Salicylanilide Analog Minimizes Relapse of Clostridioides difficile Infection in Mice.

Abstract:

:Clostridioides difficile infection (CDI) causes serious and sometimes fatal symptoms like diarrhea and pseudomembranous colitis. Although antibiotics for CDI exist, they are either expensive or cause recurrence of the infection due to their altering the colonic microbiota, which is necessary to suppress the infection. Here, we leverage a class of known membrane-targeting compounds that we previously showed to have broad inhibitory activity across multiple Clostridioides difficile strains while preserving the microbiome to develop an efficacious agent. A new series of salicylanilides was synthesized, and the most potent analog was selected through an in vitro inhibitory assay to evaluate its pharmacokinetic parameters and potency in a CDI mouse model. The results revealed reduced recurrence of CDI and diminished disturbance of the microbiota in mice compared to standard-of-care vancomycin, thus paving the way for novel therapy that can potentially target the cell membrane of C. difficile to minimize relapse in the recovering patient.

journal_name

J Med Chem

authors

Blake S,Thanissery R,Rivera AJ,Hixon MS,Lin M,Theriot CM,Janda KD

doi

10.1021/acs.jmedchem.0c00123

subject

Has Abstract

pub_date

2020-07-09 00:00:00

pages

6898-6908

issue

13

eissn

0022-2623

issn

1520-4804

journal_volume

63

pub_type

杂志文章
  • Modulation of cell differentiation, proliferation, and tumor growth by dihydrobenzyloxopyrimidine non-nucleoside reverse transcriptase inhibitors.

    abstract::A series of 5-alkyl-2-(alkylthio)-6-(1-(2,6-difluorophenyl)propyl)-3,4-dihydropyrimidin-4(3H)-one derivatives (3a-h) belonging to the F(2)-DABOs class of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) are endowed with a strong antiproliferative effect and induce cytodifferentiation in A375 melanoma cel...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm200734j

    authors: Sbardella G,Mai A,Bartolini S,Castellano S,Cirilli R,Rotili D,Milite C,Santoriello M,Orlando S,Sciamanna I,Serafino A,Lavia P,Spadafora C

    更新日期:2011-08-25 00:00:00

  • Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.

    abstract::HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimizatio...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm400164c

    authors: Jiang Y,Andrews SW,Condroski KR,Buckman B,Serebryany V,Wenglowsky S,Kennedy AL,Madduru MR,Wang B,Lyon M,Doherty GA,Woodard BT,Lemieux C,Geck Do M,Zhang H,Ballard J,Vigers G,Brandhuber BJ,Stengel P,Josey JA,Beigelm

    更新日期:2014-03-13 00:00:00

  • 4-Aryl-1,2,3-triazole: a novel template for a reversible methionine aminopeptidase 2 inhibitor, optimized to inhibit angiogenesis in vivo.

    abstract::Inhibitors of human methionine aminopeptidase type 2 (hMetAP2) are of interest as potential treatments for cancer. A new class of small molecule reversible inhibitors of hMetAP2 was discovered and optimized, the 4-aryl-1,2,3-triazoles. Compound 24, a potent inhibitor of cobalt-activated hMetAP2, also inhibits human an...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm050408c

    authors: Kallander LS,Lu Q,Chen W,Tomaszek T,Yang G,Tew D,Meek TD,Hofmann GA,Schulz-Pritchard CK,Smith WW,Janson CA,Ryan MD,Zhang GF,Johanson KO,Kirkpatrick RB,Ho TF,Fisher PW,Mattern MR,Johnson RK,Hansbury MJ,Winkler JD,

    更新日期:2005-09-08 00:00:00

  • Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains.

    abstract::Bromodomains (BD) are readers of lysine acetylation marks present in numerous proteins associated with chromatin. Here we describe a dual inhibitor of the bromodomain and PHD finger (BRPF) family member BRPF2 and the TATA box binding protein-associated factors TAF1 and TAF1L. These proteins are found in large chromati...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/acs.jmedchem.7b00306

    authors: Bouché L,Christ CD,Siegel S,Fernández-Montalván AE,Holton SJ,Fedorov O,Ter Laak A,Sugawara T,Stöckigt D,Tallant C,Bennett J,Monteiro O,Díaz-Sáez L,Siejka P,Meier J,Pütter V,Weiske J,Müller S,Huber KVM,Hartung IV,H

    更新日期:2017-05-11 00:00:00

  • Latent alkyl isocyanates as inhibitors of aldehyde dehydrogenase in vivo.

    abstract::On the basis of our previous observation that N1-alkyl substituted chlorpropamide derivatives when administered to rats nonenzymatically eliminated n-propyl isocyanate, a known inhibitor of aldehyde dehydrogenase (AlDH), we have synthesized other latentiated n-propyl isocyanates as in vivo inhibitors of AlDH. N1-Allyl...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00050a018

    authors: Nagasawa HT,Elberling JA,Goon DJ,Shirota FN

    更新日期:1994-11-25 00:00:00

  • Theoretical model-based equations for the linear free energy relationships of the biological activity of ionizable substances. 1. Equilibrium-controlled potency.

    abstract::Because of the ambiguities of how to treat ionization in empirical equations which relate biological activity to partition coefficient by use of a (log P)2 term, a theoretical approach to the problem is proposed. Based on a simplified view of assays of potency following in vitro or continuous infusion administration o...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00230a012

    authors: Martin YC,Hackbarth JJ

    更新日期:1976-08-01 00:00:00

  • Design, synthesis, and SAR of potent and selective dipeptide-derived inhibitors for dipeptidyl peptidases.

    abstract::In this paper we report the systematic search for new, potent, and selective DPP II inhibitors. A study of the structure-activity relationship was conducted starting from aminoacyl pyrrolidides as lead compounds. Rational exploration of the P(1) and P(2) building blocks led to the discovery of some very potent DPP II ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm0308803

    authors: Senten K,Van der Veken P,De Meester I,Lambeir AM,Scharpé S,Haemers A,Augustyns K

    更新日期:2003-11-06 00:00:00

  • Adamantyl Antiestrogens with Novel Side Chains Reveal a Spectrum of Activities in Suppressing Estrogen Receptor Mediated Activities in Breast Cancer Cells.

    abstract::To search for new antiestrogens more effective in treating breast cancers, we explored alternatives to the acrylic acid side chain used in many antiestrogens. To facilitate our search, we used a simple adamantyl ligand core that by avoiding stereochemical issues enabled rapid synthesis of acrylate ketone, ester, and a...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/acs.jmedchem.7b00585

    authors: Min J,Guillen VS,Sharma A,Zhao Y,Ziegler Y,Gong P,Mayne CG,Srinivasan S,Kim SH,Carlson KE,Nettles KW,Katzenellenbogen BS,Katzenellenbogen JA

    更新日期:2017-07-27 00:00:00

  • A novel approach for the development of selective Cdk4 inhibitors: library design based on locations of Cdk4 specific amino acid residues.

    abstract::Identification of a selective inhibitor for a particular protein kinase without inhibition of other kinases is critical for use as a biological tool or drug. However, this is very difficult because there are hundreds of homologous kinases and their kinase domains including the ATP binding pocket have a common folding ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm010326y

    authors: Honma T,Yoshizumi T,Hashimoto N,Hayashi K,Kawanishi N,Fukasawa K,Takaki T,Ikeura C,Ikuta M,Suzuki-Takahashi I,Hayama T,Nishimura S,Morishima H

    更新日期:2001-12-20 00:00:00

  • Potential antitumor agents. 62. Structure-activity relationships for tricyclic compounds related to the colon tumor active drug 9-oxo-9H-xanthene-4-acetic acid.

    abstract::A series of tricyclic analogues of 9-oxo-9H-xanthene-4-acetic acid have been prepared and evaluated for their ability to cause hemorrhagic necrosis in subcutaneously implanted colon 38 tumors in mice, in an effort to extend the structure-activity relationships for this series. As was found previously with analogues of...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00106a003

    authors: Rewcastle GW,Atwell GJ,Palmer BD,Boyd PD,Baguley BC,Denny WA

    更新日期:1991-02-01 00:00:00

  • Enzymatic release of antitumor ether lipids by specific phospholipase A2 activation of liposome-forming prodrugs.

    abstract::An enzymatically activated liposome-based drug-delivery concept involving masked antitumor ether lipids (AELs) has been investigated. This concept takes advantage of the cytotoxic properties of AEL drugs as well as the membrane permeability enhancing properties of these molecules, which can lead to enhanced drug diffu...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm031029r

    authors: Andresen TL,Davidsen J,Begtrup M,Mouritsen OG,Jørgensen K

    更新日期:2004-03-25 00:00:00

  • Synthesis and biological properties of benzothiazole, benzoxazole, and chromen-4-one analogues of the potent antitumor agent 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (PMX 610, NSC 721648).

    abstract::New fluorinated 2-aryl-benzothiazoles, -benzoxazoles, and -chromen-4-ones have been synthesized and their activity against MCF-7 and MDA 468 breast cancer cell lines compared with the potent antitumor benzothiazole 5. Analogues such as 9a, b and 12a, d yielded submicromolar GI50 values in both cell lines; however, non...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm800418z

    authors: Aiello S,Wells G,Stone EL,Kadri H,Bazzi R,Bell DR,Stevens MF,Matthews CS,Bradshaw TD,Westwell AD

    更新日期:2008-08-28 00:00:00

  • Hydroxyphthalocyanines as potential photodynamic agents for cancer therapy.

    abstract::A series of benzyl-substituted phthalonitriles, substituted at the 3-, 4-, and 4,5-positions, underwent varied condensations with phthalonitrile to give a series of protected (monohydroxy- and polyhydroxyphthalocyaninato)zinc(II) derivatives which were readily cleaved to give several hydroxyphthalocyanines (ZnPc) (pht...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm970336s

    authors: Hu M,Brasseur N,Yildiz SZ,van Lier JE,Leznoff CC

    更新日期:1998-05-21 00:00:00

  • Characterization of the drug binding specificity of rat liver fatty acid binding protein.

    abstract::Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in the cytosolic solubilization of fatty acids during fat absorption. In the current studies, the interaction of L-FABP with a range of lipophilic drugs has been evaluated to explore the potential for L-FABP to provide an ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm701192w

    authors: Chuang S,Velkov T,Horne J,Porter CJ,Scanlon MJ

    更新日期:2008-07-10 00:00:00

  • Design, Synthesis, and Bioactivation of O-Glycosylated Prodrugs of the Natural Nitric Oxide Precursor N(ω)-Hydroxy-l-arginine.

    abstract::Naturally occurring N(ω)-hydroxy-l-arginine (NOHA, 1) is the best substrate of NO synthases (NOS). The development of stable and bioavailable prodrugs would provide a pharmacologically valuable strategy for the treatment of cardiovascular diseases that are associated with endothelial dysfunction. To improve NOHAs drug...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/acs.jmedchem.6b00810

    authors: Litty FA,Gudd J,Girreser U,Clement B,Schade D

    更新日期:2016-09-08 00:00:00

  • Synthesis and evaluation of nitroheterocyclic carbamate prodrugs for use with nitroreductase-mediated gene-directed enzyme prodrug therapy.

    abstract::A variety of nitroheterocyclic carbamate prodrugs of phenylenediamine mustard and 5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-benz[e]indoline (amino-seco-CBI-TMI), covering a wide range of reduction potential, were prepared and evaluated for use in gene-directed enzyme prodrug ther...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm030308b

    authors: Hay MP,Anderson RF,Ferry DM,Wilson WR,Denny WA

    更新日期:2003-12-04 00:00:00

  • Tyrphostins. 3. Structure-activity relationship studies of alpha-substituted benzylidenemalononitrile 5-S-aryltyrphostins.

    abstract::In this study we describe an extension of our previous studies on cis-benzylidenemalononitrile tyrphostins. We have introduced S-aryl substituents in the 5 position (meta vis-a-vis the malononitrile moiety). We find that these compounds are potent blockers of EGFR kinase and its homolog HER-2 kinase. Interestingly, we...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00075a010

    authors: Gazit A,Osherov N,Posner I,Bar-Sinai A,Gilon C,Levitzki A

    更新日期:1993-11-12 00:00:00

  • Structure-activity relationships and pharmacophore model of a noncompetitive pyrazoline containing class of GluN2C/GluN2D selective antagonists.

    abstract::Here we describe the synthesis and structure-activity relationship for a class of pyrazoline-containing dihydroquinolone negative allosteric modulators of the NMDA receptor that show strong subunit selectivity for GluN2C- and GluN2D-containing receptors over GluN2A- and GluN2B-containing receptors. Several members of ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm400652r

    authors: Acker TM,Khatri A,Vance KM,Slabber C,Bacsa J,Snyder JP,Traynelis SF,Liotta DC

    更新日期:2013-08-22 00:00:00

  • Synthesis of Novel Potent Archazolids: Pharmacology of an Emerging Class of Anticancer Drugs.

    abstract::Vacuolar type ATPase (V-ATPase) has recently emerged as a promising novel anticancer target based on extensive in vitro and in vivo studies with archazolids, complex polyketide macrolides, which present the most potent V-ATPase inhibitors known to date. Herein, we report a biomimetic, one-step preparation of archazoli...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/acs.jmedchem.9b01887

    authors: Scheeff S,Rivière S,Ruiz J,Abdelrahman A,Schulz-Fincke AC,Köse M,Tiburcy F,Wieczorek H,Gütschow M,Müller CE,Menche D

    更新日期:2020-02-27 00:00:00

  • Development of novel potent orally bioavailable oseltamivir derivatives active against resistant influenza A.

    abstract::With the emergence of oseltamivir-resistant influenza viruses and in view of a highly pathogenic flu pandemic, it is important to develop new anti-influenza agents. Here, the development of neuraminidase (NA) inhibitors that were designed to overcome resistance mechanisms along with unfavorable pharmacokinetic (PK) pr...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm401492x

    authors: Schade D,Kotthaus J,Riebling L,Kotthaus J,Müller-Fielitz H,Raasch W,Koch O,Seidel N,Schmidtke M,Clement B

    更新日期:2014-02-13 00:00:00

  • Ketanserin analogues: structure-affinity relationships for 5-HT2 and 5-HT1C serotonin receptor binding.

    abstract::Ketanserin is the prototypic 5-HT2 serotonin antagonist; although it has been an important tool for the study of serotonin pharmacology, it has had relatively little impact on drug design because remarkably little is known about its structure-affinity relationships. Furthermore, ketanserin also binds at 5-HT1C recepto...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00104a017

    authors: Herndon JL,Ismaiel A,Ingher SP,Teitler M,Glennon RA

    更新日期:1992-12-25 00:00:00

  • Linear regression analysis of inhibitory potency of organic disulfides against Histoplasma capsulatum.

    abstract::The Free-Wilson equations are derived for the case of symmetrical substitution and are applied, in four modifications, to in vitro inhibitory activity of 77 organic disulfides against Histoplasma capsulatum. Substituent constants are listed to aid in the design of new inhibitory agents against this human pathogen (and...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00238a004

    authors: Schaad LJ,Werner RH,Dillon L,Field L,Tate CE

    更新日期:1975-04-01 00:00:00

  • Lysosomotropic agents. 7. Broad-spectrum antifungal activity of lysosomotropic detergents.

    abstract::Lysosomotropic detergents, which kill mammalian cells by disrupting lysosomal membranes, have now been found to be antifungals also. All strains in our assay are susceptible. The mode of action is as yet undetermined, but intracellular vacuoles may be the primary targets. ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00391a043

    authors: Firestone RA,Pisano JM,Garrity GM,Fromtling RA,Zimmerman SB

    更新日期:1987-08-01 00:00:00

  • Examination of the role of the acidic hydrogen in imparting selectivity of 7-(aminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (SK&F 29661) toward inhibition of phenylethanolamine N-methyltransferase vs the alpha 2-adrenoceptor.

    abstract::7-(Aminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (SK&F 29661, 1) is a potent inhibitor of the enzyme phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28). In contrast to other inhibitors of PNMT, it is also highly selective toward PNMT in comparison with its affinity toward the alpha 2-adrenoceptor (PNMT Ki = 0....

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm960235e

    authors: Grunewald GL,Dahanukar VH,Caldwell TM,Criscione KR

    更新日期:1997-12-05 00:00:00

  • Development of purine-derived 18F-labeled pro-drug tracers for imaging of MRP1 activity with PET.

    abstract::Multidrug resistance-associated protein 1 (MRP1) is a drug efflux transporter that has been implicated in the pathology of several neurological diseases and is associated with development of multidrug resistance. To enable measurement of MRP1 function in the living brain, a series of 6-halopurines decorated with fluor...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm401764a

    authors: Galante E,Okamura T,Sander K,Kikuchi T,Okada M,Zhang MR,Robson M,Badar A,Lythgoe M,Koepp M,Årstad E

    更新日期:2014-02-13 00:00:00

  • Synthesis of phosphocholine and quaternary amine ether lipids and evaluation of in vitro antineoplastic activity.

    abstract::The in vitro antineoplastic activity of many phosphorus-containing (e.g., phosphocholines) and non-phosphorus-containing (e.g., quaternary ammonium salts) ether lipids has been evaluated in the HL-60 promyelocytic cell line. These compounds are analogues of ET-18-OMe (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphochol...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00066a011

    authors: Morris-Natschke SL,Gumus F,Marasco CJ Jr,Meyer KL,Marx M,Piantadosi C,Layne MD,Modest EJ

    更新日期:1993-07-09 00:00:00

  • Identification of highly efficacious glucocorticoid receptor agonists with a potential for reduced clinical bone side effects.

    abstract::Synthesis and structure-activity relationship (SAR) of a series of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain "diazaindole" moieties and display different transcriptional regulatory profiles in vitro and are considered "dissociated" between gene transrepression and transa...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm4019178

    authors: Harcken C,Riether D,Kuzmich D,Liu P,Betageri R,Ralph M,Emmanuel M,Reeves JT,Berry A,Souza D,Nelson RM,Kukulka A,Fadra TN,Zuvela-Jelaska L,Dinallo R,Bentzien J,Nabozny GH,Thomson DS

    更新日期:2014-02-27 00:00:00

  • Flavones. 2. Synthesis and structure-activity relationship of flavodilol and its analogues, a novel class of antihypertensive agents with catecholamine depleting properties.

    abstract::(3-Phenyl-7-flavonoxy)propanolamines have been shown to exhibit antihypertensive activity in spontaneously hypertensive rats. Although they are structurally similar to classical beta-adrenergic blocking compounds, their activity is not due to inhibition of beta-adrenoceptors. In the present study, a series of simple f...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00121a034

    authors: Wu ES,Cole TE,Davidson TA,Dailey MA,Doring KG,Fedorchuk M,Loch JT 3rd,Thomas TL,Blosser JC,Borrelli AR

    更新日期:1989-01-01 00:00:00

  • Synthesis and adrenergic activity of ring-fluorinated phenylephrines.

    abstract::2-Fluoro-, 4-fluoro-, and 6-fluorophenylephrine (6-FPE) were synthesized from the corresponding fluorinated 3-hydroxybenzaldehydes. New routes to 2-fluoro- and 6-fluoro-3-hydroxybenzaldehydes were developed based on regioselective lithiation of 2- and 4-[(dimethyl-tert-butylsilyl)oxy]fluorobenzene ortho to fluorine. A...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00160a030

    authors: Kirk KL,Olubajo O,Buchhold K,Lewandowski GA,Gusovsky F,McCulloh D,Daly JW,Creveling CR

    更新日期:1986-10-01 00:00:00

  • 6,7-Dichloro-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline . A structurally novel beta-adrenergic receptor blocking agent.

    abstract::Replacement of the catecholic hydroxyl groups of the beta-adrenergic receptor agonist 6,7-dihydroxy-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline (trimetoquinol) with chloro substituents results in a compound with marked beta-adrenoceptor antagonist properties. This, therefore, parallels the similar transf...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00161a039

    authors: Kaiser C,Oh HJ,Garcia-Slanga BJ,Sulpizio AC,Hieble JP,Wawro JE,Kruse LI

    更新日期:1986-11-01 00:00:00