- Microwave assisted synthesis of melatonin
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Melatonin was prepared from phthalimide by N- and C-alkylation, cyclization, hydrolytic, decarboxylation, and acetylation. The four-pot reactions were carried out on microwave irradiation in good yield with short time.
- He, Ling,Li, Ju-Lian,Zhang, Jian-Jun,Su, Pu,Zheng, Shi-Long
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Read Online
- Discovery of imidazopyridines containing isoindoline-1,3-dione framework as a new class of BACE1 inhibitors: Design, synthesis and SAR analysis
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Alzheimer's disease is characterized by chronic neurodegeneration leading to dementia. The main cause of neurodegeneration is considered to be the accumulation of amyloid-β. Inhibiting BACE1 is a well-studied approach to lower the burden of amyloid-β aggregates. We designed a series of imidazopyridines-based compounds bearing phthalimide moieties as inhibitors of BACE1. The compounds 8a-o were synthesized by the Groebke–Blackburn–Bienaymé three-component reaction of heteroaromatic amidines, aldehydes and isocyanides. Evaluating the BACE1 inhibitory effects of the synthesized compounds revealed that introducing an aminocyclohexyl moiety in the imidazopyridine core resulted in a significant improvement in its BACE1 inhibitory potential. In this regard, compound 8e was the most potent against BACE1 with an IC50 value of 2.84 (±0.95) μM. Molecular docking revealed that the nitrogen atom of imidazopyridines and the oxygen atom of the phenoxypropyl linker were involved in hydrogen bound interactions with Asp228 and Asp32 of BACE1 active site, respectively. The phthalimide moiety oriented toward the flap pocket and interacted with phe108, lle110, Trp115, Ile118 through van der Waal's and hydrophobic interactions. These findings demonstrate that imidazopyridines-based compounds bearing phthalimide moiety have the potential to decrease amyloid-β levels and ameliorate the symptoms of Alzheimer's disease.
- Azimi, Sara,Zonouzi, Afsaneh,Firuzi, Omidreza,Iraji, Aida,Saeedi, Mina,Mahdavi, Mohammad,Edraki, Najmeh
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Read Online
- Study of the structure-bioactivity of fleximers: synthesis, crystal structure, Hirshfeld surface analysis, and anti-inflammatory assays
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Synthesized and natural pyridones/pyridines derivatives exhibiting diverse biological activities. 2-pyridone has lactam-lactim tautomerization like thymine and uracil bases. In this study, COX-2 target based series of pyridone/pyridine linked fleximers were designed, synthesized and studied. All analogues binding affinity with COX-2 active site were studied through molecular docking, and anti-inflammatory activity studied by in vivo analysis. Weak interactions were studied to find binding sites among analogues through crystal packing, Hirshfeld surface analysis and in silico analysis. All the analogues exhibited anti-inflammatory activity, while compound (3) is the most active analogue among the series. In contrast, since compound (3) is a pyridine-phthalimide ring-containing analogue, the presence of a phthalimide group probably favors anti-inflammatory activity over other types of rings. The results suggested further investigations on compounds as anti-inflammatory prodrugs.
- Singh, Ved Prakash,Dowarah, Jayanta,Marak, Brilliant N.,Sran, Balkaran Singh,Tewari, Ashish Kumar
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- Tuning DNA Supramolecular Polymers by the Addition of Small, Functionalized Nucleobase Mimics
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Nucleobase mimicking small molecules able to reconfigure DNA are a recently discovered strategy that promises to extend the structural and functional diversity of nucleic acids. However, only simple, unfunctionalized molecules such as cyanuric acid and melamine have so far been used in this approach. In this work, we show that the addition of substituted cyanuric acid molecules can successfully program polyadenine strands to assemble into supramolecular fibers. Unlike conventional DNA nanostructure functionalization, which typically end-labels DNA strands, our approach incorporates functional groups into DNA with high density using small molecules and results in new DNA triple helices coated with alkylamine or alcohol units that grow into micrometer-long fibers. We find that small changes in the small molecule functional group can result in large structural and energetic variation in the overall assembly. A combination of circular dichroism, atomic force microscopy, molecular dynamics simulations, and a new thermodynamic method, transient equilibrium mapping, elucidated the molecular factors behind these large changes. In particular, we identify substantial DNA sugar and phosphate group deformations to accommodate a hydrogen bond between the phosphate and the small-molecule functional groups, as well as a critical chain length of the functional group which switches this interaction from intra- to interfiber. These parameters allow the controlled formation of hierarchical, hybrid DNA assemblies simply through the addition and variation of small, functionalized molecules.
- Lachance-Brais, Christophe,Hennecker, Christopher D.,Alenaizan, Asem,Luo, Xin,Toader, Violeta,Taing, Monica,Sherrill, C. David,Mittermaier, Anthony K.,Sleiman, Hanadi F.
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supporting information
p. 19824 - 19833
(2021/11/30)
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- Preparation method of alkyl nitrile compound
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The invention discloses a preparation method of an alkyl nitrile compound shown as formula I. The preparation method comprises the following step: in a solvent, in the presence of an additive, carrying out substitution reaction as shown in the specification on a cyanation reagent and an alkyl halide shown as formula II to obtain the alkyl nitrile compound shown as formula I, wherein the cyanationreagent is Zn (CN) 2 and/or Cu (CN) 2; the additive is one or more of an inorganic base, an organic base and a quaternary ammonium salt.
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Paragraph 0104-0106
(2020/05/14)
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- Niraparib intermediate, preparation method and application thereof, and synthesis method of niraparib
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The invention relates to a compound alpha-(3-aminopropyl)-p-bromophenylacetic acid, a preparation method and application thereof, (S)-3-(4-bromophenyl)-piperidine-2-one, a preparation method and application thereof, and synthesis methods of (S)-3-(4-bromophenyl)-piperidine) p-toluenesulfonate, N-Boc-(3S)-(4-bromophenyl)piperidine and niraparib. 4-bromophenylacetate 5 is used as a raw material, a nucleophilic reaction is carried out on the raw material and a nitrogen source reagent 4 under the action of an alkali to generate a compound 6; the compound 6 is subjected to deprotection and hydrolysis to obtain an amino acid compound 7; and the amino acid compound 7 is subjected to chiral column separation or chemical resolution to obtain compounds 8 and 9; and the separated enantiomer 8 can besubjected to racemization and resolution conversion (or chiral column separation) to obtain a compound 9, and the process material cost is greatly reduced. After the compound 9 is obtained, a compound1 can be obtained through conventional condensation reaction ring closing, reduction and BOC loading. Splitting operation is advanced, and the enantiomer 8 is subjected to racemization recovery treatment and is repeatedly applied to different splitting batches to continuously obtain the product 9, so the process material cost is lower.
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- Synthesis, physico-chemical properties and microsomal stability of compounds bearing aliphatic trifluoromethoxy group
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Effects of the trifluoromethoxy substituent on physico-chemical properties of compounds, such as kinetic solubility, lipophilicity and microsomal clearance, was studied in a series of aliphatic derivatives. It was found that kinetic solubility of the CF3O-containing compounds was comparable to that of analogs, i.e. compounds bearing CH3O and CF3 moieties. The CF3O-substituted compounds had higher lipophilicity as compared to methoxy analogues, and nearly the same like CF3-bearing compounds. Microsomal stability studies indicated that the trifluoromethoxy group typically decreased metabolic stability of the corresponding derivatives as compared to either CH3O- or CF3-substituted counterparts, except for N-alkoxy(sulfon)amide series.
- Grygorenko, Oleksandr O.,Haufe, Günter,Kliachyna, Maria,Kondratov, Ivan S.,Logvinenko, Ivan G.,Markushyna, Yevheniia,Pivnytska, Valentyna,Tokaryeva, Yuliya,Vashchenko, Bohdan V.
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- Quaternary Ammonium Trifluoromethoxide Salts as Stable Sources of Nucleophilic OCF3
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The reaction of nucleophilic tertiary amines with trifluoromethyl and pentafluoroethyl methyl ethers provides quaternary ammonium trifluoromethoxide (NR4OCF3) and pentafluoroethoxide (NR4OCF2CF3) salts, respectively, in good yields. The new trifluoromethoxide salts disclosed herein are uniquely stable for extended periods of time in both the solid state and in solution, which complements contemporary reagents. Here we describe the preparation of a range of NR4OCF3 salts, their long-term stability, and utility in substitution reactions.
- Britton, Robert,Friesen, Chadron M.,Jelier, Benson J.,Martin, Rainer E.,Meanwell, Michael,Newton, Josiah J.
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supporting information
p. 1785 - 1790
(2020/03/24)
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- Novel CDKs inhibitors for the treatment of solid tumour by simultaneously regulating the cell cycle and transcription control
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A novel series of cyclin-dependent kinases (CDKs) inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription, were synthesised. A systematic study of enzymatic and cellular assays led to the identification of compound X22 with a nanomolar potency against CDK4 and CDK9 and potent antiproliferative activities against a panel of tumour cell lines. X22 could induce cell cycle arrest and cell apoptosis in cancer cell lines. X22 dose-dependently inhibits signalling pathways downstream of CDKs in cancer cells. In vivo antitumor activity assays, oral administration of X22 led to significant tumour regression in mouse model without obvious toxicity. Superior anti-cancer efficacy in vitro and in vivo of X22 demonstrated combined depletion of cell cycle and transcriptional CDK all contributed to antitumor activity. Taken together, concomitant inhibition of cell cycle and transcriptional CDK activities provided valuable guide for further structural optimisation.
- Deng, Kaiyuan,Fan, Yan,Huang, Zhi,Li, Yao,Ma, Yakun,Shi, Yi,Sun, Peiqing,Wang, Cheng,Wang, Tianqi,Wang, Xin,Xiang, Rong,Yang, Shengyong
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p. 414 - 423
(2020/01/08)
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- Development of phthalimide-donepezil hybrids as potent multitargetdirected ligands for the treatment of alzheimer’s disease
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Background: Due to the complex etiology of AD, multi-target-directed ligands (MTDLs), combining two or more distinct pharmacological moieties, have been developed in both symptomatic and disease-modifying efficiencies and are considered as an effective way for the treatment of AD. Methods: To test their biological activities, including AChE/BChE inhibitory activity and MAOA/MAO-B inhibitory activity. In addition, molecular modeling studies were performed to afford insight into the binding mode. Results and Discussions: The results displayed that compound 4c showed the best AChE inhibitory activity with an IC50 value of 4.2 μM, which was supported by the kinetic study and docking study. Compound 4c was also a selective MAO-B inhibitor (IC50 = 8.2 μM). Moreover, compound 4c could cross the blood-brain barrier in vitro. Conclusion: Compound 4c deserved to further study as a potential multifunctional agent for the treatment of Alzheimer’s disease.
- Yu, Lintao,Shi, Jian,Cheng, Xinfeng,Wang, Keren,Liu, Shuang,Liu, Wenmin,Sang, Zhipei
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p. 1155 - 1163
(2020/09/15)
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- Design and synthesis of novel sulphamide tethered quinazolinone hybrids as potential antitumor agents
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In an attempt to develop potential and selective antitumor agents, a series of novel sulphamide tethered quinazolinone hybrids were efficiently synthesized and evaluated for antitumor activity against four cancer cell lines such as HeLa (cervical), MDA-MB-231 (breast), PANC-1 (pancreatic), and A549 (lung) in vitro. All the compounds (5a-j, 6a-g) exhibited significant anti-proliferative activity with GI50 values ranging from 0.045 to 6.94 μM, while compound 10c showed potent activity against all the cell lines (He La, MDA-MB-231, PANC-1 and A549) with GI50 values ranging from 0.09 to 0.21 μM. We have explored the binding mode and key active site interactions in HDAC8 and EHMT2 proteins. The docking results are complementary to the experimental results.
- Venkatesh, Ramineni,Kasaboina, Suresh,Jain, Nishant,Janardhan, Sridhara,Holagunda, Uma Devi,Nagarapu, Lingaiah
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p. 403 - 411
(2019/01/21)
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- Novel salicylamide derivatives as potent multifunctional agents for the treatment of Alzheimer's disease: Design, synthesis and biological evaluation
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A series of salicylamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives were selective AChE inhibitors. They showed good inhibitory activities of self- and Cu2+-induced Aβ1–42 aggregation, and significant antioxidant activities. Among them, compound 15b exhibited good inhibitory activity toward RatAChE and EeAChE with IC50 value of 10.4 μM and 15.2 μM, respectively. Moreover, 15b displayed high antioxidant activity (2.46 Trolox equivalents), good self- and Cu2+-induced Aβ1–42 aggregation inhibitory potency (42.5% and 31.4% at 25.0 μM, respectively) and moderate disaggregation ability to self- and Cu2+-induced Aβ1–42 aggregation fibrils (23.4% and 27.0% at 25 μM, respectively). Furthermore, 15b also showed biometal chelating abilities, anti-neuroinflammatory ability and BBB permeability. These multifunctional properties indicated compound 15b was worthy of being chosen for further pharmacokinetics, toxicity and behavioral researches to test its potential for AD treatment.
- Song, Qing,Li, Yan,Cao, Zhongcheng,Qiang, Xiaoming,Tan, Zhenghuai,Deng, Yong
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p. 137 - 149
(2018/11/30)
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- Highly Selective Butyrylcholinesterase Inhibitors with Tunable Duration of Action by Chemical Modification of Transferable Carbamate Units Exhibit Pronounced Neuroprotective Effect in an Alzheimer's Disease Mouse Model
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In this study, the carbamate structure of pseudo-irreversible butyrylcholinesterase (BChE) inhibitors was optimized with regard to a longer binding to the enzyme. A set of compounds bearing different heterocycles (e.g., morpholine, tetrahydroisoquinoline, benzimidazole, piperidine) and alkylene spacers (2 to 10 methylene groups between carbamate and heterocycle) in the carbamate residue was synthesized and characterized in vitro for their binding affinity, binding kinetics, and carbamate hydrolysis. These novel BChE inhibitors are highly selective for hBChE over human acetycholinesterase (hAChE), yielding short-, medium-, and long-acting nanomolar hBChE inhibitors (with a half-life of the carbamoylated enzyme ranging from 1 to 28 h). The inhibitors show neuroprotective properties in a murine hippocampal cell line and a pharmacological mouse model of Alzheimer's disease (AD), suggesting a significant benefit of BChE inhibition for a disease-modifying treatment of AD.
- Hoffmann, Matthias,Stiller, Carina,Endres, Erik,Scheiner, Matthias,Gunesch, Sandra,Sotriffer, Christoph,Maurice, Tangui,Decker, Michael
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p. 9116 - 9140
(2019/11/03)
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- Design, synthesis and insecticide activity of novel acetylcholinesterase inhibitors: Triazolinone and phthalimide heterodimers
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Based on the “cluster effect” and the structure characters of acetylcholinesterase (AChE; EC 3.1.1.7), a new series of 1,2,4-triazolin-3-one and phthalimide heterodimers were designed, synthesized, and evaluated as potent dual acetylcholinesterase inhibitors (AChEIs). Most of the synthesized compounds showed good in vitro inhibitory activities towards both Drosophila melanogaster acetylcholinesterase (DmAChE) and Musca domestica acetylcholinesterase (MdAChE). Among them, 5g was found to be the most potent anti-AChE de-rivate (5g, IC50=8.07μM to DmAChE, IC50=32.24μM to MdAChE). It was 2.31- and 1.35-fold more active than the positive control ethion (CP, IC50=18.62μM to DmAChE, IC50=43.56μM to MdAChE). The docking model study revealed that 5g possessed the fitted spatial structure and bound to the central pocket and peripheral site of DmAChE. Moreover, most compounds demonstrated high insecticidal activity to Lipaphis erysimi and Tetranychus cinnabarinus at the concentration of 300mg/L.
- Xie, Ruliang,Mei, Xiangdong,Ning, Jun
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p. 345 - 350
(2019/05/07)
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- Design, Synthesis, Molecular Docking, and Cholinesterase Inhibitory Potential of Phthalimide-Dithiocarbamate Hybrids as New Agents for Treatment of Alzheimer's Disease
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A novel series of phthalimide-dithiocarbamate hybrids was synthesized and evaluated for in vitro inhibitory potentials against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The anti-cholinesterase results indicated that among the synthesized compounds, the compounds 7g and 7h showed the most potent anti-AChE and anti-BuChE activities, respectively. Molecular docking and dynamic studies of the compounds 7g and 7h, respectively, in the active site of AChE and BuChE revealed that these compounds as well interacted with studied cholinesterases. These compounds also possessed drug-like properties and were able to cross the BBB.
- Asadi, Mehdi,Ebrahimi, Mostafa,Mohammadi-Khanaposhtani, Maryam,Azizian, Homa,Sepehri, Saghi,Nadri, Hamid,Biglar, Mahmood,Amanlou, Massoud,Larijani, Bagher,Mirzazadeh, Roghieh,Edraki, Najmeh,Mahdavi, Mohammad
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- Radiosynthesis and evaluation of novel 99mTc(CO)3-labelled thymidine dithiocarbamate derivatives for tumor imaging with SPECT
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A series of novel thymidine dithiocarbamate derivatives (DTC-TdR) were successfully synthesized and then radiolabelled using [99mTc(CO)3]+ core with high yields. The chemical characterizations of 99mTc(CO)3-labelled dithiocarbamate derivatives have been carried out by preparing their corresponding rhenium complexes. The radiotracers were stable in vitro, and the partition coefficient results indicated that they were lipophilic. The cell uptake studies showed the uptakes of these 99mTc(CO)3-labelled thymidine derivatives were mediated by nucleoside transporters. Biodistribution of the complexes in mice bearing tumor showed that they had high tumor uptake and good tumor/muscle ratio. A clear SPECT imaging of the tumor location was obtained in mice bearing S180 tumor with one of radiotracers, suggesting they would be potential tumor imaging agents.
- Duan, Xiaojiang,Ruan, Qing,Gan, Qianqian,Song, Xiaoqing,Fang, Si'an,Zhang, Xuran,Zhang, Junbo
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p. 154 - 163
(2018/05/28)
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- Delta-aminoalkylbenzofuranol ethers, and preparation method and application thereof
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The invention relates to delta-aminoalkylbenzofuranol ethers represented by chemical structural formula I shown in the description, and an application thereof in the preparation of herbicides. In thechemical structural formula I, R is selected from C1-C2 alkyl groups, and n is selected from 2, 3 and 4.
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- Endoperoxide-8-aminoquinoline hybrids as dual-stage antimalarial agents with enhanced metabolic stability
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Hybrid compounds may play a critical role in the context of the malaria eradication agenda, which will benefit from therapeutic tools active against the symptomatic erythrocytic stage of Plasmodium infection, and also capable of eliminating liver stage parasites. To address the need for efficient multistage antiplasmodial compounds, a small library of 1,2,4,5-tetraoxane-8- aminoquinoline hybrids, with the metabolically labile C-5 position of the 8-aminoquinoline moiety blocked with aryl groups, was synthesized and screened for antiplasmodial activity and metabolic stability. The hybrid compounds inhibited development of intra-erythrocytic forms of the multidrug-resistant Plasmodium falciparum W2 strain, with EC50 values in the nM range, and with low cytotoxicity against mammalian cells. The compounds also inhibited the development of P. berghei liver stage parasites, with the most potent compounds displaying EC50 values in the low μM range. SAR analysis revealed that unbranched linkers between the endoperoxide and 8-aminoquinoline pharmacophores are most beneficial for dual antiplasmodial activity. Importantly, hybrids were significantly more potent than a 1:1 mixture of 8-aminoquinoline-tetraoxane, highlighting the superiority of the hybrid approach over the combination therapy. Furthermore, aryl substituents at C-5 of the 8-aminoquinoline moiety improve the compounds' metabolic stability when compared with their primaquine (i.e. C-5 unsubstituted) counterparts. Overall, this study reveals that blocking the quinoline C-5 position does not result in loss of dual-stage antimalarial activity, and that tetraoxane-8- aminoquinoline hybrids are an attractive approach to achieve elimination of exo- and intraerythrocytic parasites, thus with the potential to be used in malaria eradication campaigns.
- Capela, Rita,Magalh?es, Joana,Miranda, Daniela,Machado, Marta,Sanches-Vaz, Margarida,Albuquerque, Inês S.,Sharma, Moni,Gut, Jiri,Rosenthal, Philip J.,Frade, Raquel,Perry, Maria J.,Moreira, Rui,Prudêncio, Miguel,Lopes, Francisca
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- Synthesis of new analogs of tetraiodothyroacetic acid (tetrac) as novel angiogenesis inhibitors for treatment of cancer
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In the angiogenesis process, integrins, which are members of a family of cell surface transmembrane receptors, play a critical role particularly in blood vessel formation and the local release of vascular growth factors. Thyroid hormones such as L-thyroxine (T4) and 3,5,3′-triiodo-L-thyronine (T3) promote angiogenesis and tumor cell proliferation via integrin αvβ3 receptor. At or near an arginine-glycine-aspartate (RGD) recognition site on the binding pocket of integrin αvβ3, tetraiodothyroacetic acid (tetrac, a deaminated derivative of T4) is a thyrointegrin receptor antagonist and blocks the actions of T3 and T4 as well as different growth factors-mediated angiogenesis. In this study, we synthesized novel tetrac analogs by modifying the phenolic moiety of tetrac and tested them for their anti-angiogenesis activity using a Matrigel plug model for angiogenesis in mice. Pharmacological activity results showed that tetrac can accommodate numerous modifications and maintain its anti-angiogenesis activity.
- Rajabi, Mehdi,Yalcin, Murat,Mousa, Shaker A.
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supporting information
p. 1223 - 1227
(2018/03/12)
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- 8-polyamido dihydromyricetin derivative and preparation method and application thereof
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The present invention discloses an 8-polyamido dihydromyricetin derivative or a pharmaceutically acceptable hydrate and salt thereof including stereoisomers or tautomers thereof. The 8-polyamido dihydromyricetin derivative has anticancer activity and can be used for anticancer treatment drugs. The invention discloses a preparation method of the 8-polyamido dihydromyricetin derivative.
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Paragraph 0013-0014
(2018/03/28)
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- Synthesis and biological evaluation of 1,3,4-thiadiazole linked phthalimide derivatives as anticancer agents
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Background: Due to the importance of 1,3,4-thiadiazoles and phthalimides in anticancer agents, a novel series of 1,3,4-thiadiazole-phthalimide system have been synthesized and evaluated in vitro against HT-29 and MCF-7 human cancer cell lines. Methods: The target compounds were prepared through four-step reaction and their cytotoxicities were evaluated by MTT assay. Results: The results showed that 4-nitrobenzoyl moiety containing derivatives are the most potent ones. The morphological evaluation also indicated that these compounds are apoptotic inducers. Conclusion: 4-Nitro-N-(5-((3-(1,3-dioxoisoindolin-2-yl)propyl)thio)-1,3,4-thiadiazol-2-yl)benzamide (8m) exhibits the best inhibitory effect against HT-29 and MCF-7 cell lines with IC50 values of 23.83 and 27.21 μM, respectively.
- Rezaeia, Zahra,Moghimi, Setareh,Javaheri, Rezvan,Asadi, Mehdi,Mahdavi, Mohammad,Shabani, Shabnam,Edraki, Najmeh,Firuzi, Omidreza,Safavi, Maliheh,Aminia, Mohsen,Asadipour, Ali,Zeinalzadeh, Elnaz,Firoozpour, Loghman,Foroumadi, Alireza
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p. 1138 - 1144
(2017/11/14)
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- N-[(dihydrobenzofuran-7-yloxyl)alkyl]-2-aryloxy amide derivatives
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The invention discloses N-[( dihydrobenzofuran-7-yloxyl)alkyl]-2-aryloxy amide derivatives which are represented as a structural formula I and a structural formula II, and in the structural formula I or II, R is selected from a group consisting of H, C1-C2 alkyl, C3-C4 linear alkyl and C3-C4 branched alkyl; n is selected from a group consisting of 1,2,3,4,5 and 6; Y is selected from a group consisting of H, C1-C2 alkyl, F, Cl, Br and I; Y is selected from a group consisting of H, C1-C2 alkyl, F, Cl, Br, I, trifluoromethyl and trifluoroethyl; and Y is selected from a group consisting of H, C1-C2 alkyl, F, Cl, Br and I. The invention also provides an application of the N-[(dihydrobenzofuran-7-yloxyl)alkyl]-2-aryloxy amide derivatives to preparing herbicides.
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- Photoinduced, Copper-Catalyzed Decarboxylative C-N Coupling to Generate Protected Amines: An Alternative to the Curtius Rearrangement
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The Curtius rearrangement is a classic, powerful method for converting carboxylic acids into protected amines, but its widespread use is impeded by safety issues (the need to handle azides). We have developed an alternative to the Curtius rearrangement that employs a copper catalyst in combination with blue-LED irradiation to achieve the decarboxylative coupling of aliphatic carboxylic acid derivatives (specifically, readily available N-hydroxyphthalimide esters) to afford protected amines under mild conditions. This C-N bond-forming process is compatible with a wide array of functional groups, including an alcohol, aldehyde, epoxide, indole, nitroalkane, and sulfide. Control reactions and mechanistic studies are consistent with the hypothesis that copper species are engaged in both the photochemistry and the key bond-forming step, which occurs through out-of-cage coupling of an alkyl radical.
- Zhao, Wei,Wurz, Ryan P.,Peters, Jonas C.,Fu, Gregory C.
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supporting information
p. 12153 - 12156
(2017/09/12)
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- Design, synthesis and evaluation of scutellarein-O-acetamidoalkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease
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A series of scutellarein-O-acetamidoalkylbenzylamines derivatives were designed based on a multitarget-directed ligands strategy for the treatment of Alzheimer's disease. Among these compounds, compound T-22 demonstrated excellent acetylcholinesterase inhibitory, moderate inhibitory effects on self-induced Aβ1-42 aggregation, Cu2+-induced Aβ1-42 aggregation, human AChE-induced Aβ1-40 aggregation and disassembled Cu2+-induced aggregation of the well-structured Aβ1-42 fibrils, and also acted as potential antioxidant and biometals chelator. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that T-22 interacted with both the catalytic active site and peripheral anionic site of AChE. Moreover, compound T-22 showed a good neuroprotective effect against H2O2-induced PC12?cell injury and low toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test indicated T-22 significantly reversed scopolamine-induced memory deficit in mice. Taken together, the data showed that T-22 was an interesting multifunctional lead compound worthy of further study for AD.
- Sang, Zhipei,Qiang, Xiaoming,Li, Yan,Xu, Rui,Cao, Zhongcheng,Song, Qing,Wang, Ting,Zhang, Xiaoyu,Liu, Hongyan,Tan, Zhenghuai,Deng, Yong
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p. 307 - 323
(2017/05/01)
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- Design, synthesis and biological evaluation of phthalimide-alkylamine derivatives as balanced multifunctional cholinesterase and monoamine oxidase-B inhibitors for the treatment of Alzheimer's disease
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A series of novel phthalimide-alkylamine derivatives were synthesized and evaluated as multi-functions inhibitors for the treatment of Alzheimer's disease (AD). The results showed that compound TM-9 could be regarded as a balanced multi-targets active molecule. It exhibited potent and balanced inhibitory activities against ChE and MAO-B (huAChE, huBuChE, and huMAO-B with IC50 values of 1.2 μM, 3.8 μM and 2.6 μM, respectively) with low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-9 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Interestingly, compound TM-9 abided by Lipinski's rule of five. Furthermore, our investigation proved that TM-9 indicated weak cytotoxicity, and it could cross the blood-brain barrier (BBB) in vitro. The results suggest that compound TM-9, an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer's disease.
- Sang, Zhipei,Wang, Keren,Wang, Huifang,Yu, Lintao,Wang, Huijuan,Ma, Qianwen,Ye, Mengyao,Han, Xue,Liu, Wenmin
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supporting information
p. 5053 - 5059
(2017/10/18)
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- Synthesis and evaluation of antiproliferative activity of novel quinazolin-4(3H)-one derivatives
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Two series of novel quinazolin-4(3H)-one derivatives (10a–g and 11a–g) have been synthesized and evaluated for their in vitro antiproliferative activity against human HeLa, MIAPACA, MDA-MB-231, and IMR-31 cancer cell lines. The synthesized compounds were characterized by spectral (Fourier transform infrared, 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, high-resolution mass spectra) methods. Among them, compounds 11e and 11g exhibited potent in vitro antiproliferative activity with GI50 values 0.02, less than 0.01 μM against MIAPACA human cancer cell line. Significantly, compounds 10a, 10b, 10c, 10g, 11b, 11c, 11d, 11e, 11f showed activity with GI50 values ranging from 0.1 to 0.87 μM against human cancer cell lines MIAPACA, MDA-MB-231, and IMR-31. We have explored the probable binding mode and key active site interactions in HDAC8 and EHMT2 proteins. The docking results are complementary to the experimental results.
- Venkatesh, Ramineni,Kasaboina, Suresh,Janardhan, Sridhara,Jain, Nishant,Bantu, Rajashaker,Nagarapu, Lingaiah
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p. 2070 - 2081
(2016/10/03)
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- Pterostilbene-O-acetamidoalkylbenzylamines derivatives as novel dual inhibitors of cholinesterase with anti-β-amyloid aggregation and antioxidant properties for the treatment of Alzheimer's disease
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A series of pterostilbene-O-acetamidoalkylbenzylamines were designed, synthesized and evaluated as dual inhibitors of AChE and BuChE. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and inhibitory effects on self-induced Aβ1-42 aggregation and HuAChE-induced Aβ1-40 aggregation were also tested. The results showed that most of these compounds could effectively inhibit AChE and BuChE. Particularly, compound 21d exhibited the best AChE inhibitory activity (IC50 = 0.06 μM) and good inhibition of BuChE (IC50 = 28.04 μM). Both the inhibition kinetic analysis and molecular modeling study revealed that these compounds showed mixed-type inhibition, binding simultaneously to the CAS and PAS of AChE. In addition to cholinesterase inhibitory activities, these compounds showed different levels of antioxidant activity. However, the inhibitory activities against self-induced and HuAChE-induced Aβ aggregation of these new derivatives were unsatisfied. Taking into account the results of the biological evaluation, further modifications will be designed in order to increase the potency on the different targets. The results displayed in this Letter can be a new starting point for further development of multifunctional agents for Alzheimer's disease.
- Li, Yuxing,Qiang, Xiaoming,Li, Yan,Yang, Xia,Luo, Li,Xiao, Ganyuan,Cao, Zhongcheng,Tan, Zhenghuai,Deng, Yong
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supporting information
p. 2035 - 2039
(2016/04/05)
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- Bivalent carbamates as novel control agents of the malaria mosquito, Anopheles gambiae
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Widespread pyrethroid resistance has caused an urgent need to develop new insecticides for control of the malaria mosquito, Anopheles gambiae. Insecticide discovery efforts were directed towards the construction of bivalent inhibitors that occupy both the peripheral and catalytic sites of the mosquito acetylcholinesterase (AChE). It was hypothesized that this approach would yield a selective, high potency inhibitor that would also circumvent known catalytic site mutations (e.g. G119S) causing target site resistance. Accordingly, a series of bivalent phthalimide-pyrazole carbamates were prepared having an alkyl chain linker of varying length, along with other modifications. The most active compound was (1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-1H-pyrazol-4-yl methylcarbamate, 8a), which has a chain length of three carbons, good mosquito anticholinesterase activity, and ca. 5-fold selectivity compared to human AChE. Moreover, this compound was toxic to mosquitoes by topical application (LD50 = 63 ng/female) with only 6-fold cross resistance in the Akron strain of Anopheles gambiae that showed 50- to 60-fold resistance to conventional carbamate insecticides. However, contact lethality in the WHO paper assay was disappointing. The implications of these results for design of new mosquitocides are discussed.
- Mutunga, James M.,Chen, Qiao-Hong,Wong, Dawn M.,Lam, Polo C.-H.,Li, Jianyong,Totrov, Maxim M.,Gross, Aaron D.,Carlier, Paul R.,Bloomquist, Jeffrey R.
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p. 704 - 708
(2016/10/30)
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- Identification and Structure–Activity Relationship Studies of Small-Molecule Inhibitors of the Methyllysine Reader Protein Spindlin1
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The methyllysine reader protein Spindlin1 has been implicated in the tumorigenesis of several types of cancer and may be an attractive novel therapeutic target. Small-molecule inhibitors of Spindlin1 should be valuable as chemical probes as well as potential new therapeutics. We applied an iterative virtual screening campaign, encompassing structure- and ligand-based approaches, to identify potential Spindlin1 inhibitors from databases of commercially available compounds. Our in silico studies coupled with in vitro testing were successful in identifying novel Spindlin1 inhibitors. Several 4-aminoquinazoline and quinazolinethione derivatives were among the active hit compounds, which indicated that these scaffolds represent promising lead structures for the development of Spindlin1 inhibitors. Subsequent lead optimization studies were hence carried out, and numerous derivatives of both lead scaffolds were synthesized. This resulted in the discovery of novel inhibitors of Spindlin1 and helped explore the structure–activity relationships of these inhibitor series.
- Robaa, Dina,Wagner, Tobias,Luise, Chiara,Carlino, Luca,McMillan, Joel,Flaig, Ralf,Schüle, Roland,Jung, Manfred,Sippl, Wolfgang
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supporting information
p. 2327 - 2338
(2016/10/24)
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- Design, synthesis and evaluation of novel ferulic acid-memoquin hybrids as potential multifunctional agents for the treatment of Alzheimer's disease
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A novel series of ferulic acid-memoquin hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). The in vitro studies showed that most of the compounds exhibited a significant ability to inhibit acetylcholinesterase (AChE) (IC50 of 3.2-34.7 μM) and self-induced β-amyloid (Aβ1-42) aggregation (30.8-39.1%, 25 μM), to act as potential antioxidants (ORAC-FL value of 0.9-1.3). In particular, compound 17d had the greatest ability to inhibit AChE (IC50 = 3.2 μM), and Aβ1-42 aggregation (30.8%) was also an excellent antioxidant and neuroprotectant. Moreover, it is capable of disaggregating self-induced Aβ aggregation. Furthermore, 17d could cross the blood-brain barrier (BBB) in vitro. The results showed that compound 17d is a potential multifunctional agent for the treatment of AD.
- Pan, Wanli,Hu, Ke,Bai, Ping,Yu, Lintao,Ma, Qinge,Li, Tao,Zhang, Xu,Chen, Changzhong,Peng, Kelin,Liu, Wenmin,Sang, Zhipei
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supporting information
p. 2539 - 2543
(2016/07/07)
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- Benzazepine Dicarboxamide Compounds
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This invention relates to novel benzazepine dicarboxamide compounds of the formula wherein R1 to R4 are as defined in the description and in the claims, as well as pharmaceutically acceptable salts thereof. These compounds are TLR agonists and may therefore be useful as medicaments for the treatment of diseases such as cancer, autoimmune diseases, inflammation, sepsis, allergy, asthma, graft rejection, graft-versus-host disease, immunodeficiencies, and infectious diseases.
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Paragraph 0448; 0449
(2016/09/26)
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- Design, synthesis and bioactivity of novel phthalimide derivatives as acetylcholinesterase inhibitors
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A series of novel phthalimide derivatives related to benzylpiperazine were synthesized and evaluated as cholinesterase inhibitors. The results showed that all compounds were able to inhibit acetylcholinesterase (AChE), with two of them dramatically inhibiting butyrylcholinesterase (BuChE). Most compounds exhibited potent anti-AChE activity in the range of nM concentrations. In particular, compounds 7aIII and 10a showed the most potent activity with the IC50 values of 18.44 nM and 13.58 nM, respectively. To understand the excellent activity of these compounds, the structure-activity relationship was further examined. The protein-ligand docking study demonstrated that the target compounds have special binding modes and these results are in agreement with the kinetic study.
- Si, Weijie,Zhang, Tao,Zhang, Lanxiang,Mei, Xiangdong,Dong, Mengya,Zhang, Kaixin,Ning, Jun
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supporting information
p. 2380 - 2382
(2016/04/20)
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- Design, synthesis and evaluation of 4-dimethylamine flavonoid derivatives as potential multifunctional anti-Alzheimer agents
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A new series of 4-dimethylamine flavonoid derivatives were designed and synthesized as potential multifunctional anti-Alzheimer agents. The inhibition of cholinesterase activity, self-induced β-amyloid (Aβ) aggregation, and antioxidant activity by these derivatives was investigated. Most of the compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. A Lineweaver-Burk plot and molecular modeling study showed that these compounds targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. The derivatives showed potent self-induced Aβ aggregation inhibition and peroxyl radical absorbance activity. Moreover, compound 6d significantly protected PC12 neurons against H2O2-induced cell death at low concentrations. Thus, these compounds could become multifunctional agents for further development for the treatment of AD.
- Luo, Wen,Wang, Ting,Hong, Chen,Yang, Ya-Chen,Chen, Ying,Cen, Juan,Xie, Song-Qiang,Wang, Chao-Jie
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supporting information
p. 17 - 26
(2016/07/06)
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- METHODS OF MODULATING CFTR ACTIVITY
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The invention encompasses methods of modulating CFTR activity in a subject in need thereof comprising administering an effective amount of a compound of Formula (I). The invention also encompasses methods of treating a condition associated with CFTR activity or condition associated with a dysfunction of proteostasis comprising administering to a subject an effective amount of a compound of Formula (I).
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Page/Page column 97
(2015/01/16)
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- Luminescent Compounds, Complexes and Their Uses
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A method of changing the fluorescent properties of a complex, the method comprising: providing a first complex comprising a multidentate ligand that is coordinated to a lanthanide ion, wherein the lanthanide is selected from europium and terbium and the multidentate ligand has at least one optionally substituted phthalimide group coordinated to the lanthanide ion, contacting the complex with an aqueous liquid medium under appropriate conditions, such that at least one phthalimide group is hydrolysed to a phthalamate group, to form a second complex. Complexes and compounds are also disclosed.
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Page/Page column
(2014/06/23)
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- Encapsulation of a catalytic imidazolium salt into avidin: Towards the development of a biohybrid catalyst active in ionic liquids
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Herein, we report the development of biohybrid catalysts that are capable of catalyzing the aldol reaction. The use of biotinylated imidazolium salts in combination with racemic or enantiomerically pure catalytic anions allowed us to study the adaptive and cooperative positioning of the anionic catalyst inside the protein. Supramolecular encapsulation of the biotinylated catalyst into avidin resulted in good selectivity for the aldol reaction performed in ionic liquid/water mixtures. Biohybrid catalysts capable of catalyzing the aldol reaction are prepared from avidin and biotinylated imidazolium salts with either racemic or enantiomerically pure catalytic anions. Supramolecular encapsulation (see figure) of the biotinylated catalyst in avidin resulted in good selectivities for the aldol reaction when performed in ionic liquid/water mixtures and the adaptive and cooperative positioning of the anionic catalyst inside the avidin protein is discussed. Copyright
- Gauchot, Vincent,Branca, Mathieu,Schmitzer, Andreea
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supporting information
p. 1530 - 1538
(2014/03/21)
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- Hybrids consisting of the pharmacophores of salmeterol and roflumilast or phthalazinone: Dual β2-adrenoceptor agonists-PDE4 inhibitors for the treatment of COPD
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A novel class of dual pharmacology bronchodilators targeting both β2-adrenoceptor and PDE4 was designed and synthesised by combining the pharmacophores of salmeterol and roflumilast or phthalazinone. All the compounds exhibited better β2-adrenoceptor agonist activities (pEC50 = 8.47-9.20) than the reference compound salmeterol (pEC50 = 8.3) and good inhibitory activity on PDE4B2 (IC 50 = 0.235-1.093 μM).
- Liu, Anqiu,Huang, Ling,Wang, Zhiren,Luo, Zonghua,Mao, Fei,Shan, Wenjun,Xie, Jiaxing,Lai, Kefang,Li, Xingshu
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p. 1548 - 1552
(2013/03/28)
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- Synthesis and biological evaluation of sulforaphane derivatives as potential antitumor agents
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A series of sulforaphane derivatives were synthesized and evaluated in vitro for their cytotoxicity against five cancer cell lines (HepG2, A549, MCF-7, HCT-116 and SH-SY5Y). The pharmacological results showed that many of the derivatives displayed more potent cytotoxicity than sulforaphane (SFN). Furthermore, SFN and derivative 85 could induce cell cycle arrest at S or G2/M phase and cell apoptosis. SFN and 85 exhibited time- and dose-dependent activation on Nrf2 transcription factor, and 85 acted as a more potent Nrf2 inducer than SFN.
- Hu, Kun,Qi, Yan-Jie,Zhao, Juan,Jiang, He-Fei,Chen, Xin,Ren, Jie
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p. 529 - 539
(2013/07/11)
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- Inhibition of cholinesterase activity and amyloid aggregation by berberine-phenyl-benzoheterocyclic and tacrine-phenyl-benzoheterocyclic hybrids
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A series of berberine-phenyl-benzoheterocyclic (26-29) and tacrine-phenyl-benzoheterocyclic hybrids (44-46) were synthesised and evaluated as multifunctional anti-Alzheimer's disease agents. Compound 44b, tacrine linked with phenyl-benzothiazole by 3-carbon spacers, was the most potent AChE inhibitor with an IC50 value of 0.017 μM. This compound demonstrated similar Aβ aggregation inhibitory activity with cucurmin (51.8% vs 52.1% at 20 μM, respectively), indicating that this hybrid is an excellent multifunctional drug candidate for AD.
- Huang, Ling,Su, Tao,Shan, Wenjun,Luo, Zonghua,Sun, Yang,He, Feng,Li, Xingshu
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experimental part
p. 3038 - 3048
(2012/07/01)
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- Design, synthesis and evaluation of novel 2-(Aminoalkyl)-isoindoline-1,3- dione derivatives as dual-binding site acetylcholinesterase inhibitors
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A new series of 2-(diethylaminoalkyl)-isoindoline-1,3-dione derivatives intended as dual binding site cholinesterase inhibitors were designed using molecular modeling and evaluated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and the formation of the β-amyloid (Aβ) plaques. For AChE inhibitory activity, the spectrophotometric method of Ellman and the electrophoretically mediated microanalysis assay were used, giving good results. Most of the synthesized compounds had AChE inhibitory activity with IC50 values ranging from IC50 = 0.9 to 19.5 μM and weak Aβ anti-aggregation inhibitory activity. These results support the outcome of docking studies which tested compounds targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The most promising selective AChE inhibitors are compounds 10 (IC50 = 1.2 μM) and 11 (IC50 = 1.1 μM), with 6-7 methylene chains, which also inhibit Aβ fibril formation. A new series of 2-(diethylaminoalkyl)-isoindoline-1,3- dione derivatives intended as dual-binding site cholinesterase inhibitors were designed using molecular modeling. They were evaluated as inhibitors of acetylcholinesterase, butyrylcholinesterase, and the formation of β-amyloid (Aβ) plaques. The most promising selective AChE inhibitors are compounds 10 (IC50 = 1.2 μM) and 11 (IC50 = 1.1 μM), with 6-7 methylene chains, which also inhibit Aβ fibril formation. Copyright
- Ignasik, Michalina,Bajda, Marek,Guzior, Natalia,Prinz, Michaela,Holzgrabe, Ulrike,Malawska, Barbara
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experimental part
p. 509 - 516
(2012/08/28)
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- Synthesis and anti-inflammatory activity of some novel 3-phenyl-N-[3-(4- phenylpiperazin-1yl)propyl]-1H-pyrazole-5-carboxamide derivatives
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A new series of 3-phenyl-N-[3-(4-phenylpiperazin-1yl)propyl]-1H-pyrazole-5- carboxamide derivatives were synthesized and investigated their anti-inflammatory activities using carrageenan-induced rat paw edema model in vivo. All the synthesized compounds were found to be potent anti-inflammatory agents.
- Nagarapu, Lingaiah,Mateti, Jhansi,Gaikwad, Hanmant K.,Bantu, Rajashaker,Sheeba Rani,Prameela Subhashini
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scheme or table
p. 4138 - 4140
(2011/08/06)
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- Synthesis, biological evaluation of 9-N-substituted berberine derivatives as multi-functional agents of antioxidant, inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid-β aggregation
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A series of 9-N-substituted berberine derivatives were synthesized and biologically evaluated as antioxidant and inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase and amyloid-β aggregation. Most of these compounds exhibited very good antioxidant activities, inhibitive activities of AChE and amyloid-β aggregation. Among them, compound 8d, (o-methylphenethyl)amino linked at the 9-position of berberine, was found to be a good antioxidant (with 4.05 μM of Trolox equivalents), potent inhibitor of AChE (an IC50 value of 0.027 μM), and high active inhibitor of amyloid-β aggregation (an IC50 value of 2.73 μM).
- Shan, Wen-Jun,Huang, Ling,Zhou, Qi,Meng, Fan-Chao,Li, Xing-Shu
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experimental part
p. 5885 - 5893
(2012/01/04)
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- Synthesis of several MPP derivatives for 99mTc-labelling and evaluated as potential 5-HT1A receptor imaging agents
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The (2-methoxyphenyl) piperazine (MPP) was selected as the functional group and conjugated to dithiocarbamate through different spacers. A series of new MPP derivatives (MPPnDTC, n = 2-6) were synthesized and radiolabelled with 99mTc-nitrido core or 99mTc-tricarboxyl core as potential 5-HT1A receptor imaging agents. All the six 99mTc-labelled complexes were lipophilic and neutral. Biodistribution results showed that those radiotracers had moderate initial brain and hippocampus uptake. There have no significant relation was observed between the biological properties of these tracers with the length of its carbon chain. The radioactivity concentrations of hippocampus of 99mTcN-MPP2DTC, 99mTcN-MPP3DTC, 99mTcN-MPP4DTC, 99mTcN-MPP5DTC, 99mTcN-MPP6DTC and 99mTc(CO)3-MPP3DTC at 2 min post-injection time (p.i.) were 0.43, 1.15, 0.99, 1.04, 1.13 and 0.83 %ID/g, respectively.
- Yang, Wenjiang,Lin, Yan,Zhang, Xianzhong,Zhang, Junbo,Wang, Xuebin
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experimental part
p. 1148 - 1154
(2012/04/04)
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- N-alkylation of imides using phase transfer catalysts under solvent-free conditions
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(Chemical Equation Presented) N-Alkylation of imides in the reaction of imides and alkylhalides, catalyzed by PT catalysts under solvent-free conditions, has been developed. The reaction occurs in the presence of K 2CO3, and in many cases it takes place spontaneously. In the N-benzylation reaction, it has been recognized that TBAB (tetrabutylammonium bromide) and TBATFB (tetrabutylammonium tetrafluoroborate) show highest catalytic effect. Versatility and synthetic capacity of the solvent-free alkylation has been confirmed by N-benzylation and N-ethylation of various imides. The developed procedure gives easy access to N-(ω-bromoalkyl) imides.
- Jaskowska, Jolanta,Kowalski, Piotr
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scheme or table
p. 1371 - 1375
(2009/04/07)
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- 2,3,4,5-TETRAHYDRO-1H-1,5-BENZODIAZEPINE DERIVATIVE AND MEDICINAL COMPOSITION
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The present invention has its object to provide a 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine derivative represented with the Formula (1) , or the pharmaceutically acceptable salt, which is effective as a therapeutic and prophylactic agent for diabetes, diabetic nephropathy, or glomerulosclerosis.
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- Synthesis of cyclic bis- and trismelamine derivatives and their complexation properties with barbiturates
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Cyclic bis- and trismelamine derivatives were prepared from cyanuric chloride by stepwise substitutions with appropriate amines. The complexation abilities of these melamine derivatives with barbituric acid derivatives were evaluated by UV-vis spectroscopy and 1H NMR. The structure was also confirmed by X-ray crystallography. Both the acyclic and the cyclic bismelamine derivatives formed a 1: 1 complex via six hydrogen bonds with barbituric acid derivatives. van't Hoff analyses on the complexation of the bismelamines with the barbituric acid derivative revealed that the complexation of the cyclic bismelamine was entropically favored and enthalpically less favored process than those of the acyclic bismelamine. X-Ray crystallographic analysis and 1H NMR studies revealed that the cyclic trismelamine bound one barbituric acid derivative into the cavity via six hydrogen bonds by two melamine moieties and another barbituric acid via three hydrogen bonds by the residual melamine moiety. The Royal Society of Chemistry.
- Kondo, Shin-Ichi,Hayashi, Tomohiro,Sakuno, Yuichi,Takezawa, Yoko,Yokoyama, Takashi,Unno, Masafumi,Yano, Yumihiko
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p. 907 - 916
(2007/10/03)
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- METABOLITES OF 2-{3-[4-(2-ISOPROPOXYPHENYL) PIPERAZIN-1-YL]-PROPYL}-3A,4,7,7A-TETRAHYDRO-1H-ISOINDOLE-1,3-(2H)-DIONE
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The present invention relates to the metabolites of 2-{3-[4-(2-isopropoxyphenyl) piperazin-1-yl]-propyl}-3a,4,7,7a -tetrahydro-1H-isoindole-1,3(2H)-dione of Formula I. The disclosed compounds can function as 1a-adrenoceptor antagonists and thus can be used for the treatment of benign prostatic hyperplasia (BPH) and related symptoms thereof. Processes for preparing the metabolites, pharmaceutical composition containing these metabolites and the method of treating BPH and related symptoms thereof are also provided.
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Page/Page column 55-56
(2010/11/23)
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- Arylpiperazinylalkylpyridazinones and analogues as potent and orally active antinociceptive agents: Synthesis and studies on mechanism of action
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A number of arylpiperazinylalkylpyridazinones structurally related to the previously described lead A (5-{[4-(3-chlorophenyl)piperazin-1-yl]-propyl}-3- methyl-7-phenylisossazolo[4,5-d]pyridazin-4-(5H)-one) were synthesized and tested for their analgesic activity. Many of the tested molecules, at the dose of 20 mg kg-1 p.o., showed high antinociceptive activity, in particular, compounds 5a, 11c, 15a, 21 and 22, which were able to reduce the number of abdominal constrictions by more than 50% in writhing test. The pharmacological investigation of lead A led us to clarify the mechanism of action of this compound, showing that it carries out its analgesic action through the inhibition of reuptake of noradrenaline. The antinociception of some of the most interesting new molecules was completely prevented by pretreatment with α2-antagonist yohimbine, suggesting the involvement of α2-adrenoceptors, as with prototype A.
- Cesari, Nicoletta,Biancalani, Claudio,Vergelli, Claudia,Dal Piaz, Vittorio,Graziano, Alessia,Biagini, Pierfrancesco,Ghelardini, Carla,Galeotti, Nicoletta,Giovannoni, Maria Paola
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p. 7826 - 7835
(2008/02/02)
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- Methods of making 2,6-diaryl piperidine derivatives
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Methods for preparing 2,6-diaryl piperidine derivatives are described. More particularly, 2,6-diaryl piperidines having formula 1-4 are prepared by cyclocondensation of an aryl or heteroaryl aldehyde with 1,3-acetonedicarboxylic acid.
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- A novel stereoselective one-pot conversion of alcohols into alkyl halides mediated by N,N′-diisopropylcarbodiimide
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Alcohols can be converted in high yields to the corresponding alkyl halides in a one-pot procedure via the corresponding O-alkylisourea; very short reaction times are possible when microwave irradiation is used.
- Crosignani, Stefano,Nadal, Brice,Li, Zhengning,Linclau, Bruno
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p. 260 - 261
(2007/10/03)
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