- Practical synthesis and molecular structure of a potent broad-spectrum antibacterial isothiazoloquinolone
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We report the synthesis of the new 2-sulfonylquinolone ethyl 1-cyclopropyl-6,7-difluoro-2-methanesulfonyl-8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylate (5). Sulfone 5 is a key intermediate used in the optimized synthesis of the isothiazoloquinolone 9-cyclopropyl-6-fluoro-8- methoxy-7-(2-methylpyridin-4-yl)-9H-isothiazolo[5,4-b]quinoline-3,4-dione (1), a potent broad-spectrum antibacterial agent that is effective against clinically important resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA). Our synthetic method is free of chromatographic purification and amenable to large-scale synthesis. The molecular structures of 1, 9-cyclopropyl-6,7-difluoro-8-methoxy-9H-isothiazolo[5,4-b]quinoline-3,4-dione (4), 5, and ethyl 2-cyclopropylamino-6,7-difluoro-8-methoxy-4-oxo-4H- thiochromene-3-carboxylate (10) were established unambiguously using multinuclear NMR spectroscopy and X-ray crystallography.
- Hashimoto, Akihiro,Pais, Godwin C. G.,Wang, Qiuping,Lucien, Edlaine,Incarvito, Christopher D.,Deshpande, Milind,Bradburyand, Barton J.,Wiles, Jason A.
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Read Online
- Quinolone dimers as potential antibacterial agents
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A series of novel 6-fluoro1,4-dihydro-4-oxo-3-quinoline carboxylic acid dimers (34-37), were synthesized as potential antibacterial agents from commercially available fluoro benzoic acids.
- Chepyala, Naveenkumar R.,Durgi, Rajashaker R.,Tatini, Lakshmi K.,Subbaraju, Gottumukkala V.,Hindupur, Rama M.,Dhanvada, Muralimohan R.
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Read Online
- COMPOUNDS TARGETING RNA-BINDING PROTEINS OR RNA-MODIFYING PROTEINS
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The invention relates to a compound represented by Formula (I): or a pharmaceutically acceptable salt thereof, compositions comprising the same and methods of preparing and using the same. The variables are described herein.
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Page/Page column 59; 60
(2021/09/11)
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- Preparation method of 2,4,5-trifluoro-3-methoxybenzoyl chloride and intermediate thereof
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The invention discloses a preparation method of 2,4,5-trifluoro-3-methoxybenzoyl chloride and intermediate thereof. The preparation method of 2,4,5-trifluoro-3-methoxybenzoyl chloride comprises the following steps: by taking tetrafluorophthalic acid as a raw material, carrying out defluorination hydroxylation and acidification decarboxylation to obtain 2,4,5-trifluoro-3-hydroxybenzoic acid, thenreacting with dimethyl carbonate to obtain 2,4,5-trifluoro-3-methoxybenzoic acid, and finally carrying out acylating chlorination to obtain 2,4,5-trifluoro-3-methoxybenzoyl chloride. The preparation process is simple, the total reaction yield is high, the product quality is good, the process route is environment-friendly, and the method has a good industrial application prospect.
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Paragraph 0045; 0047; 0065-0094
(2020/07/02)
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- Identification of an ethyl 5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate as a catalytic inhibitor of DNA gyrase
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Fluoroquinolones are a class of antibacterial agents used clinically to treat a wide array of bacterial infections and target bacterial type-II topoisomerases (DNA gyrase and topoisomerase IV). Fluoroquinolones, however potent, are susceptible to bacterial resistance with prolonged use, which limits their use in the clinic. Quinazoline-2,4-diones also target bacterial type-II topoisomerases and are not susceptible to bacterial resistance similar to fluoroquinolones, however, their potency pales in comparison to fluoroquinolones. To meet the increasing demand for antibacterial development, nine modified quinazoline-2,4-diones were developed to probe quinazoline-2,4-dione structure modification for possible new binding contacts with the bacterial type-II topoisomerase, DNA gyrase. Evaluation of compounds for inhibition of the supercoiling activity of DNA gyrase revealed a novel ethyl 5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate derivative as a modest inhibitor of DNA gyrase, having an IC50 of 3.5 μM. However, this ethyl 5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate does not trap the catalytic intermediate like fluoroquinolones or typical quinazoline-2,4-diones do. Thus, the ethyl 5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate derivative discovered in this work acts as a catalytic inhibitor of DNA gyrase and therefore represents a new structural type of catalytic inhibitor of DNA gyrase.
- Aguirre, Arturo L.,Chheda, Pratik R.,Groves, Natalie P.,Held, Hailey A.,Hiasa, Hiroshi,Kerns, Robert J.,Lentz, Sarah R. C.
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- Synthesis method of gatifloxacin cyclic ester
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The invention belongs to a production process of a pharmaceutical intermediate, and particularly discloses a synthesis method of gatifloxacin cyclic ester. The synthesis method comprises the followingsteps: performing hydrolysis, decarboxylation and methylation on 3, 4, 5, 6-tetrafluoro-N-methylphthalimide serving as a starting material to obtain 2,4,5-trifluoro-3-methoxybenzoyl chloride, coupling the 2,4,5-trifluoro-3-methoxybenzoyl chloride with N,N-ethyl dimethylaminoacrylate, then replacing with cyclopropylamine, and finally performing cyclization to produce the gatifloxacin cyclic esterunder the action of DMF and potassium fluoride. The reaction route is short, the raw materials are wide in source; furthermore, the reaction conditions are mild and easy to operate and control, whichreduces the consumption of the raw materials, facilitates the post-treatment and reduces the cost; potassium fluoride used instead of potassium carbonate in the reaction can not only reduce productionof exhaust gas, but also make the used potassium fluoride used continuously through adjustment by potassium hydroxide, and the cost is further reduced.
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Paragraph 0031; 0039; 0042; 0045; 0048; 0051; 0054;0072-0075
(2019/11/04)
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- Novel fluoroquinolones and use thereof to treat bacterial infections
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The present invention relates to novel fluoroquinolones possessing a piperazine moiety substituted by a long alkyl chain, pharmaceutical compositions or medicament containing them and use thereof to treat bacterial infection.
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Paragraph 0063; 0065
(2016/01/12)
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- Synthesis, antimycobacterial and antibacterial evaluation of l-[(1R, 2S)-2-fluorocyclopropyl]fluoroquinolone derivatives containing an oxime functional moiety
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A series of novel 1-[(1R, 2S)-2-fluorocyclopropyl]fluoroquinolone derivatives 9aed containing an oxime functional moiety were synthesized and evaluated for their biological activity. Our results reveal that 9a1 and 9b3 have good in vitro activity against MTB H37Rv ATCC 27294 (MIC: 0.25 mg/mL) and two MDR-MTB clinical isolates (MICs: 0.065-0.125 mg/mL). Most of 9aed show potent activity against Escherichia coli and Klebsiella pneumoniae (MICs: 50s: 11.43-26.04 mg/kg).
- Liu, Hongmin,Huang, Ju,Wang, Jiayang,Wang, Minghua,Liu, Mingliang,Wang, Bin,Guo, Huiyuan,Lu, Yu
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p. 628 - 638
(2015/01/16)
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- Design, synthesis and insecticidal activity of novel anthranilic diamides with benzyl sulfide scaffold
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A series of novel anthranilic diamides with benzyl sulfide scaffold were synthesized, in which N-pyridylpyrazole moiety generally regarded as key pharmacophore was abandoned. The target compounds were characterized by 1H NMR, 13C NMR, 19F NMR and HRMS. The preliminary bioassays indicated that half of the title compounds were endowed with good insecticidal activities against armyworm (Mythimna sepatara) at the concentration of 500 mg/L. Exhilaratingly, the synthesized compound 3a was also active against Tetranychus cinnabarinus at 100 mg/L. The difference in activities between the target compounds was influenced by the substituents, which provided some hints for further investigation on structure modifications.
- Chen, Yin-Bo,Li, Ji-Ling,Shao, Xu-Sheng,Xu, Xiao-Yong,Li, Zhong
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p. 673 - 676
(2013/07/26)
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- Synthesis of gatifloxacin derivatives and their biological activities against Mycobacterium leprae and Mycobacterium tuberculosis
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Novel 3′-piperazinyl derivatives of the 8-hydrogeno and 8-methoxy-6-fluoro-1-cyclopropyl-4-quinolone-3-carboxylic acid scaffolds were designed, synthesized and characterized by 1H, 13C and 19F NMR, and HRMS. The activity of these derivatives against pathogenic mycobacteria (M. leprae and M. tuberculosis), wild-type (WT) strains or strains harboring mutations implicated in quinolone resistance, were determined by measuring drug concentrations inhibiting cell growth (MIC) and/or DNA supercoiling by DNA gyrase (IC50), or inducing 25% DNA cleavage by DNA gyrase (CC25). Compound 4 (with a methoxy in R8 and a secondary carbamate in R3′) and compound 5 (with a hydrogen in R8 and an ethyl ester in R3′) displayed biological activities close to those of ofloxacin but inferior to those of gatifloxacin and moxifloxacin against M. tuberculosis and M. leprae WT DNA gyrases, whereas all of the compounds were less active in inhibiting M. tuberculosis growth and M. leprae mutant DNA gyrases. Since R3′ substitutions have been poorly investigated previously, our results may help to design new quinolone derivatives in the future.
- Gomez, Catherine,Ponien, Prishila,Serradji, Nawal,Lamouri, Aazdine,Pantel, Alix,Capton, Estelle,Jarlier, Vincent,Anquetin, Guillaume,Aubry, Alexandra
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p. 948 - 956
(2013/03/13)
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- Synthesis and evaluation of 1-cyclopropyl-2-thioalkyl-8-methoxy fluoroquinolones
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Novel fluoroquinolone derivatives substituted with a 2-thioalkyl moiety, with and without a concomitant 3-carboxylate group, were synthesized to evaluate the effect of C-2 thioalkyl substituents on gyrase binding and inhibition. The presence of a 2-thioalkyl group universally decreased activity as compared to parent fluoroquinolones. However, with derivatives of moxifloxacin the presence of either a 2-thioalkyl group or a 3-carboxylate moiety increased activity over the 2,3-unsubstituted derivative. Energy minimization of structures provides an explanation for relative activities of fluoroquinolones having a C-2 thio moiety.
- Marks, Kevin R.,Malik, Muhammad,Mustaev, Arkady,Hiasa, Hiroshi,Drlica, Karl,Kerns, Robert J.
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scheme or table
p. 4585 - 4588
(2011/09/15)
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- AMIDE GLYCOSIDES
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The invention relates to the O-glucosylated amide derivatives, which are inhibitors of Sodium dependent glucose co transporter (SGLT), particularly SGLT2 and method of treating diseases, conditions and/or disorders inhibited by SGLT2 with them, and proces
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Page/Page column 42-43
(2010/04/03)
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- One-pot synthesis and antimicrobial activity of novel quinolone heterocyclic derivatives
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A series of novel quinolone heterocyclic derivatives from natural amino acid were synthesized in one-pot method, which is very beneficial for the industrial operation to save manufacturing costs. These new compounds were characterized by 1H NMR
- Zheng, Hui,Liu, Juan,Zhang, Pengfei
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experimental part
p. 1411 - 1414
(2011/02/22)
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- ESTER COMPOUND, AND NON-AQUEOUS ELECTROLYTE SOLUTION AND LITHIUM SECONDARY BATTERY EACH USING THE ESTER COMPOUND
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The present invention includes (1) an ester compound having a specific structure, (2) a nonaqueous electrolytic solution for lithium secondary battery comprising an electrolyte dissolved in a nonaqueous solvent and containing an ester compound having a sp
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Page/Page column 20
(2009/10/21)
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- Design, synthesis and biological evaluations of novel 7-[3-(1-aminocycloalkyl)pyrrolidin-1-yl]-6-desfluoro-8-methoxyquinolones with potent antibacterial activity against multi-drug resistant Gram-positive bacteria
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A series of novel 6-desfluoro [des-F(6)] and 6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methoxyquinolones bearing 3-(1-aminocycloalkyl)pyrrolidin-1-yl substituents at the C-7 position (1-6) was synthesized to obtain potent drugs for nosocomial infect
- Miyauchi, Rie,Kawakami, Katsuhiro,Ito, Masao,Matsuhashi, Norikazu,Ohki, Hitoshi,Inagaki, Hiroaki,Takahashi, Hisashi,Takemura, Makoto
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experimental part
p. 6879 - 6889
(2009/12/26)
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- Isothiazoloquinolones with enhanced antistaphylococcal activities against multidrug-resistant strains: Effects of structural modifications at the 6-, 7-, and 8-positions
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We describe the biological evaluation of isothiazoloquinolones (ITQs) having structural modifications at the 6-, 7-, and 8-positions. Addition of a methoxy substituent to C-8 effected an increase in antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and a decrease in cytotoxic activity against Hep2 cells. Removal of fluorine from C-6 or replacement of the C-8 carbon with a nitrogen compromised anti-MRSA activity. When the groups attached at C-7 were compared, the anti-MRSA activity decreased in the order 6-isoquinolinyl > 4-pyridinyl > 5-dihydroisoindolyl > 6-tetrahydroisoquinolinyl. The compound with the most desirable in vitro biological profile was 9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl) -9H-isothiazolo[5,4-b]quinoline-3,4-dione (7g). This ITQ demonstrated (i) strong in vitro anti-MRSA activity (MIC90 = 0.5 μg/mL), (ii) strong inhibitory activities against S. aureus DNA gyrase and topoisomerase IV, with weak activity against human topoisomerase II, (iii) weak cytotoxic activities against three cell lines, and (iv) efficacy in an in vivo murine thigh model of infection employing MRSA.
- Wang, Qiuping,Lucien, Edlaine,Hashimoto, Akihiro,Pais, Godwin C. G.,Nelson, David M.,Song, Yongsheng,Thanassi, Jane A.,Marlor, Christopher W.,Thoma, Christy L.,Cheng, Jijun,Podos, Steven D.,Ou, Yangsi,Deshpande, Milind,Pucci, Michael J.,Buechter, Douglas D.,Bradbury, Barton J.,Wiles, Jason A.
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p. 199 - 210
(2007/10/03)
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- 8-METHOXY-9H-ISOTHIAZOLO[5,4-B]QUINOLINE-3,4-DIONES AND RELATED COMPOUNDS AS ANTI-INFECTIVE AGENTS
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The invention provides compound and salts of Formula (I) and (II), disclosed herein, which includes compounds of Formula (A) and Formula (B) such compounds possess useful antimicrobial activity. The variables R2, R3, R5, R
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Page/Page column 61
(2010/11/25)
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- The preparation of two, preclinical amino-quinazolinediones as antibacterial agents
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This paper describes the synthesis of two amino-quinazolinediones which are potent gyrase/topoisomerase inhibitors and useful as antibacterial agents. The early scale-up work to prepare a chiral side chain on multigram scale and two different amino-quinaz
- Beylin, Vladimir,Boyles, David C.,Curran, Timothy T.,Macikenas, Dainius,Parlett IV, Roger V.,Vrieze, Derek
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p. 441 - 449
(2012/12/31)
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- Design, synthesis and activity against Toxoplasma gondii, Plasmodium spp., and Mycobacterium tuberculosis of new 6-fluoroquinolones
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This paper reports on the rational design of a series of new 6-fluoroquinolones by QSAR analysis against Toxoplasma (T.) gondii, their synthesis, their biological evaluation against T. gondii and Plasmodium (P.) spp., and their effect on Mycobacterium (M.) tuberculosis DNA gyrase and growth inhibition. Of the 12 computer-designed 8-ethyl(or methoxy)- and 5-ethyl-8-methoxy-6-fluoroquinolones predicted to be active against T. gondii, we succeeded in the synthesis of four 6-fluoro-8-methoxy-quinolones. The four 6-fluoro-8-methoxy-quinolones are active on T. gondii but only one is as active as predicted. One of these four compounds appears to be an antiparasitical drug of great potential with inhibitory activities comparable to or higher than that of trovafloxacin, gatifloxacin, and moxifloxacin. They also inhibit DNA supercoiling by M. tuberculosis gyrase with an efficiency comparable to that of the most active quinolones but are poor inhibitors of M. tuberculosis growth.
- Anquetin, Guillaume,Greiner, Jacques,Mahmoudi, Nassira,Santillana-Hayat, Maud,Gozalbes, Rafael,Farhati, Khemais,Derouin, Francis,Aubry, Alexandra,Cambau, Emmanuelle,Vierling, Pierre
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p. 1478 - 1493
(2007/10/03)
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- Synthesis of mono- and di-substituted 2,4,5-trifluorobenzoic acid synthons, key precursors for biologically active 6-fluoroquinolones
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In the search for new potent antiparasitical fluoroquinolones, a QSAR analysis by molecular connectivity led to the design of R5 (Me or Et)/R8 (MeO, Me or Et)-substituted analogs of the most powerful antibacterial or antiparasitical
- Anquetin, Guillaume,Greiner, Jacques,Vierling, Pierre
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p. 8394 - 8404
(2007/10/03)
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- PROCESS FOR PRODUCING QUINOLONECARBOXYLIC ACID DERIVATIVE
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Through a production process according to the following reaction scheme, compounds (2) which are useful for antibacterial agents can be provided at low cost and high yield.
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Page/Page column 12
(2008/06/13)
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- A prodrug approach toward the development of water soluble fluoroquinolones and structure-activity relationships of quinoline-3-carboxylic acids
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A fluoroquinolone prodrug, PA2808, was prepared and shown to convert to the highly active parent drug PA2789. In vitro and in vivo activation of PA2808 by alkaline phosphatase was demonstrated using disk diffusion and rat lung infection models. The water solubility of PA2808 showed a marked increase compared to PA2789 over a pH range suitable for aerosol drug delivery. A total of 48 analogues based on PA2789 were prepared and screened against a panel of Gram-positive and Gram-negative pathogens. Incorporating a cyclopropane-fused pyrrolidine (amine g) at C-7 resulted in some of the most active analogues.
- Baker, William R.,Cai, Shaopei,Dimitroff, Martin,Fang, Liming,Huh, Kay K.,Ryckman, David R.,Shang, Xiao,Shawar, Ribhi M.,Therrien, Joseph H.
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p. 4693 - 4709
(2007/10/03)
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- ANTIMICROBIAL QUINOLONES, THEIR COMPOSITIONS AND USES
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Compounds of the following formula (I) are effective antimicrobial agents.
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- Synthesis and insecticidal activity of new substituted N-aryl-N′-benzoylthiourea compounds
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Eight new substituted N -aryl- N ′-benzoylthioureas have been synthesised by a facile and mild method with high yield at room temperature. The structures of all compounds were confirmed by 1H NMR, mass and high resolution mass spectroscopy. The
- Xu, Xiaoyong,Qian, Xuhong,Li, Zhong,Huang, Qingchun,Chen, Gang
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- The Synthesis, Structure-Activity, and Structure-Side Effect Relationships of a Series of 8-Alkoxy- and 5-Amino-8-alkoxyquinolone Antibacterial Agents
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A series of 1-cyclopropyl-6-fluoro-8-alkoxy (8-methoxy and 8-ethoxy)-quinoline-3-carboxylic acids and 1-cyclopropyl-5-amino-6-fluoro-8-alkoxyquinoline-3-carboxylic acids has been prepared and evaluated for antibacterial activity.In addition, they were also compared to quinolones with classic substitution at C8 (H, F, Cl) and the naphthyridine nucleus in a phototoxicity and mammalian cell cytotoxiciry assay.The series of 8-methoxyquinolones had antibacterial activity against Gram-positive, Gram-negative, and anaerobic bacteria equivalent to that most active 8-substituted compounds (8-F and 8-Cl).There was also a concomitant reduction in several of the potential side effects (i.e., phototoxicity and clonogenicity) compared to the most active quinolones with classic substitution at C-8.The 8-ethoxy derivatives had an even better safety profile but were significantly less active (2-3 dilutions) in the antibacterial assay.
- Sanchez, Joseph P.,Gogliotti, Rocco D.,Domagala, John M.,Gracheck, Stephen J.,Huband, Michael D.,et al.
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p. 4478 - 4487
(2007/10/03)
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- Quinoline-3-carboxylic acid derivatives
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Compounds of formula (I): STR1 (in which R1 is alkoxy, R is alkyl, haloalkyl, alkylamino, cycloalkyl or optionally substituted phenyl, X is chlorine or fluorine and Y is selected from certain specific heterocycles) have excellent antibacterial activity. They may be prepared by introducing the group represented by Y into the corresponding compound in which Y is replaced by a halogen atom.
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- 8-alkoxyquinolonecarboxylic acid and salts thereof
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Quinolonecarboxylic acid derivatives of the following formula: STR1 wherein R indicates a hydrogen atom or lower alkyl group, R1 indicates a lower alkyl group, R2 indicates a hydrogen atom, amino group or nitro group, X indicates a halogen atom, and Z indicates a halogen atom, piperazino group, N-methylpiperazino group, 3-methylpiperazino group, 3-hydroxypyrrolidino group, or pyrrolidino group of the following formula, STR2 (here, n is 0 or 1, R3 indicates a hydrogen atom or lower alkyl group, R4 indicates a hydrogen atom, lower alkyl group and R5 indicates a hydrogen atom, lower alkyl group, acyl group or alkoxycarbonyl group), the hydrates and pharmaceutically acceptable salts thereof are useful as antibacterial agents.
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