- Ratiometric Fluorescent Probe for Lysosomal pH Measurement and Imaging in Living Cells Using Single-Wavelength Excitation
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A novel lysosome-targeting ratiometric fluorescent probe (CQ-Lyso) based on the chromenoquinoline chromorphore has been developed for the selective and sensitive detection of intracellular pH in living cells. In acidic media, the protonation of the quinol
- Liu, Xingjiang,Su, Yuanan,Tian, Huihui,Yang, Lei,Zhang, Hongyan,Song, Xiangzhi,Foley, James W.
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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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- Design, synthesis, biological evaluation and molecular dynamics simulation studies of (R)-5-methylthiazolidin-4-One derivatives as megakaryocyte protein tyrosine phosphatase 2 (PTP-MEG2) inhibitors for the treatment of type 2 diabetes
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PTP-MEG2 plays a significant role in insulin production and is able to enhance insulin signaling and improve insulin sensitivity. So, PTP-MEG2 inhibitors are closely associated with type 2 diabetes therapy. A series of novel (R)-5-methylthiazolidin-4-one
- Wu, Jingwei,Sun, Yingzhan,Zhou, Hui,Ma, Ying,Wang, Runling
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p. 3156 - 3165
(2019/08/26)
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- Design potential selective inhibitors for human leukocyte common antigen-related (PTP-LAR) with fragment replace approach
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The overexpression of PTP-LAR could cause the insulin resistance, so PTP-LAR might be a promising target for treating diabetes. In this study, we applied the computer modeling methods with fragment replace approach to screen the fragment database by targeting PTP domain and site B with the aim to discover potent and selective PTP-LAR inhibitors. A series of novel 4-thiazolidone derivatives were gained. The results of their ADMET predictions indicated that these new compounds might become drug candidates. The series of these derivatives were synthesized. Subsequently, their PTP-LAR inhibitory activities were assayed. The compound7d showed highly selectivity for PTP-LAR (10.41 μM) over its close homolog PTP1B (IC50=44.40 μM), SHP2 (IC50>122.81 μM) and CDC25B (IC50>122.81 μM) and docking and molecular dynamics simulation were applied to propose the most likely binding mode of compound7d with PTP-LAR. Thus, our findings reported here may pave a way for discovering potential selective PTP-LAR inhibitors. AbbreviationsPTP-LAR Human leukocyte common antigen-relatedPTP Protein Tyrosine PhosphataseIR insulin receptorPTP1B Protein tyrosine phosphatase-1BLRP Lung resistance proteinADMET absorption, distribution, metabolism, excretion, toxicityPPB plasma protein bindingBBB blood brain barrier penetrationCYP450 cytochrome P450HIA human intestinal absorptionTLC thin-layer chromatographyUV Ultra VioletNMR nuclear magnetic resonanceTMS tetramethylsilaneMS mass spectrometryANM anisotropic network modePDB Protein Data BankDMF N,N-DimethylformamidepNPP para-nitrophenyl phosphateDTT dithiothreitolMD molecular dynamicRMSD root-mean-square deviationRMSF root-mean-square fluctuationSPC single-point chargePME Particle Mesh EwaldMM-PBSA molecular mechanics Poisson Boltzmann surface areaH bond, hydrogen bondVDW Van der Waals Communicated by Ramaswamy H. Sarma.
- Li, Hong-Lian,Li, Wei-Ya,Lu, Xin-Hua,Ma, Ying,Tang, Xue,Wang, Run-Ling,Wu, Jing-Wei,Zhang, Huan,Zheng, Zhi-Hui
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p. 5338 - 5348
(2019/12/24)
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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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- ANTI-FUNGAL TREATMENT
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Provided are compounds, methods, and pharmaceutical compositions useful for treatment of fungal infections, e.g., aspergillosis, candidiasis, cryptococcosis, histoplasmosis, and the like. For example, the pharmaceutical composition may include a pharmaceutically acceptable carrier or excipient, and a compound represented by Ar— C(=NR1)NR2— A---X— Y— Het2 and pharmaceutically acceptable salts thereof. Ar may be an optionally substituted aryl or nitrogen- containing heteroaryl. R1 and R2 may independently be H, optionally substituted C1-C6 aikyi, or optionally substituted C3-C6 cyeloalkyi. A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cyeloalkyi, heterocycloalkyl, and heteroaryl. X may be O, S, amide, or a bond. Y may be optionally substituted C1-C10 alkyi or optionally substituted C2-C10 alkenyl. Het2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
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Paragraph 0096
(2018/03/25)
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- ANTI-PARASITIC COMPOUNDS
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Provided are compounds, methods, and pharmaceutical compositions useful for treatment of parasites, e.g., Leishmania. For example, the compound may he represented by Ar—C(=NR1)NR2—A—X—Y—Het2, and pharmaceutically acceptable salts thereof. Ar may be an optionally substituted, aryl or nitrogen-containing heteroaryl. R1 and R2 may independently represent H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl. A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl. X may be O, S, amide, or a bond. Y may be optionally substituted C1-C14 alkyl or optionally substituted C2-C14 alkenyl. Het2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
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Paragraph 00121
(2018/03/25)
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- With high planarity of the naphthalene structure function diamine monomer and its synthetic method and application
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The invention discloses functional diamine monomers having high planarity and containing a naphthaline structure and a synthesis method and application thereof. The novel functional diamine monomers are prepared from raw materials monomers such as dihalogenated naphthaline, naphthalic acid, naphthalenediol or naphthylenediamine through a series of chemical reactions such as substitution reaction, Suzuki reaction, amidation reaction, esterification reaction, Grignard reaction, Kumada coupling reaction. The diamine monomers containing a naphthaline structure, which have a lowest energy state 3D molecular structure and have high planarity, can be obtained. Due to planar space structure, the diamine monomers disclosed by the invention can serve as monomers used for preparing polymers with strong molecular chain interaction force, tight molecular chain packing and small free volume and the polymers can be endowed with an excellent barrier property. The synthesis method of the diamine monomers is simple in process and purification operation is easy; therefore, the synthesis method is suitable for industrial production. The diamine monomers disclosed by the invention can be used for synthesizing functional polymers such as polyamide, polyimide, polyamide-imide and polyester-imide.
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Paragraph 0063; 0064; 0065
(2017/08/25)
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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 5560-5562
(2017/02/28)
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- Preparation and application of novel lyase in-vivo pH ratio fluorescent probe
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The invention relates to preparation and application of a novel lyase in-vivo pH ratio fluorescent probe. The structure of the probe is as shown in the specification. The probe molecule is capable of dynamically monitoring variation of the lyase in-vivo p
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Paragraph 0024
(2017/08/28)
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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; 0081; 0082
(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 0329-0331
(2017/04/22)
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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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- 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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- 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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- 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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- 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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- 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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- Discovery of highly potent novel antifungal azoles by structure-based rational design
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On the basis of the active site of lanosterol 14α-demethylase from Candida albicans (CACYP51), a series of new azoles were designed and synthesized. All the new azoles show excellent in vitro activity against most of the tested pathogenic fungi, which represent a class of promising leads for the development of novel antifungal agents. The MIC80 value of compounds 8c, 8i and 8n against C. albicans is 0.001 μg/mL, indicating that these compounds are more potent than fluconazole, itraconazole and voriconazole. Flexible molecular docking was used to analyze the structure-activity relationships (SARs) of the compounds. The designed compounds interact with CACYP51 through hydrophobic, van der Waals and hydrogen-bonding interactions.
- Wang, Wenya,Sheng, Chunquan,Che, Xiaoying,Ji, Haitao,Cao, Yongbing,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian
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supporting information; experimental part
p. 5965 - 5969
(2010/07/04)
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- 9-anilinoacridine alkylating agents
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This invention relates to 9-anilinoacridine alkylating agents, their synthesis and their use in pharmaceutical compositions for treating diseases.
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Page/Page column 15
(2008/12/07)
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- Design of PAP-1, a selective small molecule Kv1.3 blocker, for the suppression of effector memory t cells in autoimmune diseases
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The lymphocyte K+ channel Kv1.3 constitutes an attractive pharmacological target for the selective suppression of terminally differentiated effector memory T (TEM) cells in T cell mediated autoimmune diseases, such as multiple sclerosis and type 1 diabetes. Unfortunately, none of the existing small molecule Kv1.3 blockers is selective, and many of them, such as correolide, 4-phenyl-4-[3-(methoxyphenyl)-3-oxo-2- azapropyl] cyclohexanone, and our own compound Psora-4 inhibit the cardiac K+ channel Kv1.5. By further exploring the structure activity relationship around Psora-4 through a combination of traditional medicinal chemistry and whole-cell patch-clamp, we identified a series of new phenoxyalkoxypsoralens that exhibit 2- to 50-fold selectivity for Kv1.3 over Kv1.5, depending on their exact substitution pattern. The most potent and "druglike" compound of this series, 5-(4-phenoxybutoxy)psoralen (PAP-1), blocks Kv1.3 in a use-dependent manner, with a Hill coefficient of 2 and an EC50 of 2 nM, by preferentially binding to the C-type inactivated state of the channel. PAP-1 is 23-fold selective over Kv1.5, 33- to 125-fold selective over other Kv1-family channels, and 500- to 7500-fold selective over Kv2.1, Kv3.1, Kv3.2, Kv4.2, HERG, calcium-activated K+ channels, Na+, Ca2+, and Cl- channels. PAP-1 does not exhibit cytotoxic or phototoxic effects, is negative in the Ames test, and affects cytochrome P450-dependent enzymes only at micromolar concentrations. PAP-1 potently inhibits the proliferation of human TEM cells and suppresses delayed type hypersensitivity, a TEM cell-mediated reaction, in rats. PAP-1 and several of its derivatives therefore constitute excellent new tools to further explore Kv1.3 as a target for immunosuppression and could potentially be developed into orally available immunomodulators. Copyright
- Schmitz, Alexander,Sankaranarayanan, Ananthakrishnan,Azam, Philippe,Schmidt-Lassen, Kristina,Homerick, Daniel,Haensel, Wolfram,Wulff, Heike
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p. 1254 - 1270
(2007/10/03)
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- Potent antitumor 9-anilinoacridines bearing an alkylating N-mustard residue on the anilino ring: Synthesis and biological activity
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A series of N-mustard derivatives of 9-anilinoacridine was synthesized for antitumor and structure-activity relationship studies. The alkylating N-mustard residue was linked to the C-3′ or C-4′ position of the anilino ring with an O-ethylene (O-C2/s
- Bacherikov, Valeriy A.,Chou, Ting-Chao,Dong, Hua-Jin,Zhang, Xiuguo,Chen, Ching-Huang,Lin, Yi-Wen,Tsai, Tsong-Jen,Lee, Rong-Zau,Liu, Leroy F.,Su, Tsann-Long
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p. 3993 - 4006
(2007/10/03)
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- Benzamidine derivatives
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The present invention relates to benzamidine derivatives corresponding to the general formula STR1 in which: A represents a linear or branched alkyl chain containing from 3 to 9 carbon atoms; and X represents the oxygen atom or a direct bond, with the restriction that if X represents a direct bond, the benzamidine and the alkanol group are located in the para position, and also the pharmaceutically acceptable salts of the products of the formula (I); it also relates to a process for the preparation of the products of the formula (I) and the drugs for external use which contain a product of the formula (I).
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