Synthesis and antibacterial activity of novel 4-pyrrolidinylthio carbapenems Part IV. 2-Alkyl substituents containing cationic heteroaromatics linked via a C-C bond.

Abstract:

:The synthesis and biological activity of a novel series of 2-alkyl-4-pyrrolidinylthio-beta-methylcarbapenems containing a variety of cationic heteroaromatic substituents linked via a C-C bond is described. As a result of these studies, we selected FR21818 (In) as a candidate compound for development. FR21818 exhibited a well balanced spectrum of antibacterial activity, including Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA), excellent urinary recovery, good stability against renal dehydropeptidase-I (DHP-I). no antigenicity and mutagenicity, weak toxicities, and good efficacy and therapeutic effect on mice systemic infections. Affinities to PBP's, permeability of outer membrane, and plasma levels in mice, dog, and cynomolgous monkey of FR21818 are also reported.

journal_name

Bioorg Med Chem

authors

Zam HA,Barrett D,Tanaka A,Sasaki H,Matsuda K,Sakurai M,Terasawa T,Shirai F,Chiba T,Matsumoto Y,Tawara S

doi

10.1016/s0968-0896(00)00314-x

subject

Has Abstract

pub_date

2001-04-01 00:00:00

pages

961-82

issue

4

eissn

0968-0896

issn

1464-3391

pii

S096808960000314X

journal_volume

9

pub_type

杂志文章
  • Evaluation of fosmidomycin analogs as inhibitors of the Synechocystis sp. PCC6803 1-deoxy-D-xylulose 5-phosphate reductoisomerase.

    abstract::Analogs of the antibiotic fosmidomycin, an inhibitor of the methylerythritol phosphate pathway to isoprenoids, were synthesized and evaluated against the recombinant Synechocystis sp. PCC6803 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR). Fosfoxacin, the phosphate analog of fosmidomycin, and its acetyl congene...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2005.11.012

    authors: Woo YH,Fernandes RP,Proteau PJ

    更新日期:2006-04-01 00:00:00

  • Axial chirality and affinity at the GABA(A) receptor of pyrimido[1,2-a][1,4]benzodiazepines and related compounds.

    abstract::The pyrimido[1,2-a][1,4]benzodiazepines (1a-c) and the 8-membered analogues (diazocines 2a and 2b) were separated into their atropisomers with HPLC on a chiral column. High stereochemical stability was observed in the atropisomer of the 8-membered derivatives (2a and 2b), and the 1,4-benzodiazepine (1c) with 2'-chloro...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2008.09.037

    authors: Lee S,Kamide T,Tabata H,Takahashi H,Shiro M,Natsugari H

    更新日期:2008-11-01 00:00:00

  • Alkyne derivatives of isocoumarins as clickable activity-based probes for serine proteases.

    abstract::Activity-based probes (ABPs) have found increasing use in functional proteomics studies. Recently, ABPs that can be employed in combination with click chemistry gained particular attention due to their flexible application in vitro and in vivo. Moreover, there is a continuous need for new ABPs that target small subset...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2011.03.014

    authors: Haedke U,Götz M,Baer P,Verhelst SH

    更新日期:2012-01-15 00:00:00

  • Effective syntheses of 2',4'-BNANC monomers bearing adenine, guanine, thymine, and 5-methylcytosine, and the properties of oligonucleotides fully modified with 2',4'-BNANC.

    abstract::We efficiently synthesized 2'-O,4'-C-aminomethylene-bridged nucleic acid (2',4'-BNANC) monomers bearing the four nucleobases, guanine, adenine, thymine, and 5-methylcytosine and incorporated these monomers into oligonucleotides. Initially, we carried out the transglycosylation reaction on several 2'-O-substituted 5-me...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2019.02.034

    authors: Fujisaka A,Hari Y,Takuma H,Rahman SMA,Yoshikawa H,Pang J,Imanishi T,Obika S

    更新日期:2019-04-15 00:00:00

  • 2D QSAR and similarity studies on cruzain inhibitors aimed at improving selectivity over cathepsin L.

    abstract::Hologram quantitative structure-activity relationships (HQSAR) were applied to a data set of 41 cruzain inhibitors. The best HQSAR model (Q(2)=0.77; R(2)=0.90) employing Surflex-Sim, as training and test sets generator, was obtained using atoms, bonds, and connections as fragment distinctions and 4-7 as fragment size....

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2007.10.048

    authors: Freitas RF,Oprea TI,Montanari CA

    更新日期:2008-01-15 00:00:00

  • Selective inhibition of methoxyflavonoids on human CYP1B1 activity.

    abstract::Cytochrome P450 (CYP) 1B1 catalyzes 17beta-estradiol (E(2)) to predominantly carcinogenic 4-hydroxy-E(2), whereas CYP1A1 and 1A2 convert E(2) to non-carcinogenic 2-hydroxy-E(2). Hence, selective inhibition of CYP1B1 is recognized to be beneficial for the prevention of E(2) related breast cancer. In this study, we firs...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2010.07.020

    authors: Takemura H,Itoh T,Yamamoto K,Sakakibara H,Shimoi K

    更新日期:2010-09-01 00:00:00

  • Comprehensive structure-activity-relationship of azaindoles as highly potent FLT3 inhibitors.

    abstract::Acute myeloid leukemia (AML) is characterized by fast progression and low survival rates, in which Fms-like tyrosine kinase 3 (FLT3) receptor mutations have been identified as a driver mutation in cancer progression in a subgroup of AML patients. Clinical trials have shown emergence of drug resistant mutants, emphasiz...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2019.01.006

    authors: Grimm SH,Gagestein B,Keijzer JF,Liu N,Wijdeven RH,Lenselink EB,Tuin AW,van den Nieuwendijk AMCH,van Westen GJP,van Boeckel CAA,Overkleeft HS,Neefjes J,van der Stelt M

    更新日期:2019-03-01 00:00:00

  • Synthesis of oligodeoxynucleotides incorporating 2-N-carbamoylguanine and evaluation of the hybridization properties.

    abstract::Previously, we reported 2-N-carbamoylguanine (cmG) as a guanine analog. We further studied the synthetic protocol and hybridization properties of oligodeoxynucleotides (ODNs) incorporating cmG. These ODNs were synthesized using the phosphoramidite of cmG without protection of the 6-O position. However, the isolated pr...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2008.11.042

    authors: Sasami T,Odawara Y,Ohkubo A,Sekine M,Seio K

    更新日期:2009-02-01 00:00:00

  • Design and synthesis of spirotryprostatin-inspired diketopiperazine systems from prolyl spirooxoindolethiazolidine derivatives.

    abstract::Based on the spirotryprostatin-A structure, we designed, synthesized, and evaluated different series of compounds belonging to the diketopiperazine structural class as potential cell cycle modulators and cytotoxic agents. Starting from the spirooxoindolthiazolidine scaffold, amide coupling with Pro derivatives and int...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2010.04.079

    authors: Bertamino A,Aquino C,Sala M,Simone Nd,Mattia CA,Erra L,Musella S,Iannelli P,Carotenuto A,Grieco P,Novellino E,Campiglia P,Gomez-Monterrey I

    更新日期:2010-06-15 00:00:00

  • Piperidine variations in search for non-imidazole histamine H(3) receptor ligands.

    abstract::Synthesis and biological evaluation of the novel histamine H(3) receptor ligands is described. Two series of ethers (aliphatic and aromatic) have been prepared by four different methods. Compounds were evaluated for their affinities at recombinant human H(3) receptor stably expressed in CHO cells. The ethers show from...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2008.07.071

    authors: Łazewska D,Kuder K,Ligneau X,Schwartz JC,Schunack W,Stark H,Kieć-Kononowicz K

    更新日期:2008-09-15 00:00:00

  • Synthesis and preliminary cytotoxicity study of glucuronide derivatives of CC-1065 analogues.

    abstract::Glucuronide derivatives of CBI-bearing CC-1065 analogues have been synthesized, and their cytotoxicities tested against U937 leukemia cells. The new compounds show potent antitumor activity in vitro. Compounds 1 and 2, and their corresponding glucuronides 3 and 4 have IC(50) values of 0.6, 0.1, 1.4 and 0.6 nM, respect...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/s0968-0896(02)00603-x

    authors: Wang Y,Yuan H,Wright SC,Wang H,Larrick JW

    更新日期:2003-04-03 00:00:00

  • Induction of potent cell growth inhibition by schizophyllan/K-ras antisense complex in combination with gemcitabine.

    abstract::Antisense oligonucleotides (AS-ODNs) specifically hybridize with target mRNAs, resulting in interference with the splicing mechanism or the regulation of protein translation. In our previous reports, we demonstrated that β-glucan schizophyllan (SPG) can form a complex with AS-ODNs attached with oligo deoxyadenosine dA...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2020.115668

    authors: Sasaki S,Izumi H,Morimoto Y,Sakurai K,Mochizuki S

    更新日期:2020-09-15 00:00:00

  • Predicting multiple drugs side effects with a general drug-target interaction thermodynamic Markov model.

    abstract::Most of present molecular descriptors just consider the molecular structure. In the present article we pretend extending the use of Markov chain models to define novel molecular descriptors, which consider in addition to molecular structure other parameters like target site or toxic effect. Specifically, this molecula...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2004.11.030

    authors: González-Díaz H,Cruz-Monteagudo M,Molina R,Tenorio E,Uriarte E

    更新日期:2005-02-15 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

  • Design, synthesis, and biological evaluation of callophycin A and analogues as potential chemopreventive and anticancer agents.

    abstract::Callophycin A was originally isolated from the red algae Callophycus oppositifolius and shown to mediate anticancer and cytotoxic effects. In our collaborative effort to identify potential chemopreventive and anticancer agents with enhanced potency and selectivity, we employed a tetrahydro-β-carboline-based template i...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2011.09.020

    authors: Shen L,Park EJ,Kondratyuk TP,Guendisch D,Marler L,Pezzuto JM,Wright AD,Sun D

    更新日期:2011-11-01 00:00:00

  • The synthesis of alpha,beta-unsaturated carbonyl derivatives with the ability to inhibit both glutathione S-transferase P1-1 activity and the proliferation of leukemia cells.

    abstract::Ethacrynic acid (EA), an alpha,beta-unsaturated carbonyl compound, is a glutathione S-transferase P1-1 (GSTP1-1) inhibitor. Twenty-one novel EA derivatives have been synthesized. The effects of these compounds on GSTP1-1 activity and on the proliferation of human leukemia HL-60 cells have been determined. Compounds wi...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2007.01.037

    authors: Zhao G,Liu C,Wang R,Song D,Wang X,Lou H,Jing Y

    更新日期:2007-04-01 00:00:00

  • Identification of new γ-hydroxybutenolides that preferentially inhibit the activity of mPGES-1.

    abstract::Microsomal prostaglandin E(2) synthase-1 (mPGES-1) has been recognized as novel, promising drug target for anti-inflammatory and anticancer drugs. mPGES-1 catalyzes the synthesis of the inducible prostaglandin E(2) in response to pro-inflammatory stimuli, rendering this enzyme extremely interesting in drug discovery p...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2012.06.032

    authors: De Simone R,Bruno I,Riccio R,Stadler K,Bauer J,Schaible AM,Laufer S,Werz O

    更新日期:2012-08-15 00:00:00

  • Targeting the Warburg Effect in cancer; relationships for 2-arylpyridazinones as inhibitors of the key glycolytic enzyme 6-phosphofructo-2-kinase/2,6-bisphosphatase 3 (PFKFB3).

    abstract::High-throughput screening of a small-molecule library identified a 5-triazolo-2-arylpyridazinone as a novel inhibitor of the important glycolytic enzyme 6-phosphofructo-2-kinase/2,6-bisphosphatase 3 (PFKFB3). Such inhibitors are of interest due to PFKFB3's control of the important glycolytic pathway used by cancer cel...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2013.12.041

    authors: Brooke DG,van Dam EM,Watts CK,Khoury A,Dziadek MA,Brooks H,Graham LJ,Flanagan JU,Denny WA

    更新日期:2014-02-01 00:00:00

  • Chemical synthesis of tetracyclic terpenes and evaluation of antagonistic activity on endothelin-A receptors and voltage-gated calcium channels.

    abstract::A class of tetracyclic terpenes was synthesized and evaluated for antagonistic activity of endothelin-1 (ET-1) induced vasoconstriction and inhibitory activity of voltage-activated Ca(2+) channels. Three repeated Robinson annulation reactions were utilized to construct the tetracyclic molecules. A stereoselective redu...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2015.06.055

    authors: Lu J,Aguilar A,Zou B,Bao W,Koldas S,Shi A,Desper J,Wangemann P,Xie XS,Hua DH

    更新日期:2015-09-01 00:00:00

  • 3,5-Diaryl-1H-pyrazole as a molecular scaffold for the synthesis of apoptosis-inducing agents.

    abstract::The scaffold of 3,5-diaryl-1H-pyrazole was selected as a molecular template to synthesize novel growth-inhibitory agents in the present study. Our findings suggested that analogs bearing electron-withdrawing groups on one ring while electron-donating groups on another reveal significant activities. In particular, 26 b...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2010.03.016

    authors: Shaw AY,Liau HH,Lu PJ,Yang CN,Lee CH,Chen JY,Xu Z,Flynn G

    更新日期:2010-05-01 00:00:00

  • Piperidine and piperazine inhibitors of fatty acid amide hydrolase targeting excitotoxic pathology.

    abstract::FAAH inhibitors offer safety advantages by augmenting the anandamide levels "on demand" to promote neuroprotective mechanisms without the adverse psychotropic effects usually seen with direct and chronic activation of the CB1 receptor. FAAH is an enzyme implicated in the hydrolysis of the endocannabinoid N-arachidonoy...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2019.115096

    authors: Lamani M,Malamas MS,Farah SI,Shukla VG,Almeida MF,Weerts CM,Anderson J,Wood JT,Farizatto KLG,Bahr BA,Makriyannis A

    更新日期:2019-12-01 00:00:00

  • 3-(1-piperazinyl)-4,5-dihydro-1H-benzo[g]indazoles: high affinity ligands for the human dopamine D4 receptor with improved selectivity over ion channels.

    abstract::3-(4-Piperidinyl)-5-arylpyrazoles, such as 1, were selective for the cloned human dopamine D4 receptor (hD4), but also showed affinity at voltage sensitive calcium, sodium and potassium ion channels. A combination of substituent changes to reduce the basicity of the piperidine nitrogen and conformational restriction t...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/s0968-0896(98)00028-5

    authors: Collins I,Rowley M,Davey WB,Emms F,Marwood R,Patel S,Patel S,Fletcher A,Ragan IC,Leeson PD,Scott AL,Broten T

    更新日期:1998-06-01 00:00:00

  • Design and synthesis of novel pyrimido[4,5-b]azepine derivatives as HER2/EGFR dual inhibitors.

    abstract::A novel 7,6 fused bicyclic scaffold, pyrimido[4,5-b]azepine was designed to fit into the ATP binding site of the HER2/EGFR proteins. The synthesis of this scaffold was accomplished by an intramolecular Claisen-type condensation. As the results of optimization lead us to 4-anilino and 6-functional groups, we discovered...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2013.02.014

    authors: Kawakita Y,Seto M,Ohashi T,Tamura T,Yusa T,Miki H,Iwata H,Kamiguchi H,Tanaka T,Sogabe S,Ohta Y,Ishikawa T

    更新日期:2013-04-15 00:00:00

  • Preparation and biological properties of biotinylated PhTX derivatives.

    abstract::We report the synthesis of several highly functionalized biotinylated philanthotoxin (PhTX) analogues (7, 8, 10, 13-16) designed on the basis of earlier structure-activity relationship studies. Despite the extensive modifications, the binding to nicotinic acetylcholine receptor (nAChR) is in the low micromolar range a...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/s0968-0896(99)00054-1

    authors: Hashimoto M,Liu Y,Fang K,Li HY,Campiani G,Nakanishi K

    更新日期:1999-06-01 00:00:00

  • Natural products in crop protection.

    abstract::The tremendous increase in crop yields associated with the 'green' revolution has been possible in part by the discovery and utilization of chemicals for pest control. However, concerns over the potential impact of pesticides on human health and the environment has led to the introduction of new pesticide registration...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.1016/j.bmc.2009.01.046

    authors: Dayan FE,Cantrell CL,Duke SO

    更新日期:2009-06-15 00:00:00

  • Probes for narcotic receptor mediated phenomena. 47. Novel C4a- and N-substituted-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols.

    abstract::A series of N-methyl rac-cis-4a-aralkyl- and alkyl-substituted-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols have been prepared (2a-l) using a simple previously designed synthetic route, in order to find a ligand that would interact with both μ- and δ-opioid receptors. A C4a-phenethyl derivative 2a, was found t...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2013.02.060

    authors: Iyer MR,Rothman RB,Dersch CM,Jacobson AE,Rice KC

    更新日期:2013-06-01 00:00:00

  • Synthesis of functionalized 2-aryl-5-nitro-1H-indoles and their activity as bacterial NorA efflux pump inhibitors.

    abstract::In order to develop structure-activity relationships and to provide access to antibacterial agents for dual action studies, a variety of aryl group-substituted 2-aryl-5-nitro-1H-indoles were synthesized and the activity of the compounds assessed as inhibitors of the NorA multidrug resistance pump in the bacterium Stap...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2005.09.019

    authors: Samosorn S,Bremner JB,Ball A,Lewis K

    更新日期:2006-02-01 00:00:00

  • Halogenated derivatives QSAR model using spectral moments to predict haloacetic acids (HAA) mutagenicity.

    abstract::The risk of the presence of haloacetic acids in drinking water as chlorination by-products and the shortage of experimental mutagenicity data for most of them requires a research work. This paper describes a QSAR model to predict direct mutagenicity for these chemicals. The model, able to describe more than 90% of the...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2008.03.070

    authors: Pérez-Garrido A,González MP,Escudero AG

    更新日期:2008-05-15 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

  • Adenosine receptors: new opportunities for future drugs.

    abstract::This review summarises current knowledge on adenosine receptors, an important G protein-coupled receptor. The four known adenosine receptor subtypes A1, A2A, A2B, and A3 are discussed with special reference to the opportunities for drug development. ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.1016/s0968-0896(98)00038-8

    authors: Poulsen SA,Quinn RJ

    更新日期:1998-06-01 00:00:00