Elucidation of antimicrobial activity and mechanism of action by N-substituted carbazole derivatives.

Abstract:

:Compounds belonging to a carbazole series have been identified as potent fungal plasma membrane proton adenosine triphophatase (H+-ATPase) inhibitors with a broad spectrum of antifungal activity. The carbazole compounds inhibit the adenosine triphosphate (ATP) hydrolysis activity of the essential fungal H+-ATPase, thereby functionally inhibiting the extrusion of protons and extracellular acidification, processes that are responsible for maintaining high plasma membrane potential. The compound class binds to and inhibits the H+-ATPase within minutes, leading to fungal death after 1-3h of compound exposure in vitro. The tested compounds are not selective for the fungal H+-ATPase, exhibiting an overlap of inhibitory activity with the mammalian protein family of P-type ATPases; the sarco(endo)plasmic reticulum calcium ATPase (Ca2+-ATPase) and the sodium potassium ATPase (Na+,K+-ATPase). The ion transport in the P-type ATPases is energized by the conversion of ATP to adenosine diphosphate (ADP) and phosphate and a general inhibitory mechanism mediated by the carbazole derivative could therefore be blocking of the active site. However, biochemical studies show that increased concentrations of ATP do not change the inhibitory activity of the carbazoles suggesting they act as allosteric inhibitors. Furthermore decreased levels of intracellular ATP would suggest that the compounds inhibit the H+-ATPase indirectly, but Candida albicans cells exposed to potent H+-ATPase-inhibitory carbazoles result in increased levels of intracellular ATP, indicating direct inhibition of H+-ATPase.

journal_name

Bioorg Med Chem Lett

authors

Clausen JD,Kjellerup L,Cohrt KO,Hansen JB,Dalby-Brown W,Winther AL

doi

10.1016/j.bmcl.2017.08.067

subject

Has Abstract

pub_date

2017-10-01 00:00:00

pages

4564-4570

issue

19

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(17)30856-9

journal_volume

27

pub_type

杂志文章
  • Amino acid conjugates as kappa opioid receptor agonists.

    abstract::A novel series of kappa (kappa) opioid receptor agonists were synthesized by incorporating the key structural features of known kappa opioid agonists while replacing the aryl acetamide portion with substituted amino acid conjugates. Compounds 3j (Ki = 6.7 nM), 3k (Ki = 3.6 nM), 3l (Ki = 4.6 nM), 3m (Ki = 0.83 nM) and ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2005.01.038

    authors: Kumar V,Guo D,Daubert JD,Cassel JA,DeHaven RN,Mansson E,DeHaven-Hudkins DL,Maycock AL

    更新日期:2005-03-01 00:00:00

  • Preparation of L-alpha-phosphatidyl-D-myo-inositol 3-phosphate (3-PIP) and 3,5-bisphosphate (3,5-PIP2).

    abstract::Practical, asymmetric total syntheses of the title phospholipids from a readily available myo-inositol derivative as well as short chain and cross-linkable aminoether analogues are described. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(00)00315-2

    authors: Falck JR,Krishna UM,Capdevila JH

    更新日期:2000-08-07 00:00:00

  • Chemical modification of the naphthoyl 3-position of JWH-015: in search of a fluorescent probe to the cannabinoid CB2 receptor.

    abstract::In silico modelling was used to guide the positioning of the fluorescent dye NBD-F on the cannabinoid CB2 receptor agonist JWH-015. While the ultimate fluorescent conjugate lost extensive binding affinity to the cannabinoid CB2 receptor, affinity and efficacy studies on the naphthoyl 3-position modified precursor mole...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2005.05.049

    authors: Yates AS,Doughty SW,Kendall DA,Kellam B

    更新日期:2005-08-15 00:00:00

  • Thieno[3,2-d]pyrimidin-4(3H)-one derivatives as PDK1 inhibitors discovered by fragment-based screening.

    abstract::Ligand efficient fragments binding to PDK1 were identified by an NMR fragment-based screening approach. Computational modeling of the fragments bound to the active site led to the design and synthesis of a series of novel 6,7-disubstituted thienopyrimidin-4-one compounds, with low micromolar inhibitory activity agains...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2012.04.080

    authors: Lee AC,Ramanujulu PM,Poulsen A,Williams M,Blanchard S,Ma DM,Bonday Z,Goh KL,Goh KC,Goh MK,Wood J,Dymock BW

    更新日期:2012-06-15 00:00:00

  • Heterobiaryl purine derivatives as potent antiproliferative agents: inhibitors of cyclin dependent kinases. Part II.

    abstract::C-6 Biarylmethylamino purine derivatives of roscovitine (1) inhibit cyclin dependent kinases and demonstrate potent antiproliferative activity. Replacement of the aryl rings of the C-6 biarylmethylamino group with heterobiaryl rings has provided compounds with significantly improved activity. In particular, derivative...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2009.10.011

    authors: Trova MP,Barnes KD,Alicea L,Benanti T,Bielaska M,Bilotta J,Bliss B,Duong TN,Haydar S,Herr RJ,Hui Y,Johnson M,Lehman JM,Peace D,Rainka M,Snider P,Salamone S,Tregay S,Zheng X,Friedrich TD

    更新日期:2009-12-01 00:00:00

  • Tri-substituted acylhydrazines as tertiary amide bioisosteres: HCV NS5B polymerase inhibitors.

    abstract::The use of a tri-substituted acylhydrazine as an isostere of a tertiary amide was explored in a series of HCV NS5B thumb site II inhibitors. Direct replacement generated an analog with similar conformational and physicochemical properties. The series was extended to produce compounds with potent binding affinities and...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2012.05.025

    authors: Canales E,Carlson JS,Appleby T,Fenaux M,Lee J,Tian Y,Tirunagari N,Wong M,Watkins WJ

    更新日期:2012-07-01 00:00:00

  • Structure-based design of ketone-containing, tripeptidyl human rhinovirus 3C protease inhibitors.

    abstract::Tripeptide-derived molecules incorporating C-terminal ketone electrophiles were evaluated as reversible inhibitors of the cysteine-containing human rhinovirus 3C protease (3CP). An optimized example of such compounds displayed potent 3CP inhibition activity (K = 0.0045 microM) and in vitro antiviral properties (EC50=0...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(99)00587-9

    authors: Dragovich PS,Zhou R,Webber SE,Prins TJ,Kwok AK,Okano K,Fuhrman SA,Zalman LS,Maldonado FC,Brown EL,Meador JW 3rd,Patick AK,Ford CE,Brothers MA,Binford SL,Matthews DA,Ferre RA,Worland ST

    更新日期:2000-01-03 00:00:00

  • An endogenous sleep-inducing compound is a novel competitive inhibitor of fatty acid amide hydrolase.

    abstract::2-Octyl gamma-bromoacetoacetate (O gamma Br), an endogenous compound originally isolated from human cerebrospinal fluid (CSF), has previously been demonstrated to increase REM sleep duration in cats. Based on the chemical structure of O gamma Br and its reported sleep-inducing effects, we synthesized O gamma Br along ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(98)00073-0

    authors: Patricelli MP,Patterson JE,Boger DL,Cravatt BF

    更新日期:1998-03-17 00:00:00

  • Synthesis of novel oxime-containing pyrazole derivatives and discovery of regulators for apoptosis and autophagy in A549 lung cancer cells.

    abstract::A series of novel oxime-containing pyrazole derivatives were synthesized by the reaction of ethyl 3-phenyl-1H-pyrazole-5-carboxylate derivatives and 2-bromo-1-phenylethanone followed by the reaction with hydroxylamine hydrochloride. The structures were determined by IR, (1)H NMR, HRMS, and X-ray analysis. A dose- and ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2010.06.121

    authors: Zheng LW,Li Y,Ge D,Zhao BX,Liu YR,Lv HS,Ding J,Miao JY

    更新日期:2010-08-15 00:00:00

  • Design and synthesis of potent, isoxazole-containing renin inhibitors.

    abstract::The design and optimization of a novel isoxazole S(1) linker for renin inhibitor is described herein. This effort culminated in the identification of compound 18, an orally bioavailable, sub-nanomolar renin inhibitor even in the presence of human plasma. When compound 18 was found to inhibit CYP3A4 in a time dependent...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2012.03.014

    authors: Fournier PA,Arbour M,Cauchon E,Chen A,Chefson A,Ducharme Y,Falgueyret JP,Gagné S,Grimm E,Han Y,Houle R,Lacombe P,Lévesque JF,MacDonald D,Mackay B,McKay D,Percival MD,Ramtohul Y,St-Jacques R,Toulmond S

    更新日期:2012-04-15 00:00:00

  • Trifluoromethyl ketones as inhibitors of histone deacetylase.

    abstract::Trifluoromethyl ketones were found to be inhibitors of histone deacetylases (HDACs). Optimization of this series led to the identification of submicromolar inhibitors such as 20 that demonstrated antiproliferative effects against the HT1080 and MDA 435 cell lines. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(02)00754-0

    authors: Frey RR,Wada CK,Garland RB,Curtin ML,Michaelides MR,Li J,Pease LJ,Glaser KB,Marcotte PA,Bouska JJ,Murphy SS,Davidsen SK

    更新日期:2002-12-02 00:00:00

  • New triple-helix DNA stabilizing agents.

    abstract::Several substituted quinolin-4-amines and heteroaromatic analogs were synthesized and evaluated for interaction with triplex polydA.2polydT and duplex polydA.polydT by using UV-thermal melting experiments. Excellent triple-helix DNA ligands with high affinity toward T.A.T triplets and triple/duplex selectivity were de...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2004.12.019

    authors: Strekowski L,Hojjat M,Wolinska E,Parker AN,Paliakov E,Gorecki T,Tanious FA,Wilson WD

    更新日期:2005-02-15 00:00:00

  • Substrate spectrum of tyrocidine thioesterase probed with randomized peptide N-acetylcysteamine thioesters.

    abstract::Apparent kinetic constants k(cat) and K(m) were determined for tyrocidine thioesterase (TycC TE) using randomized peptide N-acetylcysteamine thioesters as substrate analogues. The enzyme has been found to be adequately active for the synthesis of positional-scanning libraries for novel antibiotic screening with reduce...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(02)00067-7

    authors: Xie G,Uttamchandani M,Chen GY,Bu X,Lin SS,Wong KM,Yan W,Yao SQ,Guo Z

    更新日期:2002-03-25 00:00:00

  • Synthesis, antimycobacterial and cytotoxic activity of α,β-unsaturated amides and 2,4-disubstituted oxazoline derivatives.

    abstract::The synthesis of six α,β,-unsaturated amides and six 2,4-disubstituted oxazolines derivatives and their evaluation against two Mycobacterium tuberculosis strains (sensitive H37Rv and a resistant clinical isolate) is reported. 2,4-Disubstituted oxazolines (S)-3b,d,e were the most active in the sensitive strain with a M...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2017.01.024

    authors: Avalos-Alanís FG,Hernández-Fernández E,Carranza-Rosales P,López-Cortina S,Hernández-Fernández J,Ordóñez M,Guzmán-Delgado NE,Morales-Vargas A,Velázquez-Moreno VM,Santiago-Mauricio MG

    更新日期:2017-02-15 00:00:00

  • Effects of a novel carbocyclic analog of pyrrolo[2,3-d]pyrimidine nucleoside on pleiotropic induction of cell death in prostate cancer cells with different androgen responsiveness.

    abstract::Prostate cancer is the most frequently diagnosed cancer and is one of the leading causes of male cancer death in the world. Recently, in the course of our screening for a novel anticancer compound, we synthesized carbocyclic analogs of pyrrolo[2,3-d]pyrimidine nucleoside; compounds 5, and 6. In the current study, we r...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2016.01.057

    authors: Suh H,Choi KW,Lee J,Ryou C,Rhee H,Lee CH

    更新日期:2016-02-15 00:00:00

  • Pro-apoptotic carboxamide analogues of natural fislatifolic acid targeting Mcl-1 and Bcl-2.

    abstract::A library of 26 novel carboxamides deriving from natural fislatifolic acid has been prepared. The synthetic strategy involved a bio-inspired Diels-Alder cycloaddition, followed by functionalisations of the carbonyl moiety. All the compounds were evaluated on Bcl-xL, Mcl-1 and Bcl-2 proteins. In this series of cyclohex...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2020.127003

    authors: Gapil Tiamas S,Daressy F,Abou Samra A,Bignon J,Steinmetz V,Litaudon M,Fourneau C,Hoong Leong K,Ariffin A,Awang K,Desrat S,Roussi F

    更新日期:2020-04-01 00:00:00

  • Discovery of a potent and selective series of pyrazole bacterial methionyl-tRNA synthetase inhibitors.

    abstract::Starting with a micromolar lead identified from high-throughput screening, a series of pyrazoles were discovered with significantly improved potency on bacterial methionyl-tRNA synthetase and selectivity over human methionyl-tRNA synthetase. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(03)00298-1

    authors: Finn J,Mattia K,Morytko M,Ram S,Yang Y,Wu X,Mak E,Gallant P,Keith D

    更新日期:2003-07-07 00:00:00

  • Trifluoromethylation of flavonoids and anti-tumor activity of the trifluoromethylated flavonoid derivatives.

    abstract::3-Trifluoromethylflavonoid derivatives were prepared for the first time by trifluoromethylation of 3-iodoflavonoid derivatives. Other C ring and B ring trifluoromethylated flavonoid derivatives were also prepared. All the compounds were tested for their effect on the U2OS cell cycle in vitro. Bistrifluoromethylated ap...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2005.07.047

    authors: Wang CL,Li HQ,Meng WD,Qing FL

    更新日期:2005-10-15 00:00:00

  • N-[1-(2-Phenylethyl)pyrrolidin-3-yl]-1-adamantanecarboxamides as novel 5-HT2 receptor antagonists.

    abstract::A series of 1-adamantanecarboxamides was synthesized and examined for their potency as a selective 5-HT2 receptor antagonist. We found (S)-N-[1-[2-(4-fluorophenyl)ethyl]pyrrolidin-3-yl]-1-adamantane carboxamide hydrochloride hydrate (10-(S), Y-39241) to have a high affinity and selectivity for 5-HT2 receptors, and thi...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(00)00492-3

    authors: Fujio M,Kuroita T,Sakai Y,Nakagawa H,Matsumoto Y

    更新日期:2000-11-06 00:00:00

  • Antihypertensive activity of substituted 2,3,8,8a-tetrahydro-7H-oxazolo[3,2-a]pyridinedicarboxylate enantiomers.

    abstract::The synthesis and antihypertensive activity of racemates and enantiomers of substituted 2,3,8,8a-tetrahydro-7H-oxazolo[3,2-a]pyridinedicarboxylates have been reported. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(99)00691-5

    authors: Martín E,Morán A,Martín ML,San Román L,Puebla P,Medarde M,Caballero E,San Feliciano A

    更新日期:2000-02-21 00:00:00

  • Synthesis of new fluoroquinolones and evaluation of their in vitro activity on Toxoplasma gondii and Plasmodium spp.

    abstract::The synthesis of four new computer-designed fluoroquinolones which have been predicted by QSAR analysis to be active against the protozoa Toxoplasma gondii is described. These compounds are inhibitory in vitro for T. gondii. One of these compounds has a remarkably high activity comparable to that of trovafloxacin. It ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2004.03.070

    authors: Anquetin G,Rouquayrol M,Mahmoudi N,Santillana-Hayat M,Gozalbes R,Greiner J,Farhati K,Derouin F,Guedj R,Vierling P

    更新日期:2004-06-07 00:00:00

  • Discovery of 3-(2-aminoethyl)-5-(3-phenyl-propylidene)-thiazolidine-2,4-dione as a dual inhibitor of the Raf/MEK/ERK and the PI3K/Akt signaling pathways.

    abstract::A thiazolidine-2,4-dione derivative, 3-(2-aminoethyl)-5-(3-phenyl-propylidene)-thiazolidine-2,4-dione (2), was identified as a dual inhibitor of the Raf/MEK/ extracellular signal-regulated kinase (ERK) and the phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascades. The discovered compound inhibited cell prolifera...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2010.06.030

    authors: Li Q,Wu J,Zheng H,Liu K,Guo TL,Liu Y,Eblen ST,Grant S,Zhang S

    更新日期:2010-08-01 00:00:00

  • Synthesis and biological activities of novel 4"-alkylidene avermectin derivatives.

    abstract::Horner-Emmons reaction of 4"-dehydro-5-O-TBDMS-avermectin B(1a) with a variety of phosphorus ylides using LHMDS gave novel 4"-alkylidene avermectin derivatives in high yields. Further modifications led to derivatives bearing diverse functional groups. The new avermectin derivatives showed potent growth inhibitory acti...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2003.09.003

    authors: Nagai K,Sunazuka T,Shiomi K,Harder A,Turberg A,Omura S

    更新日期:2003-11-17 00:00:00

  • A dual fluorinated and iodinated radiotracer for PET and SPECT imaging of β-amyloid plaques in the brain.

    abstract::We report a fluorinated and iodinated radiotracer as a probe for PET/SPECT to detect of β-amyloid (Aβ) plaques in the brain of patients with Alzheimer's disease (AD). We successfully designed and synthesized the fluorinated and iodinated aurone derivative (3) and its radiolabels ([(125)I]3 and [(18)F]3). In binding ex...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2011.08.063

    authors: Watanabe H,Ono M,Kimura H,Kagawa S,Nishii R,Fuchigami T,Haratake M,Nakayama M,Saji H

    更新日期:2011-11-01 00:00:00

  • An efficient synthetic route for preparation of antimycobacterial wollamides and evaluation of their in vitro and in vivo efficacy.

    abstract::A convenient solid phase peptide synthetic (SPPS) route is reported for the preparation of antimycobacterial wollamides. The method is based on on-resin head-to-tail cyclization and is fast, efficient and amenable to automation. The in vitro antimycobacterial activities of the newly synthesized wollamides were evaluat...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2018.07.021

    authors: Asfaw H,Wetzlar T,Martinez-Martinez MS,Imming P

    更新日期:2018-09-15 00:00:00

  • Rapid nuclear import of short nucleic acids.

    abstract::Exogenous short-chain nucleic acids undergo rapid import into the nucleus. Fluorescence-labeled dT1-13 DNA microinjected into the cytoplasm domain of a HeLa cell was rapidly imported into the nucleus domain within 1min. This is much more rapid than what has been observed for intracellular diffusion of small molecules....

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2016.08.085

    authors: Kitagawa M,Okamoto A

    更新日期:2016-10-01 00:00:00

  • Synthesis and in vivo evaluation of 3,4-disubstituted gababutins.

    abstract::A range of 3,4-alkylated five-membered ring derivatives of gabapentin were synthesised. One compound (21) had an excellent level of potency against alpha(2)delta and was profiled in in vivo models of pain and anxiety. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2009.10.121

    authors: Blakemore DC,Bryans JS,Carnell P,Field MJ,Kinsella N,Kinsora JK,Meltzer LT,Osborne SA,Thompson LR,Williams SC

    更新日期:2010-01-01 00:00:00

  • Optimization of benzimidazole series as opioid receptor-like 1 (ORL1) antagonists: SAR study directed toward improvement of selectivity over hERG activity.

    abstract::A structure-activity relationship (SAR) study on the benzimidazole series of opioid receptor-like 1 (ORL1) antagonists related to 1 is described. Optimization of 1 by introduction of a hydrophilic substituent into the thioether part resulted in identification of potent ORL1 antagonists with high selectivity over bindi...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2009.04.022

    authors: Kobayashi K,Kato T,Yamamoto I,Shimizu A,Mizutani S,Asai M,Kawamoto H,Ito S,Yoshizumi T,Hirayama M,Ozaki S,Ohta H,Okamoto O

    更新日期:2009-06-01 00:00:00

  • Zwitterionic uracil derivatives as potent GnRH receptor antagonists with improved pharmaceutical properties.

    abstract::A novel series of potent zwitterionic uracil GnRH antagonists were discovered that showed reduced liability for CYP3A4 enzyme inhibition. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2008.07.059

    authors: Regan CF,Guo Z,Chen Y,Huang CQ,Chen M,Jiang W,Rueter JK,Coon T,Chen C,Saunders J,Brown MS,Betz SF,Struthers RS,Yang C,Wen J,Madan A,Zhu YF

    更新日期:2008-08-15 00:00:00

  • Novel targeting strategy based on multimeric ligands for drug delivery and molecular imaging: homooligomers of alpha-MSH.

    abstract::Homooligomers constructed with 4- and 6-amino acid fragments of melanocortin (alpha-MSH) bind with higher affinity and with apparent cooperativity to melanocortin receptor, compared to their constituent monomers. Individual ligands were tethered with various spacers of different length and rigidity and the influence o...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2003.09.079

    authors: Vagner J,Handl HL,Gillies RJ,Hruby VJ

    更新日期:2004-01-05 00:00:00