- Unprecedented folding in linker based flexible tripodal molecule and their conformational analysis
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Here, we first time report the flexible tripodal molecules, contained propylene as a linker, thiocyanuric acid as central core and, p-nitro phenol 1 and pyridazinone 2 as terminal for conformational studies. The conformational studies of these tripodal mo
- Gaurav, Archana,Kumar, Ranjeet,Gupta, Hariom,Ravikumar,Sridhar,Tewari, Ashish Kumar
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Read Online
- Selectivity in alkylation of phenols with 1-bromo-3-chloropropane using phase-transfer catalysis
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The use of various phase-transfer catalysts in the alkylation of phenol and substituted phenols with 1-bromo-3-chloropropane was investigated. When a quarternary ammonium salt of the general formula R'4N+ X-, where R' = alkyl with a minimum chain length of 4 was used, a mixture of 1-aryloxy-3-chloropropane and 1-aryloxy-3-bromopropane resulted. The effect of counterion, added potassium bromide, and catalysts other than quarternary ammonium salts were assessed for the halopropylation of 2,5-dimethylphenol.
- Reinholz,Becker,Hagenbruch,Schafer,Schmitt
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Read Online
- Delineation of G-Quadruplex Alkylation Sites Mediated by 3,6-Bis(1-methyl-4-vinylpyridinium iodide)carbazole-Aniline Mustard Conjugates
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A new G-quadruplex (G-4)-directing alkylating agent BMVC-C3M was designed and synthesized to integrate 3,6-bis(1-methyl-4-vinylpyridinium iodide)carbazole (BMVC) with aniline mustard. Various telomeric G-4 structures (hybrid-2 type and antiparallel) and an oncogene promoter, c-MYC (parallel), were constructed to react with BMVC-C3M, yielding 35 % alkylation yield toward G-4 DNA over other DNA categories (6 %) and high specificity under competition conditions. Analysis of the intact alkylation adducts by electrospray ionization mass spectroscopy (ESI-MS) revealed the stepwise DNA alkylation mechanism of aniline mustard for the first time. Furthermore, the monoalkylation sites and intrastrand cross-linking sites were determined and found to be dependent on G-4 topology based on the results of footprinting analysis in combination with mass spectroscopic techniques and in silico modeling. The results indicated that BMVC-C3M preferentially alkylated at A15 (H26), G12 (H24), and G2 (c-MYC), respectively, as monoalkylated adducts and formed A15-C3M-A21 (H26), G12-C3M-G4 (H24), and G2-C3M-G4/G17 (c-MYC), respectively, as cross-linked dialkylated adducts. Collectively, the stability and site-selective cross-linking capacity of BMVC-C3M provides a credible tool for the structural and functional characterization of G-4 DNAs in biological systems.
- Chen, Chien-Han,Hu, Tsung-Hao,Huang, Tzu-Chiao,Chen, Ying-Lan,Chen, Yet-Ran,Cheng, Chien-Chung,Chen, Chao-Tsen
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Read Online
- Synthesis and Antileishmanial Evaluation of Arylimidamide-Azole Hybrids Containing a Phenoxyalkyl Linker
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Due to the limitations of existing medications, there is a critical need for new drugs to treat visceral leishmaniasis. Since arylimidamides and antifungal azoles both show oral activity in murine visceral leishmaniasis models, a molecular hybridization approach was employed where arylimidamide and azole groups were separated by phenoxyalkyl linkers in an attempt to capitalize on the favorable antileishmanial properties of both series. Among the target compounds synthesized, a greater antileishmanial potency against intracellular Leishmania donovani was observed as the linker length increased from two to eight carbons and when an imidazole ring was employed as the terminal group compared to a 1,2,4-triazole group. Compound 24c (N-(4-((8-(1H-imidazol-1-yl)octyl)oxy)-2-isopropoxyphenyl) picolinimidamide) displayed activity against L. donovani intracellular amastigotes with an IC50 value of 0.53 μM. When tested in a murine visceral leishmaniasis model, compound 24c at a dose of 75 mg/kg/day p.o. for five consecutive days resulted in a modest 33% decrease in liver parasitemia compared to the control group, indicating that further optimization of these molecules is needed. While potent hybrid compounds bearing an imidazole terminal group were also strong inhibitors of recombinant CYP51 from L. donovani, as assessed by a fluorescence-based assay, additional targets are likely to play an important role in the antileishmanial action of these compounds.
- Abdelhameed, Ahmed,Feng, Mei,Joice, April C.,Zywot, Emilia M.,Jin, Yiru,La Rosa, Chris,Liao, Xiaoping,Meeds, Heidi L.,Kim, Yena,Li, Junan,McElroy, Craig A.,Wang, Michael Zhuo,Werbovetz, Karl A.
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p. 1901 - 1922
(2021/02/22)
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- COMPOUNDS AS NEURONAL HISTAMINE RECEPTOR-3 ANTAGONISTS AND USES THEREOF
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The present invention relates compounds of Formula (A) as H3R antagonists, as well as their preparation and uses, and further relates pharmaceutical compositions comprising these compounds and their uses as modulators of Histamine 3 Receptor (H3R) functions. The present invention also relates to the uses of the compounds or pharmaceutical compositions in treating or preventing certain disorders and diseases which relate to H3R functions in humans.
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Paragraph 0305; 0306
(2020/04/24)
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- Discovery of Diphenoxy Derivatives with Flexible Linkers as Ligands for β-Amyloid Plaques
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The highly rigid and planar scaffolds with π-conjugated systems have been widely considered to be indispensable for β-amyloid (Aβ) binding ligands. In this study, a library of diphenoxy compounds with different types of more flexible linkers as Aβ ligands were synthesized and evaluated. Most of them displayed good affinity (Ki1-42aggregates, and some ligands even showed values of Kiless than 10 nM. Structure-activity relationship analysis revealed that modification on the linkers or substituents tolerated great flexibility, which challenged the long-held belief that rigid and planar structures are exclusively favored for Aβ binding. Three ligands were labeled by iodine-125, and they exhibited good properties in vitro and in vivo, which further supported that this flexible scaffold was potential and promising for the development of Aβ imaging agents.
- Jia, Jianhua,Zhang, Longfei,Song, Jia,Dai, Jiapei,Cui, Mengchao
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p. 4089 - 4100
(2020/12/13)
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- Discovery of Carboline Derivatives as Potent Antifungal Agents for the Treatment of Cryptococcal Meningitis
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Clinical treatment of cryptococcal meningitis (CM) remains a significant challenge because of the lack of effective and safe drug therapies. Developing novel CM therapeutic agents with novel chemical scaffolds and new modes of action is of great importanc
- Tu, Jie,Li, Zhuang,Jiang, Yanjuan,Ji, Changjin,Han, Guiyan,Wang, Yan,Liu, Na,Sheng, Chunquan
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p. 2376 - 2389
(2019/03/07)
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- 1,3,4-OXADIAZOLE DERIVATIVE COMPOUNDS AS HISTONE DEACETYLASE 6 INHIBITOR, AND THE PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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The present invention relates to novel compounds having histone deacetylase 6 (HDAC6) in-hibitory activity, stereoisomers thereof or pharmaceutically acceptable salts thereof, the use thereof for the preparation of therapeutic medicaments, pharmaceutical compositions containing the same, a method for treating diseases using the composition, and methods for preparing the novel compounds. The novel compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof according to the present invention have histone deacetylase (HDAC) inhibitory activity and are effective for the prevention or treatment of HDAC6-mediated diseases, including infectious diseases; neoplasms; endocrine, nutritional and metabolic diseases; mental and be-havioral disorders; neurological diseases; diseases of the eye and adnexa; cardiovascular diseases; respiratory diseases; digestive diseases; diseases of the skin and subcutaneous tissue; diseases of the musculoskeletal system and connective tissue; or congenital malformations, de? formations and chromosomal abnormalities.
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Paragraph 5540-5542
(2017/02/28)
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- Diphenoxyl flexible molecules with high affinity with A[beta] plaque and preparation method and applications thereof
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The invention discloses diphenoxyl flexible molecules with high affinity with A[beta] plaque and a preparation method and applications thereof. After the molecules are labeled by radionuclide, the molecules can be used as an A[beta] plaque developing agen
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Paragraph 0073; 0074; 0079; 0080
(2017/12/09)
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- Piperazine substituted 1, 3 - di-substituted urea compound and piperazine substituted amide compounds and a method for its preparation and use
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The present invention relates to a class of piperazine substituted 1,3-disubstitued urea compounds and piperazine substituted amide compounds, or pharmaceutically acceptable salts of the piperazine substituted 1,3-disubstitued urea compounds and the piper
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Paragraph 0205-0207
(2017/04/22)
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- Photoresponsive ionic liquids with an azobenzene moiety
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We examined photoresponsive ionic liquids containing an azobenzene moiety. Ionic liquids with a p,p-azobenzene or o,p- tetrafluoroazobenzene moiety exhibit a reversible solid-to-liquid phase transition induced by photo- and thermal-stimulation. o,p-Azobenzene, which exists as an ionic liquid with a bent structure, is in a liquid state even as a trans-isomer. Such photoresponsive ionic liquids may be useful as novel functional materials, such as in optical sensors.
- Nobuoka, Kaoru,Kitaoka, Satoshi,Yamauchi, Toyokazu,Harran, Thomas,Ishikawa, Yuichi
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supporting information
p. 433 - 435
(2016/05/09)
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- Efficacy of novel phenoxyalkyl pyridinium oximes as brain-penetrating reactivators of cholinesterase inhibited by surrogates of sarin and VX
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Pyridinium oximes are strong nucleophiles and many are effective reactivators of organophosphate-inhibited cholinesterase (ChE). However, the current oxime reactivators are ineffective at crossing the blood-brain barrier and reactivating brain ChE in the intact organism. Our laboratories have developed a series of substituted phenoxyalkyl pyridinium oximes (US patent 9,227,937 B2) with the goal of identifying reactivators effective in crossing the blood-brain barrier. The first 35 of the series were found to have similar in?vitro efficacy as reactivators of ChE inhibited by a sarin surrogate (phthalimidyl isopropyl methylphosphonate, PIMP) or a VX surrogate (nitrophenyl ethyl methylphosphonate, NEMP) in bovine brain preparations as previously observed in rat brain preparations. A number of these novel oximes have shown the ability to decrease the level of ChE inhibition in the brains of rats treated with a high sublethal dosage of either a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) or the VX surrogate NEMP. Levels of reactivation at 2?h after oxime administration were up to 35% while the currently approved therapeutic, 2-PAM, yielded no reduction in brain ChE inhibition. In addition, there was evidence of attenuation of seizure-like behavior with several of the more effective novel oximes, but not 2-PAM. Therefore these novel oximes have demonstrated an ability to reactivate inhibited ChE in brain preparations from two species and in?vivo data support their ability to enter the brain and provide a therapeutic action. These novel oximes have the potential to be developed into improved antidotes for nerve agent therapy.
- Chambers, Janice E.,Chambers, Howard W.,Funck, Kristen E.,Meek, Edward C.,Pringle, Ronald B.,Ross, Matthew K.
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p. 154 - 159
(2016/12/06)
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- Synthesis and biological evaluation of a new series of ebselen derivatives as glutathione peroxidase (GPx) mimics and cholinesterase inhibitors against Alzheimer's disease
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A series of ebselen derivatives were designed, synthesised and evaluated as inhibitors of cholinesterases (ChEs) and glutathione peroxidase (GPx) mimics. Most of the compounds were found to be potent against AChEs and BuChE, compounds 5e and 5i, proved to be the most potent against AChE with IC50 values of 0.76 and 0.46 μM, respectively. Among these hybrids, most of the compounds were found to be good GPx mimics compare with ebselen. The selected compounds 5e and 5i were also used to determine the catalytic parameters and in vitro hydrogen peroxide scavenging activity. The results indicate that compounds 5e and 5i may be excellent multifunctional agents for the treatment of AD.
- Luo, Zonghua,Liang, Liang,Sheng, Jianfei,Pang, Yanqing,Li, Jianheng,Huang, Ling,Li, Xingshu
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supporting information
p. 1355 - 1361
(2014/03/21)
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- Room temperature, metal-free arylation of aliphatic alcohols
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Diaryliodonium salts are demonstrated as efficient arylating agents of aliphatic alcohols under metal-free conditions. The reaction proceeds at room temperature within 90 min to give alkyl aryl ethers in good to excellent yields. Aryl groups with electron
- Ghosh, Raju,Lindstedt, Erik,Jalalian, Nazli,Olofsson, Berit
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- Evaluation of novel aryloxyalkyl derivatives of imidazole and 1,2,4-triazole as heme oxygenase-1 (HO-1) inhibitors and their antitumor properties
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A novel series of aryloxyalkyl derivatives of imidazole and 1,2,4-triazole, 17-31, was designed and synthesized as inhibitors of heme oxygenase-1 (HO-1) and heme oxygenase-2 (HO-2). Some of these compounds were found to be good inhibitors of HO-1, in particular those carrying an imidazole moiety as azolyl group and a 3-bromo or 4-iodophenyl as aryl moiety. The most potent compounds 6 and 30 were selected and studied for their antitumor properties in a model of LAMA-84 R cell line overexpressing HO-1 and resistant to imatinib mesylate (IM), a tyrosine-kinase inhibitor used in the treatment of multiple types of cancer, most notably Philadelphia Chromosome positive (Ph+) Chronic Myelogenous Leukemia (CML). Results show that both 6 and 30 sensitized LAMA-84 R cell line to antitumor properties of IM.
- Salerno, Loredana,Pittalà, Valeria,Romeo, Giuseppe,Modica, Maria N.,Siracusa, Maria A.,Di Giacomo, Claudia,Acquaviva, Rosaria,Barbagallo, Ignazio,Tibullo, Daniele,Sorrenti, Valeria
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p. 5145 - 5153
(2013/09/02)
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- Discovery of potent and selective rhodanine type IKKβ inhibitors by hit-to-lead strategy
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Regulation of NF-κB activation through the inhibition of IKKβ has been identified as a promising target for the treatment of inflammatory and autoimmune disease such as rheumatoid arthritis. In order to develop novel IKKβ inhibitors, we performed high throughput screening toward around 8000 library compounds, and identified a hit compound containing rhodanine moiety. We modified the structure of hit compound to obtain potent and selective IKKβ inhibitors. Throughout hit-to-lead studies, we have discovered optimized compounds which possess blocking effect toward NF-κB activation and TNFα production in cell as well as inhibition activity against IKKβ. Among them, compound 3q showed the potent inhibitory activity against IKKβ, and excellent selectivity over other kinases such as p38α, p38β, JNK1, JNK2, and JNK3 as well as IKKα.
- Song, Hyeseung,Lee, Yun Suk,Roh, Eun Joo,Seo, Jae Hong,Oh, Kwang-Seok,Lee, Byung Ho,Han, Hogyu,Shin, Kye Jung
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scheme or table
p. 5668 - 5674
(2012/09/22)
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- Heterocyclyl linked anilines and benzaldehydes as precursors for biologically significant new chemical entities
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Benzylidene and benzyl thiazolidinediones, oxazolidinediones, isoxazolidinediones and their acyclic analogs like alpha alkylthio/alkoxy phenylpropanoic acids, beta-keto esters and tyrosine-based compounds possess broad therapeutic potential in general and as Peroxisome Proliferator Activated Receptors (PPARs) agonists in particular in the management of hyperglycemia and hyperlipidaemia for the treatment of Type 2 Diabetes (T2D). We have synthesised and characterized some novel and suitably substituted heterocyclyl linked benzaldehydes and anilines, which can be easily and very readily derivatized to all the above mentioned classes to generate new chemical entities of broader biological significance. Synthesis of their benzylidene thiazolidinedione and diethyl malonate and also benzyl diethyl malonate and alpha-bromoesters derivatives is reported in some of the cases in the present work. Indian Academy of Sciences.
- Verma, Raman K.,Kumar, Vijay,Ghosh, Prithwish,Wadhwa, Lalit K.
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p. 1063 - 1069
(2013/03/13)
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- Expeditious synthesis and biological evaluation of novel 2,N 6-disubstituted 1,2-dihydro-1,3,5-triazine-4,6-diamines as potential antimalarials
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A small set of novel 2,N6-disubstituted 1,2-dihydro-1,3,5- triazine-4,6-diamines was prepared possessing a flexible tether between the exocyclic nitrogen bonded to C-6 of the 1,2-dihydro-1,3,5-triazine-4,6-diamine heterocycle and the distal ary
- Gravestock, David,Rousseau, Amanda L.,Lourens, Anna C.U.,Moleele, Simon S.,Van Zyl, Robyn L.,Steenkamp, Paul A.
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experimental part
p. 2022 - 2030
(2011/06/21)
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- Incorporation of piperazino functionality into 1,3-disubstituted urea as the tertiary pharmacophore affording potent inhibitors of soluble epoxide hydrolase with improved pharmacokinetic properties
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The inhibition of the mammalian soluble epoxide hydrolase (sEH) is a promising new therapy in the treatment of hypertension, inflammation, and other disorders. However, the problems of limited water solubility, high melting point, and low metabolic stabil
- Huang, Shao-Xu,Li, Hui-Yuan,Liu, Jun-Yan,Morisseau, Christophe,Hammock, Bruce D.,Long, Ya-Qiu
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supporting information; experimental part
p. 8376 - 8386
(2011/02/21)
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- A light-controlled molecular brake with complete ON-OFF rotation
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A light-controlled molecular machine based on cyclic azobenzenophanes consisting of a dioxynaphthalene rotating unit and a photoisomerizable dioxyazobenzene unit bridged by methylene spacers is reported. In compounds 1 and 2, 1,5- and 2,6-dioxynaphthalene moieties, respectively, are linked to p-dioxyazobenzene by different methylene spacers (n = 2 in 1a and 2; n = 3 in 1b), whereas a 1,5-dioxynaphthalene moiety is bonded to m-dioxyazobenzene by bismethylene spacers in 3. In 1b and 2, the naphthalene ring can rotate freely in both the trans and cis states at room temperature. The rotation speed can be controlled either by photoinduced reversible trans-cis (E-Z) isomerization of the azobenzene or by keeping the system at low temperature, as is evident from its NMR spectra. Furthermore, for the first time, we demonstrate a light-controlled molecular brake, wherein the rotation of the naphthalene moiety through the cyclophane is completely OFF in the trans isomer of compound 3 due to its smaller cavity size. Such restricted rotation imparts planar chirality to the molecule, and the corresponding enantiomers could be resolved by chiral HPLC. However, the rotation of the naphthalene moiety is rendered ON in the cis isomer due to its increased cavity size, and it is manifested experimentally by the racemization of the separated enantiomers by photoinduced E-Z isomerization.
- Basheer, Meethale C.,Oka, Yoshimi,Mathews, Manoj,Tamaoki, Nobuyuki
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supporting information; experimental part
p. 3489 - 3496
(2010/07/04)
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- Hybrid ortho/allosteric ligands for the adenosine A1 receptor
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Many G protein-coupled receptors (GPCRs), including the adenosine A 1 receptor (A1AR), have been shown to be allosterically modulated by small molecule ligands. So far, in the absence of structural information, the exact location of
- Narlawar, Rajeshwar,Lane, J. Robert,Doddareddy, Munikumar,Lin, Judy,Brussee, Johannes,Ijzerman, Adriaan P.
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supporting information; experimental part
p. 3028 - 3037
(2010/09/07)
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- Antifolate and antiproliferative activity of 6,8,10-triazaspiro[4.5]deca-6,8-dienes and 1,3,5-triazaspiro[5.5]undeca-1,3-dienes
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Two series of triazaspiroalkanedienes, bearing a substituted phenoxy propyloxy side chain, were identified as potent mammalian DHFR inhibitors. One series has a 6,5-spiro bicyclic ring system and the other series has a 6,6-spiro bicyclic system. Both seri
- Ma, Xiang,Chui, Wai-Keung
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body text
p. 737 - 743
(2010/04/29)
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- Synthesis and biological evaluation of a new series of berberine derivatives as dual inhibitors of acetylcholinesterase and butyrylcholinesterase
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A series of novel berberine derivatives were designed, synthesized, and biologically evaluated as inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among these derivatives, compound 48a, berberine linked with 3-methylpyridi
- Huang, Ling,Luo, Zonghua,He, Feng,Lu, Jing,Li, Xingshu
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experimental part
p. 4475 - 4484
(2010/08/22)
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- Improved model of lanosterol 14α-demethylase by ligand-supported homology modeling: Validation by virtual screening and azole optimization
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Lanosterol 14α-demethylase (CYP51) is an important target for antifungal drugs. An improved three-dimensional model of CYP51 from Candida albicans (CACYP51) was constructed by ligand-supported homology modeling and molecular dynamics simulations. The accuracy of the constructed model was evaluated by its performance in a small-scale virtual screen. The results show that known CYP51 inhibitors were efficiently discriminated by the model, and it performed better than our previous CACYP51 model. The active site of CACYP51 was characterized by multiple copy simultaneous search (MCSS) calculations. On the basis of the MCSS results, a series of novel azoles were designed and synthesized, and they showed good in vitro antifungal activity with a broad spectrum. The MIC80 value of four of these compounds against C. albicans is 0.001 μgmL-1, indicating that they are promising leads for the discovery of novel antifungal agents.
- Sheng, Chunquan,Wang, Wenya,Che, Xiaoying,Dong, Guoqiang,Wang, Shengzheng,Ji, Haitao,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian
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experimental part
p. 390 - 397
(2010/11/18)
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- Synthesis and insecticidal activity of novel carbamate derivatives as potential dual-binding site acetylcholinesterase inhibitors
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In biological systems, bivalent ligands often possess increased functional affinity for their receptors compared with monovalent ligands. On the basis of the structure of acetylcholinesterase (AChE), a series of novel carbamate heterodimetic derivatives w
- Ma, Hong-Ju,Xie, Ru-Liang,Zhao, Qian-Fei,Mei, Xiang-Dong,Ning, Jun
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experimental part
p. 12817 - 12821
(2011/10/09)
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- New azoles with potent antifungal activity: Design, synthesis and molecular docking
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In response to the urgent need for novel antifungal agents with improved activity and broader spectrum, computer modeling was used to rational design novel antifungal azoles. On the basis of the active site of lanosterol 14α-demethylase from Candida albicans (CACYP51), a series of new azoles with substituted-phenoxypropyl piperazine side chains were rational designed and synthesized. In vitro antifungal activity assay indicates that the new azoles show good activity against most of the tested pathogenic fungi. Interestingly, the designed compounds are also active against an azole-resistant clinical strain. Compared to fluconazole and itraconazole, several compounds (such as 12i, 12j and 12n) show higher antifungal activity and broader spectrum, which are promising leads for the development of novel antifungal agents.
- Che, Xiaoying,Sheng, Chunquan,Wang, Wenya,Cao, Yongbing,Xu, Yulan,Ji, Haitao,Dong, Guoqiang,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian
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scheme or table
p. 4218 - 4226
(2009/12/09)
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- 4′-Alkoxyl substitution enhancing the anti-mitotic effect of 5-(3′,4′,5′-substituted)anilino-4-hydroxy-8-nitroquinazolines as a novel class of anti-microtubule agents
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Mitosis inhibitors are powerful anticancer drugs. Based on a novel anti-microtubule agent of 5-(4′-methoxy)anilino-4-hydroxy-8-nitroquinazoline, a series of 5-(3′,4′,5′-substituted)anilino-4-hydroxy-8- nitroquinazolines were designed and synthesized to investigate the effect of the substitution on the inhibitory activity against mitotic progression of tumor cells. The large alkoxyl substitution on the 4′-position of 5-anilino ring is beneficial for the potency. The 5-(3′,4′,5′-trimethoxy)anilino-8-nitroquinazoline (1h) displays an overwhelming activity in arresting the cells at the G2/M phase, providing a promising new template for further development of potent microtubule-targeted anti-mitotic drugs.
- Jin, Yi,Zhou, Zu-Yu,Tian, Wei,Yu, Qiang,Long, Ya-Qiu
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p. 5864 - 5869
(2007/10/03)
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- Synthesis and pharmacological evaluation of N-acyl-1,2,3,4- tetrahydroisoquinoline derivatives as novel specific bradycardic agents
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A series of N-acyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized and evaluated for their bradycardic activities in isolated guinea pig right atria and in urethane-anesthetized rats. These efforts resulted in identification of the compound 8a
- Kubota, Hideki,Watanabe, Toshihiro,Kakefuda, Akio,Masuda, Noriyuki,Wada, Kouichi,Ishii, Noe,Sakamoto, Shuichi,Tsukamoto, Shinichi
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p. 871 - 882
(2007/10/03)
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- Synthesis and Pharmacological Evaluation of 1-Oxo-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines and Related Analogues as a New Class of Specific Bradycardic Agents Possessing If Channel Inhibitory Activity
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A series of 1-oxo-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines and related analogues were prepared and evaluated for their bradycardic activities in isolated right atrium and in anesthetized rats. (± )-6,7-Dimethoxy-2-{1- [3-(3,4-methylenedioxyphenoxy)propyl]-3-piperidyl}-1,2,3, 4-tetrahydroisoquinoline (4) was chosen as a lead, and structural modifications were performed on the tetrahydroisoquinoline ring and the terminal aromatic ring. The modifications on the tetrahydroisoquinoline ring revealed that the 1-oxo-1,2,3,4-tetrahydroisoquinoline ring system was optimum structure for both in vitro potency and in vivo efficacy. Furthermore, methoxy, ethoxy, and methoxycarbonyl groups were identified as preferable substituents on the terminal aromatic ring. One of the 1-oxo-1,2,3,4-tetrahydroisoquinoline derivatives, (R)-10a, was further evaluated for its bradycardic activity and inhibitory activity against If currents. Compound (R)-10a demonstrated potent bradycardic activity in rats with minimal influence on blood pressure after oral administration. The compound also showed inhibition of If currents (IC50 = 0.32 μM) in guinea pig pacemaker cells.
- Kubota, Hideki,Kakefuda, Akio,Watanabe, Toshihiro,Ishii, Noe,Wada, Koichi,Masuda, Noriyuki,Sakamoto, Shuichi,Tsukamoto, Shin-ichi
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p. 4728 - 4740
(2007/10/03)
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- Phenoxypropoxybiguanides, prodrugs of DHFR-inhibiting diaminotriazine antimalarials
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A total of 34 analogues of the biguanide PS-15 (5s), a prodrug of the diaminotriazine WR-99210 (8s), have been prepared. Several of them, such as 5b (PS-33) and 5m (PS-26), maintain or exceed the in vivo activity of PS-15 while not requiring the use of highly regulated starting materials. The putative diaminotriazine metabolites of these new analogues (compounds 8) have also been prepared and shown to maintain the activity against resistant P. falciparum strains. The structure-activity relationships of biguanides 5 and putative metabolites 8 are discussed.
- Jensen,Ager,Bliss,Canfield,Kotecka,Rieckmann,Terpinski,Jacobus
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p. 3925 - 3931
(2007/10/03)
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- Synthesis and Activity against Multidrug Resistance in Chinese Hamster Ovary Cells of New Acridone-4-carboxamides
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A number of tricyclic carboxamides have been synthesized and tested to evaluate their ability to reverse multidrug resistance in the CHRC/5 cell line.Among them the acridone derivatives were the most potent.A key feature is the presence of a dimethoxybenzyl or phenethylamine cationic site, separated from the tricyclic lipophilic part by a carbamoylphenyl chain.Optimization led to compounds 2 orders of magnitude more active than the prototype inhibitors verapamil and amiodarone.On the basis of in vitro and in vivo activities, 9,10-dihydro-5-methoxy-9-oxo-N-phenyl>-4-acridinecarboxamide (84) has been selected for further development.
- Dodic, Nerina,Dumaitre, Bernard,Daugan, Alain,Pianetti, Pascal
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p. 2418 - 2426
(2007/10/02)
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