- Design, synthesis and biological evaluation of novel triaryldimethylaminobutan-2-ol derivatives against Mycobacterium tuberculosis
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Bedaquiline (TMC207), a typical diarylquinoline anti-tuberculosis drug, has been approved by FDA to specifically treat MDR-TB. Herein we describe design, synthesis, and in vitro biological evaluation against Mycobacterium tuberculosis of a series of triaryldimethylaminobutan-2-ol derivatives obtaining from the structural modification of TMC207. Compounds 23, 25, 28, 32, 39 and 43 provided superior anti-mycobacterial activity than positive control PC01 which shows the same configuration and contains TMC207. Compounds 16, 20, 29, 34, 37, 45 and 47 exhibited the similar activity to positive control PC01. Most importantly, the series of compounds showed excellent activity against XDR-Mtb. The result of acute toxicity suggested that this class of triaryldimethylaminobutan-2-ol derivatives should be graded as low. Further SAR analysis indicates that a large steric bulk of triaryl and 7-Br, 3-OCH3 on 1-naphthyl are critical.
- Cao, Ruiyuan,Fan, Shiyong,Li, Song,Liu, Ping,Lu, Yu,Wang, Bin,Wang, Xiaokui,Zhong, Wu
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- The discovery and optimization of naphthalene-linked P2-P4 Macrocycles as inhibitors of HCV NS3 protease
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Naphthalene-linked P2-P4 macrocycles within a tri-peptide-based acyl sulfonamide chemotype have been synthesized and found to inhibit HCV NS3 proteases representing genotypes 1a and 1b with single digit nanomolar potency. The pharmacokinetic profile of compounds in this series was optimized through structural modifications along the macrocycle tether as well as the P1 subsite. Ultimately a compound with oral bioavailability of 100% in rat, and a long half-life in plasma was obtained. However, compounds in this macrocyclic series exhibited cardiac effects in an isolated rabbit heart model and for this reason further optimization efforts were discontinued.
- Bowsher, Michael,Hiebert, Sheldon,Li, Rongti,Wang, Alan X.,Friborg, Jacques,Yu, Fei,Hernandez, Dennis,Wang, Ying-Kai,Klei, Herbert,Rajamani, Ramkumar,Mosure, Kathy,Knipe, Jay O.,Meanwell, Nicholas A.,McPhee, Fiona,Scola, Paul M.
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supporting information
p. 43 - 48
(2017/11/29)
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- Aromatic 2-butanol chiral compound, asymmetric synthesis and medical application of aromatic 2-butanol chiral compound
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The invention relates to an aromatic 2-butanol chiral compound, a chiral synthetic method and a medical application of the aromatic 2-butanol chiral compound. The aromatic 2-butanol chiral compound has a chemical structure of the general formula I, contains two chiral centers, and is prepared through 18-step reaction. In the reaction, the optical purity of the final product is decided through the Sharpless asymmetric epoxidation step. Compared with the method in the prior art, the method allows four optical isomers of the compound with the general formula I to be conveniently prepared, and the enantioselectivity is high (the e.e. value can reach 87-97%). The invention further relates to the compound, pharmaceutically acceptable salt and solvate thereof, and an application of a pharmaceutical composition containing the compound to prevent or treat diseases or symptoms related to mycobacterium tuberculosis infection.
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Paragraph 0075; 0076; 0077
(2017/08/29)
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- Asymmetric synthesis and absolute configuration assignment of a new type of bedaquiline analogue
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Bedaquiline is the first FDA-approved new chemical entity to fight multidrug-resistant tuberculosis in the last forty years. Our group replaced the quinoline ring with a naphthalene ring, leading to a new type of triarylbutanol skeleton. An asymmetric synthetic route was established for our bedaquiline analogues, and the goal of assigning their absolute configurations was achieved by comparison of experimental and calculated electronic circular dichroism spectra, and was confirmed by the combined use of circular dichroism and NMR spectroscopy.
- Qiao, Chang-Jiang,Wang, Xiao-Kui,Xie, Fei,Zhong, Wu,Li, Song,Dehaen, Wim
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p. 22272 - 22285
(2016/01/25)
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- AROMATIC BUTAN-2-OL COMPOUNDS, PREPARATION METHODS AND USES THEREOF
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The present invention relates to aromatic butan-2-ol compounds and preparation methods and uses thereof. Specifically, the present invention relates to the compound of Formula I, or an optical isomer, racemate, diastereomer, pharmaceutically acceptable salt or solvate thereof: wherein each of the substituents have the definitions as given in the specification. The present invention further relates to a pharmaceutical composition containing the compound, and the use of the compound in manufacture of a medicament for the treatment and/or prophylaxis of a disease or disorder caused by tubercle bacillus infection. The compound of Formula I of the present invention has advantages in treatment and/or prophylaxis of a disease or disorder caused by tubercle bacillus infection.
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Paragraph 0051; 0052
(2013/04/10)
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- Substituted 6-phenyl-2-naphthols. Potent and selective nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1): Design, synthesis, biological evaluation, and pharmacokinetics
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17β-Estradiol (E2) is implicated in the genesis and the development of estrogen-dependent diseases. Its concentration is mainly regulated by 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), which catalyzes the reduction of the weak estrogen estrone (E1) to the highly potent E2. This enzyme is thus an important target for the treatment of hormone-dependent diseases. Thirty-seven novel substituted 6-phenyl-2-naphthols were synthesized and evaluated for 17β-HSD1 inhibition, selectivity toward 17β-HSD2 and the estrogen receptors (ERs) α and β, and pharmacokinetic properties. SAR studies revealed that the compounds most likely bind according to binding mode B to the active site, i.e., the 6-phenyl moiety mimicking the steroidal A-ring. While substitution at the phenyl ring decreased activity, introduction of substituents at the naphthol moiety led to highly active compounds, especially in position 1. The 1-phenyl compound 32 showed a very high inhibitory activity for 17β-HSD1 (IC50 = 20 nM) and good selectivity (17β-HSD2 and ERs) and pharmacokinetic properties after peroral application.
- Marchais-Oberwinkler, Sandrine,Krachten, Patricia,Frotscher, Martin,Ziegler, Erika,Neugebauer, Alexander,Bhoga, Umadevi,Bey, Emmanuel,Müller-Vieira, Ursula,Messinger, Josef,Thole, Hubert,Hartmann, Rolf W.
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scheme or table
p. 4685 - 4698
(2009/07/19)
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- PHAMACEUTICAL PREPARATIONS COMPRISING INSULIN
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Novel preparations comprising ligands for the HisB10 Zn2+ sites of the R-state insulin hexamer wherein the ligand is extended by protamine that are capable of prolonging the ac-tion of insulin preparations.
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Page/Page column 240
(2010/02/15)
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- Stabilised insulin compositions
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The present invention provides pharmaceutical compositions comprising insulin and novel ligands for the HisB10 Zn2+ sites of the R-state insulin hexamer. The resulting preparations have improved physical and chemical stability.
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Page/Page column 130
(2008/06/13)
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- Synthesis and characterization of iodobenzamide analogues: Potential D-2 dopamine receptor imaging agents
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(S)-N-[(1-Ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-3-iodo-6-methoxybenza mide ([123I]IBZM) is a central nervous system (CNS) D-2 dopamine receptor imaging agent. In order to investigate the versatility of this parent structure in specific dopamine receptor localization and the potential for developing new dopamine receptor imaging agents, a series of new iodinated benzamides with fused ring systems, naphthalene (INAP) and benzofuran (IBF), was synthesized and radiolabeled, and the in vivo and in vitro biological properties were characterized. The best analogue of IBZM is IBF (21). The specific binding of [125I]IBF (21) with rat striatal tissue preparation was found to be saturable and displayed a K(d) of 0.106 ± 0.015 nM. Competition data of various receptor ligands (for [125I]IBF (21) binding show the following rank order of potency: spiperone > IBF (21) > IBZM > (+)-butaclamol > (±)-ADTN,6,7 > ketanserin > SCH-23390 >> propranolol. The in vivo biodistribution results confirm that [125I]IBF (21) concentrated in the striatal area after iv injection into rats. The study demonstrates that [123I]IBF (21) is a potential agent for imaging CNS D-2 dopamine receptors.
- Murphy,Kung,Kung,Billings
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p. 171 - 178
(2007/10/02)
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