1,2,4-Triazolidine-3-thiones as Narrow Spectrum Antibiotics against Multidrug-Resistant Acinetobacter baumannii.


:With only two new classes of antibiotics developed in the last 40 years, novel antibiotics are desperately needed to combat the growing problem of multidrug-resistant and extensively drug resistant bacteria, particularly Gram-negative bacteria. Described in this letter is the synthesis and antibiotic activity of 1,2,4-triazolidine-3-thiones as narrow spectrum antibiotics. Optimization of the 1,2,4-triazolidine-3-thione scaffold identified a small molecule with potent antibiotic activity against multiple strains of multidrug-resistant and extensively drug-resistant Acinetobacter baumannii. This small molecule also shows single dose, in vivo activity in a Galleria mellonella infection model with A. baumannii and represents a promising start in the development of a class of drugs that can target this bacterial pathogen.


ACS Med Chem Lett


Huggins WM,Minrovic BM,Corey BW,Jacobs AC,Melander RJ,Sommer RD,Zurawski DV,Melander C




Has Abstract


2016-11-12 00:00:00










  • The impact of ionization States of matrix metalloproteinase inhibitors on docking-based inhibitor design.

    abstract::The influence of ionization states of hydroxamates and retrohydroxamates and the presence of zinc ions in the active site were investigated using the wild-type and E402Q mutant of MMP-9. The deprotonated hydroxamates showed a significantly enhanced enrichment factor in the presence of zinc ions. A pharmacophore model ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Zhong H,Wees MA,Faure TD,Carrillo C,Arbiser J,Bowen JP

    更新日期:2011-03-29 00:00:00

  • Pharmacophore-Based Design of New Chemical Scaffolds as Translational Readthrough-Inducing Drugs (TRIDs).

    abstract::Translational readthrough-inducing drugs (TRIDs) rescue the functional full-length protein expression in genetic diseases, such as cystic fibrosis, caused by premature termination codons (PTCs). Small molecules have been developed as TRIDs to trick the ribosomal machinery during recognition of the PTC. Herein we repor...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Tutone M,Pibiri I,Perriera R,Campofelice A,Culletta G,Melfi R,Pace A,Almerico AM,Lentini L

    更新日期:2020-02-18 00:00:00

  • Consequences of Depsipeptide Substitution on the ClpP Activation Activity of Antibacterial Acyldepsipeptides.

    abstract::The acyldepsipeptide (ADEP) antibiotics operate through a clinically unexploited mechanism of action and thus have attracted attention from several antibacterial development groups. The ADEP scaffold is synthetically tractable, and deep-seated modifications have produced extremely potent antibacterial leads against Gr...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Li Y,Lavey NP,Coker JA,Knobbe JE,Truong DC,Yu H,Lin YS,Nimmo SL,Duerfeldt AS

    更新日期:2017-10-19 00:00:00

  • Identification of 8-aminoadenosine derivatives as a new class of human concentrative nucleoside transporter 2 inhibitors.

    abstract::Purine-rich foods have long been suspected as a major cause of hyperuricemia. We hypothesized that inhibition of human concentrative nucleoside transporter 2 (hCNT2) would suppress increases in serum urate levels derived from dietary purines. To test this hypothesis, the development of potent hCNT2 inhibitors was requ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Tatani K,Hiratochi M,Nonaka Y,Isaji M,Shuto S

    更新日期:2015-01-28 00:00:00

  • EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in Vivo Activity.

    abstract::Inhibitors of the protein methyltransferase Enhancer of Zeste Homolog 2 (EZH2) may have significant therapeutic potential for the treatment of B cell lymphomas and other cancer indications. The ability of the scientific community to explore fully the spectrum of EZH2-associated pathobiology has been hampered by the la...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Campbell JE,Kuntz KW,Knutson SK,Warholic NM,Keilhack H,Wigle TJ,Raimondi A,Klaus CR,Rioux N,Yokoi A,Kawano S,Minoshima Y,Choi HW,Porter Scott M,Waters NJ,Smith JJ,Chesworth R,Moyer MP,Copeland RA

    更新日期:2015-03-04 00:00:00

  • Discovery of Pyridopyrimidinones as Potent and Orally Active Dual Inhibitors of PI3K/mTOR.

    abstract::The identification and lead optimization of a series of pyridopyrimidinone derivatives are described as a novel class of efficacious dual PI3K/mTOR inhibitors, resulting in the discovery of 31. Compound 31 exhibited high enzyme activity against PI3K and mTOR, potent suppression of Akt and p70s6k phosphorylation in cel...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Yu T,Li N,Wu C,Guan A,Li Y,Peng Z,He M,Li J,Gong Z,Huang L,Gao B,Hao D,Sun J,Pan Y,Shen L,Chan C,Lu X,Yuan H,Li Y,Li J,Chen S

    更新日期:2018-02-27 00:00:00

  • N-Methylated sst2 Selective Somatostatin Cyclic Peptide Analogue as a Potent Candidate for Treating Neurogenic Inflammation.

    abstract::A focused multiply N-methylated library of a cyclic hexapeptidic somatostatin analogue: MK678 cyclo(-MeAYwKVF-) was generated, which resulted in the unexpected observation of an efficacious tetra-N-methylated analogue, cyclo(-MeAYMewMeKVMeF-) with a potent inhibitory action on sensory neuropeptide release in vitro and...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Chatterjee J,Laufer B,Beck JG,Helyes Z,Pintér E,Szolcsányi J,Horvath A,Mandl J,Reubi JC,Kéri G,Kessler H

    更新日期:2011-04-04 00:00:00

  • Synthesis and Structure-Activity Relationship of Pyxinol Derivatives as Novel Anti-Inflammatory Agents.

    abstract::Pyxinol, the main metabolite of 20S-protopanaxadiol in human liver, was chosen as a novel skeleton for the development of anti-inflammatory agents. Pyxinol derivatives modified at C-3, C-12, or C-25 and selected stereoisomers were designed, prepared, and investigated for in vitro anti-inflammatory activities. Structur...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Sun Y,Fang X,Gao M,Wang C,Gao H,Bi W,Tang H,Cui Y,Zhang L,Fan H,Yu H,Yang G

    更新日期:2020-02-12 00:00:00

  • Discovery of Sulfonamidebenzamides as Selective Apoptotic CHOP Pathway Activators of the Unfolded Protein Response.

    abstract::Cellular proteins that fail to fold properly result in inactive or disfunctional proteins that can have toxic functions. The unfolded protein response (UPR) is a two-tiered cellular mechanism initiated by eukaryotic cells that have accumulated misfolded proteins within the endoplasmic reticulum (ER). An adaptive pathw...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Flaherty DP,Miller JR,Garshott DM,Hedrick M,Gosalia P,Li Y,Milewski M,Sugarman E,Vasile S,Salaniwal S,Su Y,Smith LH,Chung TD,Pinkerton AB,Aubé J,Callaghan MU,Golden JE,Fribley AM,Kaufman RJ

    更新日期:2014-10-29 00:00:00

  • Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy.

    abstract::Inhibition of Itk potentially constitutes a novel, nonsteroidal treatment for asthma and other T-cell mediated diseases. In-house kinase cross-screening resulted in the identification of an aminopyrazole-based series of Itk inhibitors. Initial work on this series highlighted selectivity issues with several other kinas...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Alder CM,Ambler M,Campbell AJ,Champigny AC,Deakin AM,Harling JD,Harris CA,Longstaff T,Lynn S,Maxwell AC,Mooney CJ,Scullion C,Singh OM,Smith IE,Somers DO,Tame CJ,Wayne G,Wilson C,Woolven JM

    更新日期:2013-08-12 00:00:00

  • INCB050465 (Parsaclisib), a Novel Next-Generation Inhibitor of Phosphoinositide 3-Kinase Delta (PI3Kδ).

    abstract::A medicinal chemistry effort focused on identifying a structurally diverse candidate for phosphoinositide 3-kinase delta (PI3Kδ) led to the discovery of clinical candidate INCB050465 (20, parsaclisib). The unique structure of 20 contains a pyrazolopyrimidine hinge-binder in place of a purine motif that is present in o...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Yue EW,Li YL,Douty B,He C,Mei S,Wayland B,Maduskuie T,Falahatpisheh N,Sparks RB,Polam P,Zhu W,Glenn J,Feng H,Zhang K,Li Y,He X,Katiyar K,Covington M,Feldman P,Shin N,Wang KH,Diamond S,Li Y,Koblish HK,Hall

    更新日期:2019-10-17 00:00:00

  • Discovery of Potent and Selective MTH1 Inhibitors for Oncology: Enabling Rapid Target (In)Validation.

    abstract::We describe the discovery of three structurally differentiated potent and selective MTH1 inhibitors and their subsequent use to investigate MTH1 as an oncology target, culminating in target (in)validation. Tetrahydronaphthyridine 5 was rapidly identified as a highly potent MTH1 inhibitor (IC50 = 0.043 nM). Cocrystalli...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Farand J,Kropf JE,Blomgren P,Xu J,Schmitt AC,Newby ZE,Wang T,Murakami E,Barauskas O,Sudhamsu J,Feng JY,Niedziela-Majka A,Schultz BE,Schwartz K,Viatchenko-Karpinski S,Kornyeyev D,Kashishian A,Fan P,Chen X,Lansdon EB

    更新日期:2019-11-19 00:00:00

  • Identification of New Nonsteroidal RORα Ligands; Related Structure-Activity Relationships and Docking Studies.

    abstract::A high throughput screen was developed to identify novel, nonsteroidal RORα agonists. Among the validated hit compounds, the 4-(4-(benzyloxy)phenyl)-5-carbonyl-2-oxo-1,2,3,4-tetrahydropyrimidine scaffold was the most prominent. Among the numerous analogues tested, compounds 8 and 9 showed the highest activity. Key str...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Dubernet M,Duguet N,Colliandre L,Berini C,Helleboid S,Bourotte M,Daillet M,Maingot L,Daix S,Delhomel JF,Morin-Allory L,Routier S,Walczak R

    更新日期:2013-04-10 00:00:00

  • Discovery of MK-4409, a Novel Oxazole FAAH Inhibitor for the Treatment of Inflammatory and Neuropathic Pain.

    abstract::We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in v...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Chobanian HR,Guo Y,Liu P,Chioda MD,Fung S,Lanza TJ,Chang L,Bakshi RK,Dellureficio JP,Hong Q,McLaughlin M,Belyk KM,Krska SW,Makarewicz AK,Martel EJ,Leone JF,Frey L,Karanam B,Madeira M,Alvaro R,Shuman J,Salituro G

    更新日期:2014-04-10 00:00:00

  • Original Design of Fluorescent Ligands by Fusing BODIPY and Melatonin Neurohormone.

    abstract::An original design and synthesis of fluorescent ligands for melatonin receptor studies is presented and consists in the fusion of the endogenous ligand with the fluorescent BODIPY core. Probes I-IV show high affinities for MT1 and MT2 melatonin receptors and exhibit fluorescence properties compatible with cell observa...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Thireau J,Marteaux J,Delagrange P,Lefoulon F,Dufourny L,Guillaumet G,Suzenet F

    更新日期:2013-11-20 00:00:00

  • Identification of Human Toll-like Receptor 2-Agonistic Activity in Dihydropyridine-Quinolone Carboxamides.

    abstract::Using a multiplexed, reporter gene-based, high-throughput screen, we identified 9-fluoro-7-hydroxy-3-methyl-5-oxo-N-(pyridin-3-ylmethyl)-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxamide as a TLR2 agonist. Preliminary structure-activity relationship studies on the carboxamide moiety led to the identification o...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hu Z,Banothu J,Beesu M,Gustafson CJ,Brush MJH,Trautman KL,Salyer ACD,Pathakumari B,David SA

    更新日期:2018-12-20 00:00:00

  • Discovery of a Series of Indazole TRPA1 Antagonists.

    abstract::A series of TRPA1 antagonists is described which has as its core structure an indazole moiety. The physical properties and in vitro DMPK profiles are discussed. Good in vivo exposure was obtained with several analogs, allowing efficacy to be assessed in rodent models of inflammatory pain. Two compounds showed signific...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Pryde DC,Marron BE,West CW,Reister S,Amato G,Yoger K,Antonio B,Padilla K,Cox PJ,Turner J,Warmus JS,Swain NA,Omoto K,Mahoney JH,Gerlach AC

    更新日期:2017-05-18 00:00:00

  • Polysaccharide-Based Nanoparticles for Two-Step Responsive Release of Antitumor Drug.

    abstract::A novel two-step in situ method for targeted antitumor drug release by supramolecular assembly (Fc-CPT@HACD) was constructed using camptothecin prodrug (Fc-CPT) and β-cyclodextrin (β-CD)-modified hyaluronic acid (HACD). Benefiting from the overexpressed H2O2 and glutathione (GSH) in tumor cells, Fc-CPT@HACD can be dis...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Fu HG,Chen Y,Yu Q,Liu Y

    更新日期:2020-05-18 00:00:00

  • Synthesis and Biological Evaluation of Pyrroloindolines as Positive Allosteric Modulators of the α1β2γ2 GABAA Receptor.

    abstract::γ-Aminobutyric acid type A (GABAA) receptors are key mediators of central inhibitory neurotransmission and have been implicated in several disorders of the central nervous system. Some positive allosteric modulators (PAMs) of this receptor provide great therapeutic benefits to patients. However, adverse effects remain...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Blom AEM,Su JY,Repka LM,Reisman SE,Dougherty DA

    更新日期:2020-09-15 00:00:00

  • Maturing from embryonic to adult policy on stem cell therapeutics.

    abstract::The National Institutes of Health (NIH) closure of the agency's Center for Regenerative Medicine (CRM), which focused on therapeutic development of induced pluripotent stem cells (iPS), was caused by the lack of progress in practical development of the iPSs for use in human therapies. As the NIH evaluates priorities i...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Maguire G

    更新日期:2014-10-08 00:00:00

  • Correction to "Accelerated Discovery of Novel Ponatinib Analogs with Improved Properties for the Treatment of Parkinson's Disease".

    abstract::[This corrects the article DOI: 10.1021/acsmedchemlett.9b00612.]. ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 已发布勘误


    authors: Kaiser TM,Dentmon ZW,Dalloul CE,Sharma SK,Liotta DC

    更新日期:2020-06-24 00:00:00

  • Discovery of Bivalent Kinase Inhibitors via Enzyme-Templated Fragment Elaboration.

    abstract::We have employed novel fragment-based screening methodology to discover bivalent kinase inhibitors with improved selectivity. Starting from a low molecular weight promiscuous kinase inhibitor, we appended a thiol for subsequent reaction with a library of acrylamide electrophiles. Enzyme-templated screening was perform...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kwarcinski FE,Steffey ME,Fox CC,Soellner MB

    更新日期:2015-07-13 00:00:00

  • Supramolecular Inhibition of Neurodegeneration by a Synthetic Receptor.

    abstract::Cucurbit[7]uril (CB[7]) was found in vitro to sequester the neurotoxins MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP(+) (N-methyl-4-phenylpyridine). The CB[7]/neurotoxin host-guest complexes were studied in detail with (1)H NMR, electrospray ionization mass spectrometry, UV-visible spectroscopic titrati...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Li S,Chen H,Yang X,Bardelang D,Wyman IW,Wan J,Lee SM,Wang R

    更新日期:2015-10-16 00:00:00

  • Rational Design of Novel Pyridinol-Fused Ring Acetaminophen Analogues.

    abstract::Acetaminophen (ApAP) is an electron donor capable of reducing radicals generated by redox cycling of hemeproteins. It acts on the prostaglandin H synthases (cyclooxygenases; COXs) to reduce the protoporphyrin radical cation in the peroxidase site of the enzyme, thus preventing the intra-molecular electron transfer tha...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Shchepin RV,Liu W,Yin H,Zagol-Ikapitte I,Amin T,Jeong BS,Roberts LJ 2nd,Oates JA,Porter NA,Boutaud O

    更新日期:2013-08-08 00:00:00

  • Identification of Novel, Potent, and Orally Available GCN2 Inhibitors with Type I Half Binding Mode.

    abstract::General control nonderepressible 2 (GCN2) is a master regulator kinase of amino acid homeostasis and important for cancer survival in the tumor microenvironment under amino acid depletion. We initiated studies aiming at the discovery of novel GCN2 inhibitors as first-in-class antitumor agents and conducted modificatio...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Fujimoto J,Kurasawa O,Takagi T,Liu X,Banno H,Kojima T,Asano Y,Nakamura A,Nambu T,Hata A,Ishii T,Sameshima T,Debori Y,Miyamoto M,Klein MG,Tjhen R,Sang BC,Levin I,Lane SW,Snell GP,Li K,Kefala G,Hoffman ID,Ding

    更新日期:2019-09-19 00:00:00

  • meso-Thiophenium Porphyrins and Their Zn(II) Complexes: A New Category of Cationic Photosensitizers.

    abstract::A new category of cationic meso-thiophenium porphyrins are introduced as possible alternatives to the popular meso-pyridinium porphyrins. Combinations of cationic porphyrins bearing meso-2-methylthiophenium and meso-4-hydroxyphenyl moieties T2(OH)2M (A2B2 type) and T(OH)3M (AB3 type) along with their zinc(II) complexe...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Mazumdar ZH,Sharma D,Mukherjee A,Basu S,Shukla PK,Jha T,Sengupta D

    更新日期:2020-09-10 00:00:00

  • Design, Synthesis, and Anti-HBV Activity of New Bis(l-amino acid) Ester Tenofovir Prodrugs.

    abstract::A series of bis(l-amino acid) ester prodrugs of tenofovir (TFV) were designed and synthesized as new anti-HBV agents in this work. Four compounds 11, 12a, 12d, and 13b displayed better anti-HBV activity (IC50: 0.71-4.22 μM) than the parent drug TFV. The most active compound 11 (IC50: 0.71 μM), a bis(l-valine) ester pr...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Wang A,Wu S,Tao Z,Li X,Lv K,Ma C,Li Y,Li L,Liu M

    更新日期:2019-05-16 00:00:00

  • Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation.

    abstract::The first allosteric, type III inhibitor of LIM-kinase 2 (LIMK2) is reported. A series of molecules that feature both an N-phenylsulfonamide and tertiary amide were not only very potent at LIMK2 but also were extremely selective against a panel of other kinases. Enzymatic kinetic studies showed these molecules to be n...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Goodwin NC,Cianchetta G,Burgoon HA,Healy J,Mabon R,Strobel ED,Allen J,Wang S,Hamman BD,Rawlins DB

    更新日期:2014-08-07 00:00:00

  • Identification of a New Series of STAT3 Inhibitors by Virtual Screening.

    abstract::The signal transducer and activator of transcription 3 (STAT3) is considered to be an attractive therapeutic target for oncology drug development. We identified a N-[2-(1,3,4-oxadiazolyl)]-4-quinolinecarboxamide derivative, STX-0119, as a novel STAT3 dimerization inhibitor by a virtual screen using a customized versio...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Matsuno K,Masuda Y,Uehara Y,Sato H,Muroya A,Takahashi O,Yokotagawa T,Furuya T,Okawara T,Otsuka M,Ogo N,Ashizawa T,Oshita C,Tai S,Ishii H,Akiyama Y,Asai A

    更新日期:2010-07-13 00:00:00

  • Discovery of Tirasemtiv, the First Direct Fast Skeletal Muscle Troponin Activator.

    abstract::The identification and optimization of the first activators of fast skeletal muscle are reported. Compound 1 was identified from high-throughput screening (HTS) and subsequently found to improve muscle function via interaction with the troponin complex. Optimization of 1 for potency, metabolic stability, and physical ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Collibee SE,Bergnes G,Muci A,Browne WF 4th,Garard M,Hinken AC,Russell AJ,Suehiro I,Hartman J,Kawas R,Lu PP,Lee KH,Marquez D,Tomlinson M,Xu D,Kennedy A,Hwee D,Schaletzky J,Leung K,Malik FI,Morgans DJ Jr,Morgan BP

    更新日期:2018-02-13 00:00:00