic agents in this series. Alth...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00389a011
更新日期：1987-06-01 00:00:00
abstract：:The delta-selective opioid peptide deltorphin C(H-Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2) (DEL C) was modified by para-substitution of Phe3 with halogens (F, Cl, Br, I), amino, or nitro groups. The bioactive potencies in peripheral tissues and brain receptor selectivities of these analogues depended upon the particular sub...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00103a001
更新日期：1992-12-11 00:00:00
abstract：:A series of 2'- and 3'-fluorinated 2',3'-dideoxynucleosides and 3'-azido-2',3'-dideoxynucleosides were synthesized and evaluated for their inhibitory activity against human immunodeficiency virus-1 (HIV-1) replication in MT-4 cells. Neither conversion of 3'-fluoro- or 3'-azido-2',3'-dideoxyadenosine to the correspondi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00128a013
更新日期：1989-08-01 00:00:00
abstract：:A series of the anti-HIV nucleoside conjugates of either (1-O-alkyl) and thioether (1-S-alkyl) lipids linked by a pyrophosphate diester bond has been synthesized as micelle-forming prodrugs of the nucleosides to improve their therapeutic efficiency. These include AZT 5'-diphosphate-rac-1-S-octadecyl-2-O-palmitoyl-1-th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950620o
更新日期：1996-04-26 00:00:00
abstract：:The resurgence of tuberculosis (TB), the incidence of drug-resistant strains of Mycobacterium tuberculosis (MTB), and the coinfection between TB and HIV have led to serious infections, high mortality, and a global health threat, resulting in the urgent search for new classes of antimycobacterial agents. Herein, we rep...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm901235p
更新日期：2010-01-28 00:00:00
abstract：:The prevalence of multidrug resistance among clinically significant bacterial pathogens underscores a critical need for the development of new classes of antibiotics with novel mechanisms of action. Here we describe the synthesis and evaluation of a guanidinomethyl biaryl compound {1-((4'-(tert-butyl)-[1,1'-biphenyl]-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm3012728
更新日期：2012-11-26 00:00:00
abstract：:In an attempt to synthesize pentamidine-aplysinopsin hybrid molecule 25, a lead molecule 8 (containing Z-configured aplysinopsin moiety) was identified for antileishmanial activity. Optimization of lead 8 provided 24 (containing E-configured aplysinopsin) possessing 10 times more activity and 401-fold less toxicity th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900564x
更新日期：2009-10-08 00:00:00
abstract：:The synthesis and biological evaluation of the two known phenolic metabolites of paclitaxel are described. The C3'-phenolic metabolite 2 of paclitaxel was prepared from 7-(triethylsilyl)-baccatin III (8) and enantioenriched N-benzoyl-2-azetidinone 7. The C2-phenolic metabolite 3 was synthesized from paclitaxel (1a) vi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960142x
更新日期：1996-07-05 00:00:00
abstract：:Oxadiazoles are five-membered heteroaromatic rings containing two carbons, two nitrogens, and one oxygen atom, and they exist in different regioisomeric forms. Oxadiazoles are frequently occurring motifs in druglike molecules, and they are often used with the intention of being bioisosteric replacements for ester and ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm2013248
更新日期：2012-03-08 00:00:00
abstract：:N-(5,5-Diacetoxypent-1-yl)doxorubicin (DAPDOX) (3), a new, water-soluble analogue of doxorubicin, has been synthesized by coupling doxorubicin with 5-oxopentane-1,1-diacetate in the presence of NaBH3CN. This analogue was designed to be converted to the corresponding aldehyde, N-(5-oxopent-1-yl)doxorubicin, in the pres...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00095a017
更新日期：1992-08-21 00:00:00
abstract：:A cell-free assay was developed for the orphan nuclear receptor LXRalpha that measures the ligand-dependent recruitment of a peptide from the steroid receptor coactivator 1 (SRC1) to the nuclear receptor. Using this ligand-sensing assay (LiSA), the structural requirements for activation of the receptor by oxysterols a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0004749
更新日期：2001-03-15 00:00:00
abstract：:Human neutrophil elastase (HNE) is an important therapeutic target for treatment of pulmonary diseases. Previously, we identified novel N-benzoylindazole derivatives as potent, competitive, and pseudoirreversible HNE inhibitors. Here, we report further development of these inhibitors with improved potency, protease se...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm400742j
更新日期：2013-08-08 00:00:00
abstract：:The chemokine receptor CXCR4 is a critical regulator of inflammation and immune surveillance, and it is specifically implicated in cancer metastasis and HIV-1 infection. On the basis of the observation that several of the known antagonists remarkably share a C(2) symmetry element, we constructed symmetric dimers with ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm2009716
更新日期：2011-11-10 00:00:00
abstract：:(4-Methoyx-2,3,6-trimethylphenyl)nonatetraenoic acids, esters, and amides (analogues of retinoic acid) bearing a fluorine atom(s) or a trifluoromethyl group on the polyene side chain were synthesized. The biological activities of these compounds and of 10-, 12-, and 14-fluororetinoic acid esters were evaluated in vivo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00195a010
更新日期：1979-09-01 00:00:00
abstract：:Cholecystokinin (CCK) has been identified as a pronociceptive endogenous peptide which also possesses antiopioid actions. CCK may be upregulated in conditions of chronic pain or during sustained morphine administration resulting in attenuation of opioid-mediated pain relief. These complex interactions between opioids ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050921q
更新日期：2006-05-18 00:00:00
abstract：:The parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for significant human suffering in the form of human African trypanosomiasis (HAT) and Chagas disease. Drugs currently available to treat these neglected diseases leave much to be desired. Herein we report optimization of a novel class of N-(2-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00442
更新日期：2016-11-10 00:00:00
abstract：:Ras proteins regulate signal transduction processes that control cell growth and proliferation. Their disregulation is a common cause of human tumors. Atomic level structural and dynamical information in a membrane environment is crucial for understanding signaling specificity among Ras isoforms and for the design of ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm061053f
更新日期：2007-02-22 00:00:00
abstract：:The synthesis and antihypertensive activity of a series of novel 3-[(substituted-carbonyl)amino]-2H-1-benzopyran-4-ols, administered orally to spontaneously hypertensive rats, are described. Optimum activity in this series was observed for compounds with branched alkyl or branched alkylamino groups flanking the carbon...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00087a018
更新日期：1992-05-01 00:00:00
abstract：:We recently described a number of inhibitors of P450(17 alpha), the key enzyme of androgen biosynthesis. Here, we report the synthesis and activity of novel 17-imidazolyl, pyrazolyl, and isoxazolyl androstene derivatives as potential agents for the treatment of prostatic cancer. A number of 17-(4'-Imidazolyl) derivati...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970337k
更新日期：1997-09-26 00:00:00
abstract：:Members of the class of 9-anilinoacridine topoisomerase II inhibitors bearing lipophilic electron-donating 1'-anilino substituents are active against both the promastigote and amastigote forms of the parasite Leishmania major. A series of analogues of the known 1'-NHhexyl lead compound were prepared and evaluated agai...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970232h
更新日期：1997-08-01 00:00:00
abstract：:The highly CB2 selective cannabinoid receptor inverse agonist, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid N-benzo[1,3]dioxol-5-ylmethyl)amide (JTE-907; 9b), served as the lead compound for investigating the structure-activity relationships of its analogues and in the search for more potent and ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050879z
更新日期：2006-03-23 00:00:00
abstract：:Photodynamic therapy uses a combination of light, oxygen, and a photosensitizer to induce the death of malignant cells. To improve the selectivity of a photosensitizer toward cancerous cells that express gonadotropin-releasing hormone (GnRH) receptors, protoporphyrin IX (PpIX) was conjugated to a GnRH agonist, [d-Lys6...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020535y
更新日期：2003-09-11 00:00:00
