- Investigation of Transfer Group, Tether Proximity, and Alkene Substitution for Intramolecular Silyloxypyrone-Based [5 + 2] Cycloadditions
-
Systematic investigation of intramolecular silyloxypyrone-based [5 + 2] cycloadditions revealed three significant factors impacting conversion to cycloadduct: (1) the silyl transfer group has a substantial influence on the rate of reaction, and the robust t-butyldiphenylsilyl group was found to be more effective overall than the conventional t-butyldimethylsilyl group; (2) α,β-unsaturated esters were generally more reactive than terminal olefins and afforded appreciable quantity of cycloadduct even at room temperature; and (3) the proximity of the tether to the silyl transfer group revealed a critical alignment trend between the pyrone and the alkene. Taken together, these investigations provided insight regarding the steric and electronic parameters that impact the scope and limitation of these reactions.
- Bulandr, Jacob J.,Grabowski, Jacob P.,Law, Chunyin M.,Shaw, Jessica L.,Goodell, John R.,Mitchell, T. Andrew
-
-
Read Online
- A new “Mitsunobu homocoupling” reaction using aldol adducts of kojic acid
-
In this study, we attempted to carry out the Mitsunobu 1,4-elimination using the kojic acid analog 3, which carries a hydroxymethyl group on C-6 introduced by aldol condensation, to obtain an effective Michael acceptor 4. To the ethyl acetate solution of
- Azuma, Hideki,Morishima, Yasuhito,Nakaguro, Keijin,Kato, Reiko,Nagasaki, Takeshi
-
-
Read Online
- Synthesis and Evaluation of Bicyclic Hydroxypyridones as Inhibitors of Catechol O-Methyltransferase
-
A series of bicyclic pyridones were identified as potent inhibitors of catechol O-methyltransferase (COMT). Substituted benzyl groups attached to the basic nitrogen of the core scaffold gave the most potent inhibitors within this series. Rat pharmacokinetic studies showed medium to high levels of clearance for this series, but with high free fraction due to remarkably low levels of protein and tissue binding. In rat biomarker studies, levels of unbound drug exposure are seen in the brain, which exceed their respective IC50s, leading to changes in the levels of dopamine metabolites in a manner consistent with COMT inhibition.
- Ernst, Glen,Akuma, Daniel,Au, Vinh,Buchler, Ingrid P.,Byers, Spencer,Carr, Gregory V.,Defays, Sabine,De León, Pablo,Demaude, Thierry,Depasquale, Michael,Durieu, Véronique,Huang, Yifang,Jigorel, Emilie,Kimos, Martha,Kolobova, Anna,Montel, Florian,Moureau, Florence,Poslusney, Michael,Swinnen, Dominique,Vandergeten, Marie-Christine,Van Houtvin, Nathalie,Wei, Huijun,White, Noelle,Wood, Martyn,Barrow, James C.
-
-
Read Online
- Design, synthesis and biological evaluation of novel DNA gyrase inhibitors and their siderophore mimic conjugates
-
Bacterial DNA gyrase is an important target for the development of novel antibacterial drugs, which are urgently needed because of high level of antibiotic resistance worldwide. We designed and synthesized new 4,5,6,7-tetrahydrobenzo[d]thiazole-based DNA gyrase B inhibitors and their conjugates with siderophore mimics, which were introduced to increase the uptake of inhibitors into the bacterial cytoplasm. The most potent conjugate 34 had an IC50 of 58 nM against Escherichia coli DNA gyrase and displayed MIC of 14 μg/mL against E. coli ΔtolC strain. Only minor improvements in the antibacterial activities against wild-type E. coli in low-iron conditions were seen for DNA gyrase inhibitor – siderophore mimic conjugates.
- Baran?oková, Michaela,Cruz, Cristina D.,Ila?, Janez,Kikelj, Danijel,Lamut, Andra?,Ma?i?, Lucija Peterlin,Skok, ?iga,Tammela, P?ivi,Toma?i?, Tihomir,Zega, Anamarija,Zidar, Nace
-
-
- D-AMINO ACID OXIDASE INHIBITORS AND THERAPEUTIC USES THEREOF
-
The present invention relates to compounds of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: each of A, B, C, D, and E, independently, is C, N, N—H, O, S, or absent is a single bond or a double bond; each of X, Y, and Z, independentl
- -
-
Paragraph 0145
(2019/04/29)
-
- Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections
-
Conjugating a siderophore to an antibiotic is a promising strategy to overcome the permeability-mediated resistance of Gram-negative pathogens. On the basis of the structure of BAL30072, novel pyridone-conjugated monosulfactams incorporating diverse substituents into the methylene linker between the 1,3-dihydroxypyridin-4(1H)-one and the aminothiazole oxime were designed and synthesized. Structure-activity relationship studies revealed that a variety of substituents were tolerated, with isopropyl (compound 12c) and methylthiomethyl (compound 16a) showing the best efficacy against multidrug-resistant (MDR) Gram-negative pathogens. In addition, compound 12c exhibits a good free fraction rate in an in vitro human plasma protein binding test, along with a low clearance and favorable plasma exposure in vivo. In a murine systemic infection model with MDR Klebsiella pneumoniae, compound 12c shows an ED50 of 10.20 mg/kg. Taken together, the results indicate that compound 12c is a promising drug candidate for the treatment of serious infections caused by MDR Gram-negative pathogens.
- Tan, Liang,Tao, Yunliang,Wang, Ting,Zou, Feng,Zhang, Shuhua,Kou, Qunhuan,Niu, Ao,Chen, Qian,Chu, Wenjing,Chen, Xiaoyan,Wang, Haidong,Yang, Yushe
-
supporting information
p. 2669 - 2684
(2017/04/21)
-
- COMT INHIBITING METHODS AND COMPOSITIONS
-
Compounds that inhibit COMT enzyme and pharmaceutical compositions comprising the same are provided herein. Methods of treating various psychiatric and neurological disorders with the compounds and pharmaceutical compositions described herein are also provided.
- -
-
Page/Page column 101
(2017/07/14)
-
- Identification of 2-subsituted benzothiazole derivatives as triple-functional agents with potential for AD therapy
-
A novel series of 2-subsituted benzothiazole derivatives as MTDLs were designed and synthesized for AD therapy using pharmacophore-combine strategy. The benzothiazole moiety from ThT and the HPO moiety from deferiprone were connected with vinyl linker to
- Jiang, Liu,Zhang, Minkui,Tang, Li,Weng, Qinjie,Shen, Yanhong,Hu, Yongzhou,Sheng, Rong
-
p. 17318 - 17327
(2016/02/20)
-
- NOVEL KOJIC ACID CONJUGATED COMPOUNDS AND THEIR BIOLOGICAL APPLICATIONS
-
The present invention relates to a novel kojic acid conjugated compound conjugated by a click reaction of kojic acid and an antioxidant derivative, an antioxidant dietary supplement comprising the same, and a composition for external application on skin h
- -
-
Paragraph 0067-0070
(2016/10/10)
-
- Design, synthesis and antibacterial activity of novel pleuromutilin derivatives with 4H-pyran-4-one and pyridin-4-one substitution in the C-14 side chain
-
A series of novel pleuromutilin derivatives with 4H-pyran-4-one and pyridin-4-one substitution in the C-14 side chain have been designed and synthesized. In vitro antibacterial activity evaluation showed that most of the derivatives exhibited potent antib
- Ling, Chen-Yu,Tao, Yun-Liang,Chu, Wen-Jing,Wang, Hui,Wang, Hai-Dong,Yang, Yu-She
-
supporting information
p. 235 - 240
(2018/03/22)
-
- Design, synthesis and biological evaluation of LpxC inhibitors with novel hydrophilic terminus
-
Abstract In order to develop novel LpxC inhibitors with good activities and metabolic stability, two series of compounds with hydrophilic terminus have been synthesized and their in vitro antibacterial activities against Escherichial coli and Pseudomonas aeruginosa were evaluated. Especially, compounds 22b and c exhibited comparable antibacterial activities to CHIR-090 and better metabolic stability than CHIR-090 and LPC-011 in liver microsomes (rat and mouse), which indicated the terminal methylsulfone may be a preferred structure in the design of LpxC inhibitors and worthy of further investigations.
- Ding, Shi,Wang, Wen-Ke,Cao, Qiao,Chu, Wen-Jing,Lan, Le-Fu,Hu, Wen-Hao,Yang, Yu-She
-
p. 763 - 767
(2015/08/03)
-
- NOVEL CEPHALOSPORIN DERIVATIVE AND PHARMACEUTICAL COMPOSITION THEREOF
-
The present invention relates to novel cephalosporin derivatives represented by Chemical Formula 1. Wherein, X, Y, L, R1, and R2 are as same as defined in the description of the invention. The present invention also relates to pharmaceutical antibiotic compositions comprising a novel celphalosporin derivative represented by Chemical Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof as an effective ingredient. According to the present invention, novel cephalosporin derivatives, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof as an effective ingredient for the broad spectrum of antibiotic resistant, low toxicity, particularly in Gram-negative bacteria, which can be useful with strong antimicrobial activity.
- -
-
Paragraph 0072
(2014/03/25)
-
- Synthesis of kojic acid-derived copper-chelating apoptosis inducing agents
-
Three classes of kojic acid derivatives were synthesized and examined for their antiproliferative activity against HeLa cells. Both 8b and 11 co-treated with copper ion exhibited synergistic effect on the HeLa cell growth inhibition with GI50 v
- Chen, Yu-Hua,Lu, Pei-Jung,Hulme, Christopher,Shaw, Arthur Y.
-
p. 995 - 1003
(2013/04/24)
-
- HETEROBICYCLIC COMPOUNDS AS BETA-LACTAMASE INHIBITORS
-
The present invention is directed to compounds which are beta-lactamase inhibitors. The compounds and their pharmaceutically acceptable salts, are useful in combination with beta-lactam antibiotics, or alone, for the treatment of bacterial infections, including infections caused by drug resistant organisms, including multi-drug resistant organisms. The present invention includes compounds according to formula (Ia): or a pharmaceutically acceptable salt thereof, wherein the values of R1, R 2, R 3 and R 4 are described herein.
- -
-
Page/Page column 235
(2013/10/22)
-
- ANTIBACTERIAL COMPOUNDS
-
The present Invention relates to cephalosporin antibacterial compounds of Formula (!): corresponding pharmaceutically acceptable salts thereof, corresponding pharmaceutical compositions, compound preparation and treatment methods for bacterial infections, especially those caused by gram-negative bacteria.
- -
-
Page/Page column 80
(2013/04/24)
-
- Pyridone-conjugated monobactam antibiotics with gram-negative activity
-
Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli. Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1.
- Brown, Matthew F.,Mitton-Fry, Mark J.,Arcari, Joel T.,Barham, Rose,Casavant, Jeffrey,Gerstenberger, Brian S.,Han, Seungil,Hardink, Joel R.,Harris, Thomas M.,Hoang, Thuy,Huband, Michael D.,Lall, Manjinder S.,Lemmon, M. Megan,Li, Chao,Lin, Jian,McCurdy, Sandra P.,McElroy, Eric,McPherson, Craig,Marr, Eric S.,Mueller, John P.,Mullins, Lisa,Nikitenko, Antonia A.,Noe, Mark C.,Penzien, Joseph,Plummer, Mark S.,Schuff, Brandon P.,Shanmugasundaram, Veerabahu,Starr, Jeremy T.,Sun, Jianmin,Tomaras, Andrew,Young, Jennifer A.,Zaniewski, Richard P.
-
supporting information
p. 5541 - 5552
(2013/07/26)
-
- NOVEL CEPHALOSPORIN DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS THEREOF
-
The present invention relates to novel cephalosporin derivatives represented by Chemical Formula 1. Wherein, X, Y, L, R1, and R2 are as same as defined in the description of the invention. The present invention also relates to pharmaceutical antibiotic compositions comprising a novel celphalosporin derivative represented by Chemical Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof as an effective ingredient. According to the present invention, novel cephalosporin derivatives, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof as an effective ingredient for the broad spectrum of antibiotic resistant, low toxicity, particularly in Gram-negative bacteria, which can be useful with strong antimicrobial activity.
- -
-
Page/Page column 34
(2012/10/23)
-
- MONOBACTAMS
-
The present invention is directed to a new class of monobactam derivatives and their use for treating bacterial infections.
- -
-
Page/Page column 53
(2012/06/16)
-
- The design of efficient and selective routes to pyridyl analogues of 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde
-
This Letter describes the synthetic routes to challenging pyridyl analogues of 2,3-dihydro-1,4-benzodioxin- 6-carbaldehyde which were key intermediates for our antibacterial medicinal chemistry programme. All routes described started from kojic acid (8) and have been used to give multigram quantities of each aldehyde.
- Barfoot, Christopher W.,Brown, Pamela,Dabbs, Steven,Davies, David T.,Hennessy, Alan J.,Miles, Timothy J.,Pearson, Neil D.
-
scheme or table
p. 5038 - 5040
(2011/01/04)
-
- Synthesis of tyrosinase inhibitory kojic acid derivative
-
Kojic acid derivative 2 was synthesized by joining two pyrone rings through an ethylene linkage by Horner-Emmons reaction of phosphonate 6 with aldehyde 7. The intermediates 6 and 7 were derived from kojic acid. The tyrosinase inhibitory activity of 2 was
- Lee, Yong Sup,Park, Jang Hyun,Kim, Min Hwan,Seo, Seon Hee,Kim, Hyoung Ja
-
p. 111 - 114
(2007/10/03)
-
- ANTIBACTERIAL AGENTS
-
Naphthalene, quinoline, quinoxaline and naphthyridine derivatives useful in the treatment of bacterial infections in mammals, particularly humans, are disclosed herein.
- -
-
Page/Page column 90
(2010/02/15)
-
- ANTIBACTERIAL AGENTS
-
Naphthalene, quinoline, quinoxaline and naphthyridine derivatives useful in the treatment of bacterial infections in mammals, particularly humans, are disclosed herein.
- -
-
Page/Page column 40-41
(2010/10/19)
-
- The monoethyl ester of meconic acid is an active site inhibitor of HCV NS5B RNA-dependent RNA polymerase
-
Screening of the in-house sample collection for compounds with HCV NS5B RNA dependent RNA polymerase inhibition led to the identification of a new lead. Afterwards, we discovered that the screening lead, rather than containing the expected structure 1, was comprised of roughly a 1:1 mixture of meconic acid 2 and its monoethyl ester 3, with all inhibitory potency residing with 3. We propose that this compound shares critical common features for activity with α,γ-diketoacids inhibitors previously discovered by our group. SAR around this molecule will be presented to provide an improved basis for structure-based ligand design.
- Pace, Paola,Nizi, Emanuela,Pacini, Barbara,Pesci, Silvia,Matassa, Victor,De Francesco, Raffaele,Altamura, Sergio,Summa, Vincenzo
-
p. 3257 - 3261
(2007/10/03)
-
- 3-Hydroxy-4-pyrones as precursors of 4-methoxy-3-oxidopyridinium ylides. An expeditious entry to highly substituted 8-azabicyclo[3.2.1]octanes
-
3-Hydroxy-4-pyridones, which are easily prepared from commercially available 3-hydroxy-4-pyrones, can be readily transformed into 4-methoxy-3-oxidopyridinium ylides by treatment with methyl trifluoromethanesulfonate and subsequent deprotonation with a non-nucleophilic base. These ylides are capable of undergoing cycloaddition to several electron-deficient alkenes, thus allowing the synthesis of highly functionalized azabicyclo[3.2.1]octane moieties. The rich substitution patterns of these frameworks might allow their divergent conversion to a variety of natural and non-natural tropane alkaloids.
- Rumbo, Antonio,Mourino, Antonio,Castedo, Luis,Mascarenas, Jose L.
-
p. 6114 - 6120
(2007/10/03)
-
- Piperaziniocephalosporins
-
Antibacterial hydroxyarylpiperazinocephalosporins of the formula: STR1 wherein R1 is amino or acylamino; R2 is H or methoxy; R3 is alkyl; R4 is --(P--C--Q)n --, where P and Q each are H, alkyl or OH, or P and Q combine to form oxo, and n is 0 or 4; R5 is substituted or unsubstituted hydroxyaryl; R6 has a negative charge and is COO, or an anion in combination with an optionally protected carboxy; and X is O, S or S→O; an antibacterial preparation containing the same; a method for killing bacteria and preventing or treating bacterial infection by using the same; and syntheses of the cephalosporins are provided.
- -
-
-
- Cephalosporin compounds and antibacterial agents
-
Cephalosporin compounds of the formula (I): STR1 wherein R1 and R2 may be the same or different and are a hydrogen atom or a lower alkyl group of 1-5 carbon atoms and A is a hydrogen atom or a nucleophilic compound residue or pharmacologically acceptable salts thereof have excellent antibacterial activity against Gram positive and Gram negative microorganisms.
- -
-
-
- Cephalosporin compounds and antibacterial agents
-
Novel cephalosporin compounds represented by formula (I): STR1 wherein R1 represents a lower alkyl group which may optionally have a substituent; each of R2 and R3 independently represents a hydrogen atom or hydroxy group; and A represents a hydrogen atom or a residue of nucleophilic compound, and pharmacologically acceptable salts or esters thereof exhibit a potent antibacterial activity against gram positive and gram negative bacteria.
- -
-
-
- Cephalosporins, processes for their preparation and pharmaceutical compositions containing them
-
Antibacterial agents have the formula (Ia) or are pharmaceutically acceptable salts or invivohydrolysable esters thereof: wherein R1 is an acyl group, in particular that of an antibacterially active cephalosporin; R2 is hydrogen, methoxy, or formamido; Y is S, SO, SO2, O or CH2; X is oxygen, sulphur, or -NH- and R4 is a group of the formula CO Z R5 wherein Z is -CH=CH-, -(CH2)n- or -NH-; n is 0, 1 or 2; and R5 is: wherein R6 and R7 are the same or different, each representing hydroxy or protected hydroxy and R8 is hydroxy, amino, halogen or carboxy. The use of the compounds of formula (Ia) and intermediates for their preparation are also disclosed.
- -
-
-
- Cephalosporins, process for their preparation, pharmaceutical compositions containing them and intermediates
-
β-Lactam antibiotics are disclosed which have the formula (IA) or are pharmaceutically acceptable salts or pharmaceutically acceptable invivohydrolysable esters thereof: wherein Y is a 1-(optionally substituted amino)-1H-tetrazol-5-yl, 4-(optionally subst
- -
-
-