Simple exploration of 4-(4-((2,4-Dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile

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Quinolones used as MRS inhibitors and bactericides

Compounds of formula (I) are inhibitors of the bacterial enzyme S aureus methionyl tRNA synthetase and are of use in treating bacterial infections.

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Molecular Docking Studies and Synthesis of Amino-oxy-diarylquinoline Derivatives as Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors

In this study, amino-oxy-diarylquinolines were designed using structure-guided molecular hybridization strategy and fusing of the pharmacophore templates of nevirapine (NVP), efavirenz (EFV), etravirine (ETV, TMC125) and rilpivirine (RPV, TMC278). The anti-HIV-1 reverse transcriptase (RT) activity was evaluated using standard ELISA method, and the cytotoxic activity was performed using MTT and XTT assays. The primary bioassay results indicated that 2-amino-4-oxy-diarylquinolines possess moderate inhibitory properties against HIV-1 RT. Molecular docking results showed that 2-amino-4-oxy-diarylquinolines 8(a-d) interacted with the Lys101 and His235 residue though hydrogen bonding and interacted with Tyr318 residue though pi-pi stacking in HIV-1 RT. Furthermore, 8a and 8d were the most potent anti-HIV agents among the designed and synthesized compounds, and their inhibition rates were 34.0% and 39.7% at 1 muM concentration. Interestingly, 8a was highly cytotoxicity against MOLT-3 (acute lymphoblastic leukemia), with an IC 50 of 4.63¡À0.62 mug/mL, which was similar with that in EFV and TMC278 (IC 50 7.76¡À0.37 and 1.57¡À0.20 mug/ml, respectively). Therefore, these analogs of the synthesized compounds can serve as excellent bases for the development of new anti-HIV-1 agents in the near future.

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Large-scale solvent-free chlorination of hydroxy-pyrimidines,-pyridines,- pyrazines and-amides using equimolar POCl3

Chlorination with equimolar POCl3 can be efficiently achieved not only for hydroxypyrimidines, but also for many other substrates such as 2-hydroxy-pyridines,-quinoxalines, or even-amides. The procedure is solvent-free and involves heating in a sealed reactor at high temperatures using one equivalent of pyridine as base. It is suitable for large scale (multigram) batch preparations.

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PYRIDINE COMPOUNDS AND METHODS OF THEIR USE

Novel pyridine compounds, pharmaceutical compositions containing the pyridine compounds, and methods of their pharmaceutical use are disclosed. In certain embodiments, the pyridine compounds are agonists and/or ligands of cannabinoid receptors and may be useful, inter alia, for treating and/or preventing pain, gastrointestinal disorders, inflammation, auto-immune diseases, ischemic conditions, immune-related disorders, hypertension, neurological disorders, and neurodegenerative diseases, for providing cardioprotection against ischemic and reperfusion effects, for inducing apoptosis in malignant cells, for inhibiting mechanical hyperalgesia associated with nerve injury, and as an appetite stimulant.

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Discovery and SAR study of piperidine-based derivatives as novel influenza virus inhibitors

A series of piperidine-based derivatives were identified as novel and potent inhibitors of the influenza virus through structural modification of a compound that was selected from a high-throughput screen. Various analogues were synthesized and confirmed as inhibitors. The structure-activity relationship (SAR) studies suggested that the ether linkage between the quinoline and piperidine is critical for the inhibitory activity. The optimized compound tert-butyl 4-(quinolin-4-yloxy)piperidine-1-carboxylate 11e had an excellent inhibitory activity against influenza virus infection from a variety of influenza virus strains, with EC50values as low as 0.05 muM. The selectivity index value (SI = MLD50/EC50) of 11e is over 160 000 based on cytotoxicity, measured by MTT assays of three cell lines. We carried out a time-of-addition experiment to delineate the mechanism of inhibition. The result indicates that 11e interferes with the early to middle stage of influenza virus replication.

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Regioselective reactions of organozinc reagents with 2,4- dichloroquinoline and 5,7-dichloropyrazolo[1,5-alpha]pyrimidine

Strategies for controlling the regioselective reactions between 2,4- dichloroquinoline and organozinc reagents are described. 2,4- Dichloroquinoline has been found to react with benzylic zinc and phenylzinc reagents in the presence of catalytic amounts of palladium complexes to exclusively give alpha-substituted products. Several metal salts were examined as an additive for gamma-selective coupling reactions. The most effective additive for selective coupling reaction at the gamma-position has been found to be LiCl. These conditions for alpha- or gamma-selective coupling reactions were applied to the reaction between 5,7-dichloropyrazolo[1,5-alpha]pyrimidine and a biphenylmethylzinc reagent in the synthesis of the angiotensin II receptor antagonists. This regioselectivity should be generally applicable to other alpha,gamma-dichloroazine systems.

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Brief introduction of 1055361-35-7

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A Fe(III)/NaBH4-Promoted Free-Radical Hydroheteroarylation of Alkenes

A free-radical-mediated intermolecular hydroheteroarylation of simple alkenes was developed. Through simply mixing heteroarenes, alkenes, Fe(III), and NaBH4 at 0 C together, a wide range of alkylated heteroarenes could be afforded in moderate to excellent yields within 1 h.

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Synthesis of aryl-heteroaryl ureas (AHUs) based on 4-aminoquinoline and their evaluation against the insulin-like growth factor receptor (IGF-1R)

The insulin-like growth factor receptor (IGF-1R) is a receptor tyrosine kinase (RTK) involved in all stages of the development and propagation of breast and other cancers. The inhibition of IGF-1R by small molecules remains a promising strategy to treat cancer. Herein, we explore SAR around previously characterized lead compound (1), which is an aryl-heteroaryl urea (AHU) consisting of 4-aminoquinaldine and a substituted aromatic ring system. A library of novel AHU compounds was prepared based on derivatives of the 4-aminoquinoline heterocycle (including various 2-substituted derivatives, and naphthyridines). The compounds were screened for in vitro inhibitory activity against IGF-1R, and several compounds with improved activity (3-5 muM) were identified. Furthermore, a computational docking study was performed, which identifies a fairly consistent lowest energy mode of binding for the more-active set of inhibitors in this series, while the less-active inhibitors do not adopt a consistent mode of binding.

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More research is needed about 4-(4-((2,4-Dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile

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Effect of substituents in the syntheses of phenyl-substituted dibenzonaphthyridines

A facile and elegant syntheses of linear and angular phenyl-substituted dibenzonaphthyridines from 2,4-dichloroquinolines through anilinoquinolines have been developed. The substituents in the 4th position of the anilinoquinoline and the temperature were found to play a vital role in the regulation of the yield towards the synthesis of the final compounds. The methyl group in the 7th position of the naphthyridin-11-ones was found to hinder the N-methylation reaction sterically, consequently increasing the reaction time than other derivatives.

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MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators

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