- Multi-targeting exploration of new 2-aminothiazolyl quinolones: Synthesis, antimicrobial evaluation, interaction with DNA, combination with topoisomerase IV and penetrability into cells
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A series of new potentially multi-targeting antimicrobial 2-aminothiazolyl quinolones were designed, synthesized and characterized by1H NMR,13C NMR, IR, MS and HRMS spectra. Bioactive assay manifested that some of the prepared compounds showed moderate to good antibacterial and antifungal activities. Noticeably, compound 10f could effectively inhibit the growth of B. typhi and MRSA with MIC values of 1 and 8 μg/mL, respectively. Experimental results revealed that compound 10f was membrane-active and had the ability to rapidly kill the tested strains and effectively prevent the development of bacterial resistance. Moreover, this compound also exhibited low toxicity against L929 cells. Molecular docking indicated that compound 10f could bind with topoisomerase IV–DNA complexes through hydrogen bonds and hydrophobic interactions. Quantum chemical studies were also performed on 10f to understand the structural features essential for activity. The preliminary mechanism research suggested that compound 10f could intercalate into calf thymus DNA to form a steady supramolecular complex which might block DNA replication to exert the powerful bioactivities.
- Cheng, Yu,Avula, Srinivasa Rao,Gao, Wei-Wei,Addla, Dinesh,Tangadanchu, Vijai Kumar Reddy,Zhang, Ling,Lin, Jian-Mei,Zhou, Cheng-He
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- Molecular Cobalt Catalysts for O2 Reduction: Low-Overpotential Production of H2O2 and Comparison with Iron-Based Catalysts
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A series of mononuclear pseudomacrocyclic cobalt complexes have been investigated as catalysts for O2 reduction. Each of these complexes, with CoIII/II reduction potentials that span nearly 400 mV, mediate highly selective two-electron reduction of O2 to H2O2 (93-99%) using decamethylferrocene (Fc?) as the reductant and acetic acid as the proton source. Kinetic studies reveal that the rate exhibits a first-order dependence on [Co] and [AcOH], but no dependence on [O2] or [Fc?]. A linear correlation is observed between log(TOF) vs E1/2(CoIII/II) for the different cobalt complexes (TOF = turnover frequency). The thermodynamic potential for O2 reduction to H2O2 was estimated by measuring the H+/H2 open-circuit potential under the reaction conditions. This value provides the basis for direct assessment of the thermodynamic efficiency of the different catalysts and shows that H2O2 is formed with overpotentials as low as 90 mV. These results are compared with a recently reported series of Fe-porphyrin complexes, which catalyze four-electron reduction of O2 to H2O. The data show that the TOFs of the Co complexes exhibit a shallower dependence on E1/2(MIII/II) than the Fe complexes. This behavior, which underlies the low overpotential, is rationalized on the basis of the catalytic rate law.
- Wang, Yu-Heng,Pegis, Michael L.,Mayer, James M.,Stahl, Shannon S.
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- Synthesis and Herbicidal Activity of 1,2,4-Triazole Derivatives Containing a Pyrazole Moiety
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A series of triazole derivatives containing a pyrazole moiety were synthesized and characterized by 1H NMR, 13C NMR, and HRMS. The herbicidal activities of these compounds were tested against lettuce and bentgrass. Most of the tested compounds were moderately herbicidal activity against lettuce and bentgrass. Among them, compounds 6f and 6g had the highest herbicidal activity (80% inhibitory) against lettuce and bentgrass.
- Mu, Jin-Xia,Zhai, Zhi-Wen,Tan, Cheng-Xia,Weng, Jian-Quan,Wu, Hong-Ke,Duke, Stephen O.,Zhang, Yong-Gang,Liu, Xing-Hai
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- Synthesis and Nematocidal Activity of N-Substituted 3-Methyl-1H-pyrazole-4-carboxamide Derivatives Against Meloidogyne incognita
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A series of novel pyrazole carboxamides were designed and synthesized through multi-step reactions from ethyl acetoacetate and triethyl orthoformate, and their structures were characterized by Fourier transform infrared, 1H-NMR, 13C-NMR, mass spectrometry, and elemental analysis. The preliminary insecticidal activity showed that some of them possessed good insecticidal activities against Meloidogyne incognita.
- Cheng, Long,Shen, Zhong-Hua,Xu, Tian-Ming,Tan, Cheng-Xia,Weng, Jian-Quan,Han, Liang,Peng, Wei-Li,Liu, Xing-Hai
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- Lanthanide complexes based on ethyl 2-hydroxymethylidene-3-oxobutanoate
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The reaction of europium(iii) or terbium(iii) chlorides with ethyl 2-hydroxymethylidene-3-oxobutanoate in the presence of 2,2'-bipyridine (2,2'-bipy) resulted in the luminescent complexes [LnL3]·2,2'-bipy (L = ethyl 2-hydroxymethylidene-3-oxobutanoate, Ln = Tbiii or Euiii), whose molecular structure has been determined by X-ray analysis.
- Kudyakova, Yulia S.,Bazhin, Denis N.,Burgart, Yanina V.,Saloutin, Victor I.
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- Synthesis and biological activity of novel 1,3,4-oxadiazole derivatives containing a pyrazole moiety
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Several new 1,3,4-oxadiazole derivatives containing a pyrazole ring were designed and synthesized from ethyl acetoacetate and triethyl orthoformate as starting materials via multi-step reactions. The compound structures were confirmed by melting point, 1H NMR and HRMS. They were evaluated for fungicidal and herbicidal activities. Four of the compounds exhibited moderate fungicidal activity against Colletotrichum species. Most of the compounds had moderate-to-good activity as a herbicide.
- Yu, Wei,Zhai, Zhi-Wen,Wedge, David E.,Duke, Stephen O.,Wu, Hong-Ke,Weng, Jian-Quan,Tan, Cheng-Xia,Zhang, Yong-Gang,Liu, Xing-Hai
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- Preparation method of azabenzoazulene derivative
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The invention belongs to the technical field of preparation of medicinal chemistry, and particularly relates to a preparation method of an azabenzoazulene derivative, ethyl acetoacetate and triethyl orthoformate are used as raw materials, and the azabenzoazulene derivative is prepared after a series of reactions. Compared with the existing synthetic method of the azabenzoazulene derivative, the method disclosed by the invention has the advantages that the raw materials are simple and easy to obtain, the synthetic route is simple and easy to implement, the yield is high, the operation is convenient, the cost is low, and the method can be easily applied to laboratory drug modification.
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Paragraph 0109-0115
(2021/06/13)
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- Expedient discovery for novel antifungal leads targeting succinate dehydrogenase: Pyrazole-4-formylhydrazide derivatives bearing a diphenyl ether fragment
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The pyrazole-4-carboxamide scaffold containing a flexible amide chain has emerged as the molecular skeleton of highly efficient agricultural fungicides targeting succinate dehydrogenase (SDH). Based on the above vital structural features of succinate dehydrogenase inhibitors (SDHI), three types of novel pyrazole-4-formylhydrazine derivatives bearing a diphenyl ether moiety were rationally conceived under the guidance of a virtual docking comparison between bioactive molecules and SDH. Consistent with the virtual verification results of a molecular docking comparison, the in vitro antifungal bioassays indicated that the skeleton structure of title compounds should be optimized as an N′-(4-phenoxyphenyl)-1H-pyrazole-4-carbohydrazide scaffold. Strikingly, N′-(4-phenoxyphenyl)-1H-pyrazole-4-carbohydrazide derivatives 11o against Rhizoctonia solani, 11m against Fusarium graminearum, and 11g against Botrytis cinerea exhibited excellent antifungal effects, with corresponding EC50 values of 0.14, 0.27, and 0.52 μg/mL, which were obviously better than carbendazim against R. solani (0.34 μg/mL) and F. graminearum (0.57 μg/mL) as well as penthiopyrad against B. cinerea (0.83 μg/mL). The relative studies on an in vivo bioassay against R. solani, bioactive evaluation against SDH, and molecular docking were further explored to ascertain the practical value of compound 11o as a potential fungicide targeting SDH. The present work provided a non-negligible complement for the structural optimization of antifungal leads targeting SDH.
- Chen, Min,Li, Guohua,Lu, Aimin,Qiu, Lingling,Wang, An,Wang, Xiaobin,Xue, Wei,Yang, Chunlong
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p. 14426 - 14437
(2020/12/22)
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- Optimization of the in Vivo Potency of Pyrazolopyrimidine MALT1 Protease Inhibitors by Reducing Metabolism and Increasing Potency in Whole Blood
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The paracaspase MALT1 has gained increasing interest as a target for the treatment of subsets of lymphomas as well as autoimmune diseases, and there is a need for suitable compounds to explore the therapeutic potential of this target. Here, we report the optimization of the in vivo potency of pyrazolopyrimidines, a class of highly selective allosteric MALT1 inhibitors. High doses of the initial lead compound led to tumor stasis in an activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) xenograft model, but this compound suffered from a short in vivo half-life and suboptimal potency in whole blood. Guided by metabolism studies, we identified compounds with reduced metabolic clearance and increased in vivo half-life. In the second optimization step, masking one of the hydrogen-bond donors of the central urea moiety through an intramolecular interaction led to improved potency in whole blood. This was associated with improved in vivo potency in a mechanistic model of B cell activation. The optimized compound led to tumor regression in a CARD11 mutant ABC-DLBCL lymphoma xenograft model.
- Quancard, Jean,Simic, Oliver,Pissot Soldermann, Carole,Aichholz, Reiner,Blatter, Markus,Renatus, Martin,Erbel, Paulus,Melkko, Samu,Endres, Ralf,Sorge, Mickael,Kieffer, Laurence,Wagner, Trixie,Beltz, Karen,McSheehy, Paul,Wartmann, Markus,Régnier, Catherine H.,Calzascia, Thomas,Radimerski, Thomas,Bigaud, Marc,Weiss, Andreas,Bornancin, Frédéric,Schlapbach, Achim
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p. 14594 - 14608
(2020/12/23)
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- Design and synthesis of aminothiazolyl norfloxacin analogues as potential antimicrobial agents and their biological evaluation
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A series of aminothiazolyl norfloxacin analogues as a new type of potential antimicrobial agents were synthesized and screened for their antimicrobial activities. Most of the prepared compounds exhibited excellent inhibitory efficiencies. Especially, norfloxacin analogue II-c displayed superior antimicrobial activities against K. pneumoniae and C. albicans with MIC values of 0.005 and 0.010 mM to reference drugs, respectively. This compound not only showed broad antimicrobial spectrum, rapid bactericidal efficacy and strong enzymes inhibitory potency including DNA gyrase and chitin synthase (CHS), low toxicity against mammalian cells and no obvious propensity to trigger the development of bacterial resistance, but also exerted efficient membrane permeability, and could effectively intercalate into K. pneumoniae DNA to form a steady supramolecular complex, which might block DNA replication to exhibit their powerful antimicrobial activity. Quantum chemical studies were also performed to explain the high antimicrobial activities. Molecular docking showed that compound II-c could bind with gyrase–DNA and topoisomerase IV–DNA through hydrogen bonds and π-π stacking.
- Wang, Liang-Liang,Battini, Narsaiah,Bheemanaboina, Rammohan R.Yadav,Zhang, Shao-Lin,Zhou, Cheng-He
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p. 105 - 123
(2019/02/15)
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- A new exploration towards aminothiazolquinolone oximes as potentially multi-targeting antibacterial agents: Design, synthesis and evaluation acting on microbes, DNA, HSA and topoisomerase IV
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This work did a new exploration towards aminothiazolquinolone oximes as potentially multi-targeting antimicrobial agents. A class of novel hybrids of quinolone, aminothiazole, piperazine and oxime fragments were designed for the first time, conveniently synthesized as well as characterized by 1H NMR, 13C NMR and HRMS spectra. Biological activity showed that some of the synthesized compounds exhibited good antimicrobial activities in comparison with the reference drugs. Especially, O-methyl oxime derivative 10b displayed excellent inhibitory efficacy against MRSA and S. aureus 25923 with MIC values of 0.009 and 0.017 mM, respectively. Further studies indicated that the highly active compound 10b showed low toxicity toward BEAS-2B and A549 cell lines and no obvious propensity to trigger the development of bacterial resistance. Quantum chemical studies have also been conducted and rationally explained the structural features essential for activity. The preliminarily mechanism exploration revealed that compound 10b could not only exert efficient membrane permeability by interfering with the integrity of cells, bind with topoisomerase IV–DNA complex through hydrogen bonds and π-π stacking, but also form a steady biosupramolecular complex by intercalating into DNA to exert the efficient antibacterial activity. The supramolecular interaction between compound 10b and human serum albumin (HSA) was a static quenching, and the binding process was spontaneous, where hydrogen bonds and van der Waals force played vital roles in the supramolecular transportation of the active compound 10b by HSA.
- Wang, Liang-Liang,Battini, Narsaiah,Bheemanaboina, Rammohan R. Yadav,Ansari, Mohammad Fawad,Chen, Jin-Ping,Xie, Yun-Peng,Cai, Gui-Xin,Zhang, Shao-Lin,Zhou, Cheng-He
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p. 166 - 181
(2019/07/02)
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- (1H-pyrazole-4-carboxamido) ethyl benzoate compound as well as preparation method and application thereof
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The invention discloses an ethyl (1H-pyrazole-4-carboxamido) benzoate compound as well as a preparation method and application thereof. The structural formula of the (1H-pyrazole-4-carboxamido) ethylbenzoate compound is as shown in the formula (I), wherein the substituent groups R1 are phenyl or substituted phenyl, the number of substituent groups on a benzene ring of the substituted phenyl is one or more, and each substituent group is independently selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C3 halogenated alkyl or nitro; and the substituent R2 is methyl, monofluoromethyl, difluoromethyl or trifluoromethyl. The invention discloses a novel compound with bactericidal activity, which is simple in preparation method and convenient to operate, and the obtained compound has betterinhibitory activity on pathogenic bacteria such as cucumber botrytis cinerea, fusarium oxysporum, cucumber corynespora leaf spot and the like under the concentration of 50 mg/mL.
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Paragraph 0140-0142
(2020/01/08)
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- N → N acyl group migration in N-acylpyrazoles: Isomerization of 1,4-diacyl-5-methyl-1H-pyrazoles to 1,4-diacyl-3-methyl-1H-pyrazoles
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1,4-Diacyl-5-methyl-1H-pyrazoles on heating in toluene undergo isomerization to 1,4-diacyl-3-methyl-1H-pyrazoles via intermolecular N → N acyl group migration. 1,4,5-Trisubstituted pyrazoles obtained by reaction of 2-ethoxymethylidene derivatives of 1,3-diketones with 1,3-benzothiazol-2-ylhydrazine or phenylhydrazine failed to isomerize to 1,3,4-trisubstituted pyrazoles.
- Petrov,Pakal’nis,Zerov,Yakimovich
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p. 381 - 392
(2017/05/10)
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- Synthesis and in vivo antifibrotic activity of novel leflunomide analogues
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Novel Leflunomide analogues were synthesized and evaluated in vivo against thioacetamide (TAA) induced liver fibrosis in rats. All the animals which were treated with the new analogues showed improved or comparable survival rates to those treated with Leflunomide. Animals which were treated with compounds 8d, 8e, 9 and 11 have shown improved liver parameters than Leflunomide treated animals. Histopathology of the liver has shown that compound 8a is the most active compound, which decreases fibrosis to a minimal level and compounds 8c, 8e and 11 are active compounds with fibrosis score 2-3 which is better than that of Leflunomide.
- Hamdi, Abdelrahman,Said, Eman,Farahat, Abdelbasset A.,El-Bialy, Serry A.A.,Massoud, Mohammed A.M.
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p. 912 - 920
(2016/10/31)
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- Novel 3-Aminothiazolquinolones: Design, Synthesis, Bioactive Evaluation, SARs, and Preliminary Antibacterial Mechanism
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A series of novel 3-aminothiazolquinolones as analogues of quinolone antibacterial agents were designed and synthesized in an effort to circumvent quinolone resistance. Among these 3-aminothiazolquinolones, 3-(2-aminothiazol-4-yl)-7-chloro-6-(pyrrolidin-1-yl) quinolone 12b exhibited potent antibacterial activity, low cytotoxicity to hepatocyte cells, strong inhibitory potency to DNA gyrase, and a broad antimicrobial spectrum including against multidrug-resistant strains. This active molecule 12b also induced bacterial resistance more slowly than norfloxacin. Analysis of structure-activity relationships (SARs) disclosed that the 2-aminothiazole fragment at the 3-position of quinolone plays an important role in exerting antibacterial activity. Molecular modeling and experimental investigation of aminothiazolquinolone 12b with DNA from a sensitive methicillin-resistant Staphylococcus aureus (MRSA) strain revealed that the possible antibacterial mechanism might be related to the formation of a compound 12b-Cu2+-DNA ternary complex in which the Cu2+ ion acts as a bridge between the backbone of 3-aminothiazolquinolone and the phosphate group of the nucleic acid.
- Cui, Sheng-Feng,Addla, Dinesh,Zhou, Cheng-He
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p. 4488 - 4510
(2016/06/13)
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- Application of 1,3,4-thiadiazole thioether derivative in preparing herbicide
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The invention discloses application of a 1,3,4-thiadiazole thioether derivative in preparing herbicide. A compound (I-1) and a compound (I-14) of the compound at the concentration of 100 micrograms/mL have good activity on wheat, sorghum, barnyard grass, cucumbers, rape and radishes, and the compound I-1, a compound I-9, a compound I-13 and the compound I-14 can achieve the suppression ratio of higher than 80% on winter rape and radishes. The compounds are new and have the herbicidal activity, and a basis is provided for research and development of new pesticides.
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Paragraph 0031; 0032
(2017/01/17)
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- Application of triazole compound containing methylpyrazole to bactericide preparation
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The invention relates to the application of a triazole compound containing methylpyrazole to bactericide preparation. The triazole compound containing methylpyrazole is a 5-(1-methyl-3-methyl-1H-pyrazol-4-base)-4-phenyl-4H-1,2,4-triazole-3-thioether compound. Specifically, a bactericide prepared from the compound has a remarkable effect when used for controlling rice sheath blight disease, tomato early blight, cucurbits anthracnose and cucumber gray mold. The compound is a novel compound with bactericidal activity, and a basis is provided for research and development of novel pesticides.
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Paragraph 0027-0029
(2017/05/05)
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- 1,3,4-thiadiazole thioether derivative, and preparation method and applications thereof
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The invention discloses a 1,3,4-thiadiazole thioether derivative, and a preparation method and applications thereof. The 1,3,4-thiadiazole thioether derivative is 5-(4-(1,3-dimethyl-1H-pyrazol))-1,3,4-thiadiazole-2-thioether derivative, and possesses certain inhibition effects on botrytis cinerea, colletotrichum orbiculare, botryospuaeria berengeriana, and rhizoctonia solani at a concentration of 20g/ml; inhibition ratio of a compound (I-10) on colletotrichum orbiculare is 43.06%. The 1,3,4-thiadiazole thioether derivative is a novel compound with antibacterial activity, and foundation is provided for development of new pesticides.
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Paragraph 0027; 0028
(2017/08/25)
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- Synthesis and antifungal activity of the derivatives of novel pyrazole carboxamide and isoxazolol pyrazole carboxylate
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A series of pyrazole carboxamide and isoxazolol pyrazole carboxylate derivatives were designed and synthesized in this study. The structures of the compounds were elucidated based on spectral data (infrared, proton nuclear magnetic resonance and mass spectroscopy). Then, all of the compounds were bioassayed in vitro against four types of phytopathogenic fungi (Alternaria porri, Marssonina coronaria, Cercospora petroselini and Rhizoctonia solani ) using the mycelium growth inhibition method. The results showed that some of the synthesized pyrazole carboxamides displayed notable antifungal activity. The isoxazole pyrazole carboxylate 7ai exhibited significant antifungal activity against R. solani, with an EC50 value of 0.37 μg/mL. Nonetheless, this value was lower than that of the commercial fungicide, carbendazol.
- Sun, Jialong,Zhou, Yuanming
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p. 4383 - 4394
(2015/05/06)
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- 1,5-NAPHTHYRIDINE DERIVATIVES AND MELK INHIBITORS CONTAINING THE SAME
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The present invention directs a compound represented by formula (I).
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Page/Page column 141
(2013/07/31)
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- Convergent and streamlined synthesis of 6-etherified imidazo[1,2-b] pyridazine-2-amine derivatives possessing VEGFR-2 kinase inhibitory activity
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A convergent and streamlined synthesis of selective vascular endothelial growth factor receptor (VEGFR) 2 kinase inhibitors has been achieved using a synthetic strategy based on an SNAr reaction of 6-chloroimidazo[1,2- b]pyridazine with phenols in the final step. For the synthesis of 6-chloroimidazo[1,2-b]pyridazine, a one-pot reaction using 3-amino-6- chloropyridazine, cyclopropanecarboxamide, and bromoacetyl bromide was developed. The phenols were easily prepared by chemoselective acylation of 3-aminophenols with pyrazole carboxylic acids, and an efficient and high-yielding synthesis of N-ethylpyrazole was also developed. The S NAr reaction of 6-chloroimidazo[1,2-b]pyridazine with phenols in DMSO in the presence of cesium carbonate successfully proceeded at 100-110 C to give the target products in good yields. This new chromatography-free process will be not only useful for the further bulk supply of these compounds but also applicable to the synthesis of other compounds containing the 6-etherified imidazo[1,2-b]pyridazin-2-amine core.
- Ishimoto, Kazuhisa,Sawai, Yasuhiro,Fukuda, Naohiro,Nagata, Toshiaki,Ikemoto, Tomomi
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p. 8564 - 8571
(2013/09/12)
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- Synthesis and properties of water-soluble 2-aminomethylidene derivatives of 1,3-dicarbonyl compounds
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A series of [(2-dimethylamino)ethylamino]methylidene-1,3-dicarbonyl compounds was synthesized for the first time starting from the corresponding 2-ethoxymethylidene derivatives and N,N-dimethylethylenediamine. It was shown that further alkylation of aminomethylidene derivatives with methyl iodide occurs regioselectively at the tertiary nitrogen atom. Quaternization products obtained exhibit high corrosion inhibition of mild steel in hydrochloric acid medium.
- Bazhin,Kudyakova,Gorbunova,Burgart,Zapevalov,Saloutin
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p. 1330 - 1335
(2013/09/23)
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- Novel 3,6,7-substituted pyrazolopyrimidines as positive allosteric modulators for the hydroxycarboxylic acid receptor 2 (GPR109A)
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A number of pyrazolopyrimidines were synthesized and tested for their positive allosteric modulation of the HCA2 receptor (GPR109A). Compound 24, an efficacious and potent agonist and allosteric enhancer of nicotinic acid's action, was the basis for most other compounds. Interestingly, some of the compounds were found to increase the efficacy of the endogenous ligand 3-hydroxybutyrate and enhance its potency almost 10-fold. This suggests that the pyrazolopyrimidines may have therapeutic value when given alone.
- Blad, Clara C.,Van Veldhoven, Jacobus P. D.,Klopman, Corné,Wolfram, Dieter R.,Brussee, Johannes,Lane, J. Robert,Ijzerman, Adriaan P.
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supporting information; experimental part
p. 3563 - 3567
(2012/06/04)
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- BENZAZEPINE DERIVATIVES FOR THE TREATMENT OF CENTRAL NERVOUS SYSTEM DISORDERS
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A compound having the formula (1) wherein: Ra represents C1-6 alkyl, cyclobutyl or cyclopentyl; R1 represents H or C1-6 alkyl; R2 represents H or R1 and R2 together represent =0; X1 represents CR3 or N; X2 represents CR4 or N; X3 represents CR5 or N; X4 represents CR6 or N; wherein one or two of X1, X2, X3 and X4 represents N; R3, R4, R5 and R6 each independently represent H, C1-6 alkoxy or -NR7R8; R7 and R8 independently represent H or C1-6 alkyl; or R7 and R8 and the N atom to which they are attached are joined to form a N-containing heterocyclyl ring optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl and C1-6 alkoxy; or a pharmaceutically acceptable salt thereof, is provided. Compounds of the invention have been found to modulate the histamine H3 receptor.
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Page/Page column 52-53
(2011/08/03)
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- Organocatalytic enantioselective synthesis of nitrogen-substituted dihydropyran-2-ones, a key synthetic intermediate of 1β-methylcarbapenems
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Organocatalytic enantioselective cycloadditions providing nitrogen-substituted dihydropyran-2-ones were developed in two catalytic systems. The (3R,4R)-product was a versatile intermediate in the synthesis of 1β-methylcarbapenem antibiotics.
- Kobayashi, Shoji,Kinoshita, Tatsuhiro,Uehara, Hisatoshi,Sudo, Tomoko,Ryu, Llhyong
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supporting information; experimental part
p. 3934 - 3937
(2009/12/05)
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- Methods for the preparation of pyrrolotriazine compounds
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A method for preparing a compound having the formula: including the steps of: (a) cyclizing a compound of formula II: to form a compound of formula I: (b) deprotecting the nitrogen atom of the compound of formula I by amination or hydrogenation to form compound III.
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Page/Page column 10-11
(2008/06/13)
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- Chiral DNA gyrase inhibitors. 3. Probing the chiral preference of the active site of DNA gyrase. Synthesis of 10-fluoro-6-methyl-6,7-dihydro-9- piperazinyl-2H-benzo[a]quinolizin-20-one-3-carboxylic acid analogues
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In pursuit of an apparent literature anomaly, S- and R-6-methyl-6,7- dihydro-2H-benzo[a]-quinolizin-2-one-3-carboxylic acids (12 and 22) were synthesized by an unambiguous route from optically active norephedrines, and their antibacterial potencies were measured. Against Gram-negative microorganisms and DNA gyrase a preference for S-absolute configuration was found whereas R-absolute stereochemistry was more active against Gram-positives. These results are in partial conflict with an earlier report. In an attempt to enhance potency, racemic 10-fluoro-9-piperazinyl (35) and related analogues were synthesized by a novel route. The latter analogues were surprisingly unimproved in potency. The implications of these findings are briefly discussed.
- Fecik, Robert A.,Devasthale, Pratik,Pillai, Segaran,Keschavarz-Shokri, Ali,Shen, Linus,Mitscher, Lester A.
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p. 1229 - 1236
(2007/10/03)
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- Indolyl and dihydroindolyl derivatives, their manufacture and use as pharmaceutical agents
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This invention relates to compounds of the formula wherein one of R6, R7 and R8 is and X, Y1 to Y4, R1 to R14 and n are as defined in the description, and to all enantiomers and pharmaceutically acceptable salts and/or esters thereof The invention further relates to pharmaceutical compositions containing such compounds, to a process for their preparation and to their use for the treatment and/or prevention of diseases which are modulated by PPARδ and/or PPARα agonists.
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Page/Page column 21
(2008/06/13)
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- Solvent-free synthesis of quinolone derivatives
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Quinolones can be prepared in a three step procedure from triethylorthoformate and activated methylene derivatives leading to alkoxymethylenemalonates followed by reaction with aromatic amines and finally a cyclization. All the reactions were carried out under solvent-free conditions possibly under microwave activation with benefits for the first step.
- Cernuchova, Petra,Vo-Thanh, Giang,Milata, Viktor,Loupy, Andre
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p. 177 - 191
(2007/10/03)
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- Solid-phase synthesis of 5-biphenyl-2-yl-1h-tetrazoles
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(Equation presented) The combinatorial synthesis of novel biphenyl tetrazoles is described. Key steps include the simultaneous biphenyl formation and phenol deallylation under Suzuki cross-coupling conditions as well as the tetrazole ring formation on solid support. A representative library of 20 biphenyl tetrazoles was synthesized.
- Kivrakidou, Olga,Braese, Stefan,Huelshorst, Frank,Griebenow, Nils
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p. 1143 - 1146
(2007/10/03)
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- Inhibitors of NF-kappaB and AP-1 gene expression: SAR studies on the pyrimidine portion of 2-chloro-4-trifluoromethylpyrimidine-5-[N-(3', 5'-bis(trifluoromethyl)phenyl)carboxamide].
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We investigated the structure-activity relationship studies of N-[3, 5-bis(trifluoromethyl)phenyl][2-chloro-4-(trifluoromethyl)pyrimidin-5 -yl]carboxamide (1), an inhibitor of transcription mediated by both NF-kappaB and AP-1 transcription factors, with the goal of improving its potential oral bioavailability. Compounds were examined for cell-based activity, were fit to Lipinski's rule of 5, and were examined for potential gastrointestinal permeability using the intestinal epithelial cell line, Caco-2. Selected groups were substituted at the 2-, 4-, and 5-positions of the pyrimidine ring using solution-phase combinatorial methodology. The introduction of a fluorine in the place of 2-chlorine of 1 resulted in a compound with comparable activity. However, other substitutions at the 2-position resulted in a loss of activity. The trifluoromethyl group at the 4-position could be replaced with a methyl, ethyl, chlorine, or phenyl without a substantial loss of activity. The carboxamide group at the 5-position is critical for activity. If it was moved to the 6-position, the activity was lost. The 2-methyl analogue of 1 (81) showed comparable in vitro activity and improved Caco-2 permeability compared to 1.
- Palanki,Erdman,Gayo-Fung,Shevlin,Sullivan,Goldman,Ransone,Bennett,Manning,Suto
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p. 3995 - 4004
(2007/10/03)
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- Reversible inhibitors of the gastric (H+/K+)-ATPase. 3. 3-Substituted-4- (phenylamino)quinolines
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Previously, gastric (H+/K+)-ATPase inhibitors such as 2 have been prepared as analogues of 1a on the presumption that the 3-carbethoxy substituent plays a key role in establishing the orientation of the 4- arylamino group. In this paper we explore further the contribution made to activity by the quinoline 3-substituent. We show that, for compounds bearing such a substituent, only a particular combination of properties provides high activity, both in vitro and as inhibitors of gastric acid secretion in vivo. The ability of the substituent to affect activity by restricting rotation about the C(quin)-N bond through a combination of both a π-electron withdrawal and hydrogen bonding is supported by the current study. However, high activity is only achieved if the effect of this group on the quinoline pK(a) is kept to a minimum. 3-Acyl substituents provide an optimum combination of electronic properties. From this series, compound 17c (SK and F 96067) was shown to be a potent inhibitor of histamine-stimulated gastric acid secretion after oral dosing in the Heidenhain pouch dog and was selected for further development and evaluation in man.
- Ife,Brown,Keeling,Leach,Meeson,Parsons,Reavill,Theobald,Wiggall
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p. 3413 - 3422
(2007/10/02)
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- Isoxazole-Oxazole Conversion by Beckmann Rearrangement
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A novel base-catalysed isoxazole-oxazole ring transformation was realized in the conversion of ethyl 5-hydroxy-3-(5-methylisoxazol-4-yl)isoxazole-4-carboxylate into 4-cyano-5-methyloxazol-2-ylacetic acid.A new process was developed for the preparation of t-4-amino-c-2-methyl-6-oxotetrahydropyran-r-3-carboxylic acid hydrochloride, a starting material for the synthesis of thienamycin.
- Doleschall, Gabor,Seres, Peter
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p. 1875 - 1880
(2007/10/02)
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