- Synthesis of lariat diazacrown ethers with terminal amino groups in the side chains
-
Treatment of diazacrown ethers with N-(haloalkyl)- and N-(haloethoxy) phthalimides gives the corresponding N,N′- substituted diazacrown ether. Hydrazinolysis of the latter then gives diazacrown ethers with terminal primary amino groups in the side chain. Their reductive methylation using formaldehyde in formic acid gives the dimethylamino derivatives. The presence of a lariat effect was demonstrated by treating the compounds obtained with picrates of alkali and alkaline-earth metals.
- Lukyanenko,Kirichenko,Shcherbakov
-
-
Read Online
- Synthesis and Bioevaluation of Novel [18F]FDG-Conjugated 2-Nitroimidazole Derivatives for Tumor Hypoxia Imaging
-
Hypoxia imaging can guide tumor treatment and monitor changes in hypoxia during treatment. However, there is still no ideal hypoxia imaging agent for clinical applications. In this study, two novel 2-nitromidazole derivatives were synthesized and directly radiolabeled by [18F]FDG in high radiochemical yield and excellent radiochemical purity. Cell experiments, biodistribution, and positron emission tomography (PET) imaging studies were also conducted in mice-bearing S180 or OS732 tumors. [18F]FDG-2NNC2ON [(2R,3S,4R,E)-2-18F-fluoro-3,4,5,6-tetrahydroxyhexanal O-3-(2-(2-nitro-1H-imidazole-1-yl)ethylamino)-2-oxopropyl oxime] and [18F]FDG-2NNC5ON [(2R,3S,4R,E)-2-18F-fluoro-3,4,5,6-tetrahydroxyhexanal-O-3-(5-(2-nitro-1H-imidazole-1-yl)pentylamino)-2-oxopropyl oxime] can be cleared from the blood quickly and specifically target hypoxic tumor cells. The uptake of the probes by hypoxic cells gradually increases with time. After 4 h, the uptake value of [18F]FDG-2NNC2ON in hypoxic cells is 3.2 times higher than that in normoxia cells. In contrast, there is no difference in the uptake of [18F]FDG between hypoxic cells and normoxia cells. Biodistribution resulting from two tumor models indicate that the uptake values of the two radiotracers in the tumor are higher at 1 h than those at 2 and 4 h. At 1 and 2 h, the tumors are clearly observed on the PET images and the imaging features of [18F]FDG-2NNC5ON and [18F]FDG-2NNC2ON are distinct from those of [18F]FDG. Compared with [18F]FDG-2NNC5ON, [18F]FDG-2NNC2ON has a higher proportion of renal excretion, lower digestive tract uptake, and better imaging contrast because of its higher hydrophilicity. At 2 h, [18F]FDG-2NNC2ON shows a good tumor-to-blood (T/B) ratio, tumor-to-muscle ratio based on biodistribution (Bio-T/M ratio), and tumor-to-muscle ratio based on regions of interest on the PET images [region of interest (ROI)-T/M ratio] in the two tumor models (T/B, Bio-T/M, and ROI-T/M ratios are 3.2, 2.6, and 3.9 in the S180 tumor model and are 3.4, 4.2, and 4.6 in the OS732 tumor model, respectively). The imaging features visualized with autoradiography mostly coincided with the positive areas of HIF1α staining by immunofluorescence. Meanwhile, the biodistribution study and PET imaging revealed that the uptake of the radiotracers in the tumor cannot be competed by 5% glucose, confirming that [18F]FDG-2NNC2ON targets the hypoxic regions of the tumors instead of targeting tumors through the glucose metabolism pathway. These results suggest that the new 2-nitroimidazole derivative conjugated with [18F]FDG, [18F]FDG-2NNC2ON, has potential as an imaging agent for hypoxia.
- Yang, Xianteng,Wang, Fan,Zhu, Hua,Yang, Zhi,Chu, Taiwei
-
-
Read Online
- Lanthanide(iii) complexes of aminoethyl-DO3A as PARACEST contrast agents based on decoordination of the weakly bound amino group
-
2-Aminoethyl DOTA analogues with unsubstituted (H3L 1), monomethylated (H3L2) and dimethylated (H3L3) amino groups were prepared by improved synthetic procedures. Their solid-state structures exhibit an extensive system of intramolecular hydrogen bonds, which is probably present in solution and leads to the rather high value of the last dissociation constant. The protonation sequence of H3L1 in solution corresponds to that found in the solid state. The stability constants of the H3L1 complexes with La3+ and Gd3+ (20.02 and 22.23, respectively) are similar to those of DO3A and the reduction of the pK A value of the pendant amino group from 10.51 in the free ligand to 6.06 and 5.83 in the La3+ and Gd3+ complexes, respectively, points to coordination of the amino group. It was confirmed in the solid state structure of the [Yb(L1)] complex, where disorder between the SA′ and TSA′ isomers was found. A similar situation is expected in solution, where a fast equilibration among the isomers hampers the unambiguous determination of the isomer ratio in solution. The PARACEST effect was observed in Eu(iii)-H3L1/H3L2 and Yb(iii)-H3L1/H3L2 complexes, being dependent on pH in the region of 4.5-7.5 and pH-independent in more alkaline solutions. The decrease of the PARACEST effect parallels with the increasing abundance of the complex protonated species, where the pendant amino group is not coordinating. Surprisingly, a small PARACEST effect was also observed in solutions of Eu(iii)/Yb(iii)-H3L3 complexes, where the pendant amino group is dimethylated. The effect is detectable in a narrow pH region, where both protonated and deprotonated complex species are present in equilibrium. The data points to the new mechanism of the PARACEST effect, where the slow coordination-decoordination of the pendant amine is coupled with the fast proton exchange between the free amino group and bulk water mediates the magnetization transfer. The pH-dependence of the effect was proved to be measurable by MRI and, thus, the complexes extend the family of pH-sensitive probes. This journal is The Royal Society of Chemistry 2013.
- Krchova, Tereza,Kotek, Jan,Jirak, Daniel,Havlickova, Jana,Cisarova, Ivana,Hermann, Petr
-
-
Read Online
- Tuning DNA Supramolecular Polymers by the Addition of Small, Functionalized Nucleobase Mimics
-
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.
-
supporting information
p. 19824 - 19833
(2021/11/30)
-
- Study of the structure-bioactivity of fleximers: synthesis, crystal structure, Hirshfeld surface analysis, and anti-inflammatory assays
-
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
-
-
- Synthesis of hydroxyethyl methyl morpholinium azide (HEM Morph)N3: A highly efficient new task specific azide-based ionic liquid and its dual application as an azide source and media for synthesis of some novel aromatic O-oxime ethers-1,2,3-triazole conjugates as a potential antihistaminic agents
-
The synthesis, characterization and application of hydroxyethyl methyl morpholinium azide (HEM Morph)N3 as a new azide-based ionic liquid (ABIL) has been described. (HEM Morph)N3 is used as a source of azide and reaction media for three components ‘Click’ Huisgen cycloaddition reaction between O-propargyl oxime ether and alkyl bromide to acquire novel aromatic O-oxime ethers-1,2,3-triazole conjugates as potential antihistaminic agents in good yields. The influence of parameters like temperature, amount of IL, type of azide-based ionic liquids and its reusability is investigated. The (HEM Morph)N3 is proved to be an efficient, thermally stable, inexpensive and recyclable azide-based ionic liquid which can be easily synthesized and used as both azide's source and reaction media for ‘Click’ Huisgen cycloaddition reaction.
- Rad, Mohammad Navid Soltani,Behrouz, Somayeh,Saremi, Hossein,Mohammadtaghi-Nezhad, Javad
-
-
- COMPOUND INHIBITING BUTYRYLCHOLINESTERASE
-
The invention concerns a compound according to formula (I), wherein 3 n 11, wherein R comprises or consists of a heterocycle comprising one tertiary amino group providing the binding of R to the rest of the molecule and at least three carbon atoms, wherein all carbon atoms of the heterocycle are unsubstituted or wherein R is a fused bicyclic compound comprising the heterocycle and one further cyclic compound.
- -
-
Page/Page column 9
(2020/07/31)
-
- ω-Quinazolinonylalkyl aryl ureas as reversible inhibitors of monoacylglycerol lipase
-
The serine hydrolase monoacylglycerol lipase (MAGL) is involved in a plethora of pathological conditions, in particular pain and inflammation, various types of cancer, metabolic, neurological and cardiovascular disorders, and is therefore a promising target for drug development. Although a large number of irreversible-acting MAGL inhibitors have been discovered over the past years, there are only few compounds known so far which inhibit the enzyme in a reversible manner. Therefore, much effort is put into the development of novel chemical entities showing reversible inhibitory behavior, which is thought to cause less undesired side effects. To explore a wide range of chemical structures as MAGL binders, we have applied a virtual screening approach by docking small molecules into the crystal structure of human MAGL (hMAGL) and envisaged a library of 45 selected compounds which were then synthesized. Biochemical investigations included the determination of the inhibitory potency on hMAGL and two related hydrolases, i.e. human fatty acid amide hydrolase (hFAAH) and murine cholesterol esterase (mCEase). The most promising candidates from theses analyses, i.e. three ω-quinazolinonylalkyl aryl ureas bearing alkyl spacers of three to five methylene groups, exhibited IC50 values of 20–41 μM and reversible, detergent-insensitive behavior towards hMAGL. Among these compounds, the inhibitor 1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)butyl)urea (96) was selected for further kinetic characterization, yielding a dissociation constant Ki = 15.4 μM and a mixed-type inhibition with a pronounced competitive component (α = 8.94). This mode of inhibition was further supported by a docking experiment, which suggested that the inhibitor occupies the substrate binding pocket of hMAGL.
- Dato, Florian M.,Neud?rfl, J?rg-Martin,Gütschow, Michael,Goldfuss, Bernd,Pietsch, Markus
-
supporting information
(2019/11/13)
-
- 9,10-anthraquinone compound, pharmaceutically-acceptable salts and pharmaceutical application thereof
-
The invention belongs to the field of pharmaceutical chemistry and relates to a 9,10-anthraquinone compound and a pharmaceutical application thereof, in particular to the 9,10-anthraquinone compound and the application thereof in the preparation of a phosphoglycerate mutase inhibitor and in the preparation of drugs for treating cancer. In particular, the invention discloses the application of the9,10-anthraquinone compound shown in the structure of a formula I, pharmaceutically-acceptable salts thereof, or a pharmaceutical composition taking the 9,10-anthraquinone compound as an effective active ingredient in preparing drugs for preventing and treating tumors. The compound can inhibit phosphoglycerate mutase activity and reduce cell metabolism level, and can be used for treating diseasessuch as solid tumors and blood tumors, and the tumors involved are pancreatic cancer, lung cancer, liver cancer, gastric cancer, esophageal cancer, intestinal cancer, breast cancer, cervical cancer, leukemia and melanoma.
- -
-
Paragraph 0036-0039; 0216; 0218-0220
(2019/10/22)
-
- Design, synthesis and insecticide activity of novel acetylcholinesterase inhibitors: Triazolinone and phthalimide heterodimers
-
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
-
p. 345 - 350
(2019/05/07)
-
- 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
-
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
-
p. 9116 - 9140
(2019/11/03)
-
- Design, Synthesis, Molecular Docking, and Cholinesterase Inhibitory Potential of Phthalimide-Dithiocarbamate Hybrids as New Agents for Treatment of Alzheimer's Disease
-
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
-
-
- Identification of novel lysine demethylase 5-selective inhibitors by inhibitor-based fragment merging strategy
-
Histone lysine demethylases (KDMs) have drawn much attention as targets of therapeutic agents. KDM5 proteins, which are Fe(II)/α-ketoglutarate-dependent demethylases, are associated with oncogenesis and drug resistance in cancer cells, and KDM5-selective inhibitors are expected to be anticancer drugs. However, few cell-active KDM5 inhibitors have been reported and there is an obvious need to discover more. In this study, we pursued the identification of highly potent and cell-active KDM5-selective inhibitors. Based on the reported KDM5 inhibitors, we designed several compounds by strategically merging two fragments for competitive inhibition with α-ketoglutarate and for KDM5-selective inhibition. Among them, compounds 10 and 13, which have a 3-cyano pyrazolo[1,5-a]pyrimidin-7-one scaffold, exhibited strong KDM5-inhibitory activity and significant KDM5 selectivity. In cellular assays using human lung cancer cell line A549, 10 and 13 increased the levels of trimethylated lysine 4 on histone H3, which is a specific substrate of KDM5s, and induced growth inhibition of A549 cells. These results should provide a basis for the development of cell-active KDM5 inhibitors to highlight the validity of our inhibitor-based fragment merging strategy.
- Miyake, Yuka,Itoh, Yukihiro,Hatanaka, Atsushi,Suzuma, Yoshinori,Suzuki, Miki,Kodama, Hidehiko,Arai, Yoshinobu,Suzuki, Takayoshi
-
p. 1119 - 1129
(2019/02/13)
-
- Synthesis of [15N]-cholamine bromide hydrobromide
-
[15N]-Cholamine is an isotope tag for metabolomics research, because it possesses 2 important properties: an NMR active isotope and a permanent charge for MS sensitivity. Here, we present a scalable synthesis of [15N]-cholamine.
- Szeto, Judy,Lemoine, Remy,Nguyen, Rosary,Olson, Lori L.,Tanga, Mary J.
-
p. 391 - 394
(2018/04/02)
-
- Delta-aminoalkylbenzofuranol ethers, and preparation method and application thereof
-
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.
- -
-
Paragraph 0025
(2018/04/01)
-
- Synthesis of new analogs of tetraiodothyroacetic acid (tetrac) as novel angiogenesis inhibitors for treatment of cancer
-
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.
-
supporting information
p. 1223 - 1227
(2018/03/12)
-
- Radiosynthesis and evaluation of novel 99mTc(CO)3-labelled thymidine dithiocarbamate derivatives for tumor imaging with SPECT
-
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
-
p. 154 - 163
(2018/05/28)
-
- Design, synthesis and evaluation of scutellarein-O-acetamidoalkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease
-
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
-
p. 307 - 323
(2017/05/01)
-
- N-[(dihydrobenzofuran-7-yloxyl)alkyl]-2-aryloxy amide derivatives
-
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.
- -
-
Paragraph 0027; 0028; 0029; 0031
(2017/12/27)
-
- A phthalimide derivative and its preparation method and application
-
The invention belongs to the technical field of insect killing and sterilization of chemical pesticides, and in particular relates to phthalimide derivatives as well as a preparation method and application thereof. The phthalimide derivatives can be prepared from raw materials such as phthalimide, potassium hydroxide, dibromoalkane, substituted piperazinyl phenol, acyl chloride (phosphoryl chloride) and the like by virtue of multi-step chemical reactions. The phthalimide derivatives disclosed by the invention can be used for killing insects such as aphids, cabbage worms, plant hoppers, thrips, tetranychus cinnabarinus, root-knot nematodes and the like, also have certain sterilization and bacterium inhibition effects, can be used for effectively controlling plant inset pests, harmful mites, nematodes and harmful bacteria, and can also be applied to prevention and control of diseases, insect pests and pathogenic bacteria in agriculture.
- -
-
Paragraph 0040
(2017/08/24)
-
- 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
-
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
-
supporting information
p. 5053 - 5059
(2017/10/18)
-
- Synthesis and biological evaluation of 1,3,4-thiadiazole linked phthalimide derivatives as anticancer agents
-
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
-
p. 1138 - 1144
(2017/11/14)
-
- Silver-Catalyzed Decarboxylative Bromination of Aliphatic Carboxylic Acids
-
The silver-catalyzed Hunsdiecker bromination of aliphatic carboxylic acids is described. With Ag(Phen)2OTf as the catalyst and dibromoisocyanuric acid as the brominating agent, various aliphatic carboxylic acids underwent decarboxylative bromination to provide the corresponding alkyl bromides under mild conditions. This method not only is efficient and general but also enjoys wide functional group compatibility. An oxidative radical mechanism involving Ag(II) intermediates is proposed.
- Tan, Xinqiang,Song, Tao,Wang, Zhentao,Chen, He,Cui, Lei,Li, Chaozhong
-
supporting information
p. 1634 - 1637
(2017/04/11)
-
- Design, synthesis and biological evaluation of new phthalimide and saccharin derivatives with alicyclic amines targeting cholinesterases, beta-secretase and amyloid beta aggregation
-
The complexity of Alzheimer's disease (AD) calls for search of multifunctional compounds as potential candidates for effective therapy. A series of phthalimide and saccharin derivatives linked by different alicyclic fragments (piperazine, hexahydropyrimidine, 3-aminopyrrolidine or 3-aminopiperidine) with phenylalkyl moieties attached have been designed, synthesized, and evaluated as multifunctional anti-AD agents with cholinesterase, β-secretase and β-amyloid inhibitory activities. In?vitro studies showed that the majority of saccharin derivatives with piperazine moiety and one phthalimide derivative with 3-aminopiperidine fragment exhibited inhibitory potency toward acetylcholinesterase (AChE) with EeAChE IC50values ranging from 0.83?μM to 19.18?μM. The target compounds displayed inhibition of human β-secretase-1 (hBACE1) ranging from 26.71% to 61.42% at 50?μM concentration. Among these compounds, two multifunctional agents (26, [2-(2-(4-benzylpiperazin-1-yl)ethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide] and 52, 2-(2-(3-(3,5-difluorobenzylamino)piperidin-1-yl)ethyl)isoindoline-1,3-dione) have been identified. Compound 26 exhibited the highest inhibitory potency against EeAChE (IC50?=?0.83?μM) and inhibitory activity against hBACE1 (33.61% at 50?μM). Compound 52 is a selective AChE inhibitor (IC50 AChE?=?6.47?μM) with BACE1 inhibitory activity (26.3% at 50?μM) and it displays the most significant Aβ anti-aggregating properties among all the obtained compounds (39% at 10?μM). Kinetic and molecular modeling studies indicate that 26 may act as non-competitive AChE inhibitor able to interact with both catalytic and peripheral active site of the enzyme.
- Panek, Dawid,Wi?ckowska, Anna,Wichur, Tomasz,Bajda, Marek,Godyń, Justyna,Jończyk, Jakub,Mika, Kamil,Janockova, Jana,Soukup, Ondrej,Knez, Damijan,Korabecny, Jan,Gobec, Stanislav,Malawska, Barbara
-
p. 676 - 695
(2016/10/13)
-
- Synthesis and antiviral, insecticidal, and fungicidal activities of gossypol derivatives containing alkylimine, oxime or hydrazine moiety
-
Gossypol is a part of the cotton plant's defense system against pathogens and herbivorous insects. To discover gossypol analogs with broad spectrum and high activity, a series of gossypol alkylamine Schiff base, oxime and hydrazone derivatives were synthesised and bioassayed. The biological results indicated that most of these derivatives exhibited higher anti-TMV activity than gossypol. Interestingly, the activities of compounds 10, 15, 18, 20, 23 and 26 were much higher than that of ribavirin. Furthermore, compound 26, which was low toxicity to rat, showed better activity than control plant virus inhibitors in the field. Additionally, allyl amine Schiff base (9) displayed remarkable insecticidal activities against Mythimna separata, Helicoverpa armigera and Ostrinia nubilalis, whereas (pyridin-3-yl)methanamine Schiff base (13) showed excellent activity against Culex pipiens pallens. The fungicidal results revealed that all of compounds exhibited good activity against Physalospora piricola.
- Li, Ling,Li, Zheng,Wang, Kailiang,Liu, Yuxiu,Li, Yongqiang,Wang, Qingmin
-
p. 474 - 483
(2016/01/25)
-
- Design, synthesis and bioactivity of novel phthalimide derivatives as acetylcholinesterase inhibitors
-
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
-
supporting information
p. 2380 - 2382
(2016/04/20)
-
- Discovery of naphthalimide conjugates as fluorescent probes for α1-adrenoceptors
-
α1-Adrenoceptors (α1-ARs), including at least three subtypes, α1A, α1B and α1D, which play essential roles in G protein-coupled receptors (GPCRs), can convey multiple pivotal extracellular signals in varied tissues and organs. In this research, a series of napthalimide-based small-molecule fluorescent probes (1a–1f) for α1-ARs, including two parts, a pharmacophore (quinazoline and phenylpiperazine) for α1-AR recognition and a fluorophore (naphthalimide) for visualization, were designed and synthesized successfully. These compounds display excellent fluorescence property and high affinity to receptors, which were used successfully for in vitro visualization of α1-adrenoceptors.
- Zhang, Wei,Zhou, Xin-Yang,Yu, Qin-Ying,Du, Lu-Pei,Li, Min-Yong
-
supporting information
p. 185 - 189
(2018/03/22)
-
- Design, synthesis and evaluation of 4-dimethylamine flavonoid derivatives as potential multifunctional anti-Alzheimer agents
-
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
-
supporting information
p. 17 - 26
(2016/07/06)
-
- Thioether allyl isothiocyanate compounds, and preparation method and applications thereof
-
The invention provides a series of novel thioether allyl isothiocyanate compounds with a general structure disclosed in the invention, and a simple method used for rapid synthesis of the thioether allyl isothiocyanate compounds. According to the method, double-terminal halogen-substituted alkanes are taken as initial raw materials, are reacted with phthalimide potassium so as to introduce N atoms, are reacted with sodium hydrosulfide so as to produce mercaptan, and mercaptan is reacted with benzyl bromide or is reacted with a heterocyclic compound with sulfydryl so as to introduce the thioether structure, an obtained product is reacted with hydrazine hydrate so as to obtain a primary amine, and the primary amine is reacted with an alkali, carbon disulfide, and methylsufonyl chloride so as to prepare the thioether allyl isothiocyanate compounds with heterocyclic nitrogen structures. The method contains few steps; operation is simple; the obtained products can be easily purified; and yield is high. The series of novel thioether allyl isothiocyanate compounds possess obvious killing activity on tumor cells, and possess obvious killing activity on cervical carcinoma cells and lung cancer cells.
- -
-
Paragraph 0051; 0055; 0056; 0057; 0058
(2016/10/08)
-
- 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
-
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
-
supporting information
p. 2035 - 2039
(2016/04/05)
-
- Metal-free C-N cross-coupling of electrophilic compounds and N-haloimides
-
When DBU is added, the cross-coupling reaction between alkyl halides (halogen = Cl, Br and I) and N-haloimides (halogen = Cl, Br) occurs, resulting in the formation of aminated products. A halogen bond activated nucleophilic substitution mechanism was proposed. The methodology represents an elegant example of applying the halogen bond activation strategy in an organic transformation.
- Zhang, Luyan,Li, Yanru,Jin, Long-Yi,Liang, Fushun
-
p. 65600 - 65603
(2015/08/18)
-
- Synthesis of novel conjugates of a saccharide, amino acids,nucleobase and the evaluation of their cell compatibility
-
This article reports the synthesis of a novel type of conjugate of three fundamental biological build blocks (i.e., saccharide, amino acids, and nucleobase) and their cell compatibility. The facile synthesis starts with the synthesis of nucleobase and saccharide derivatives, then uses solid-phase peptide synthesis (SPPS) to build the peptide segment (Phe-Arg-Gly-Asp or naphthAla-Phe-Arg- Gly-Asp with fully protected groups), and later, an amidation reaction in liquid phase connects these three parts together. The overall yield of these multiple step synthesis is about 34%. Besides exhibiting excellent solubility, these conjugates of saccharide-amino acids-nucleobase (SAN), like the previously reported conjugates of nucleobase-amino acids-saccharide (NAS) and nucleobase-saccharide-amino acids (NSA), are mammalian cell compatible.
- Yuan, Dan,Du, Xuewen,Shi, Junfeng,Zhou, Ning,Baoum, Abdulgader Ahmed,Xu, Bing
-
supporting information
p. 2406 - 2413
(2014/12/11)
-
- Synthesis, in vitro cytotoxicity and radiosensitizing activity of novel 3-[(2,4-dinitrophenylamino)alkyl] derivatives of 5-fluorouracil
-
Previously, it was reported that 3[3-(2,4-dinitrophenylamino)-propyl]-5- fluorouracil 8c unlike its components 5-fluorouracil (5-FU) 6 and 2,4-dinitroaniline 2 in HT-29 cells under aerobic conditions had no cytotoxicity but showed radiosensitizing activity. In this study several analogues of 8c differing in the number of linking methylene groups were prepared and tested for in vitro cytotoxicity and radiosensitizing activity under both aerobic and hypoxic conditions. Tethered compound 8a was prepared in one pot by the reaction of 5-FU 6 with paraformaldehyde and 2,4-dinitroaniline 2 in the presence of the concentrated hydrochloric acid, and compounds 8b-f were prepared by the reaction of N-(bromoalkyl) - 2,4-dinitrobenzeneamines 5b-f with 1-(t-butoxycarbonyl)-5-fluorouracil 7 followed by hydrolysis of the protecting group. The cytotoxicity of the tested compounds were measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and propidium iodide (PI)-digitonin assays and values of sensitization enhancement ratio (SER) as a measure of the radiosensitizing activity were measured from radiation survival curves in the absence and presence of each sensitizer for 37% survival respectively. Results showed that tethered compounds 8a-f induced time- and concentration-dependent cytotoxicity under hypoxia but had no significant effect under aerobic conditions. These compounds also showed selective and concentration-dependent radiocytotoxicity under hypoxic conditions. Several novel 3[3-(2,4-dinitro-phenylamino)-alkyl]-5-fluorouracil resulting from linkage of 2,4-dinitrophenylamine through 1-6 methylene units with 5-fluorouracil were prepared and tested for in vitro cytotoxicity in HT-29 cell line under aerobic and hypoxic conditions with and without radiation. These compounds induced time- and concentration-dependent cytotoxicity which were higher under hypoxic than aerobic conditions, and showed selective radiosensitizing activities under hypoxic conditions.
- Khalaj, Ali,Abdi, Khosrou,Ostad, Seyed Nasser,Khoshayand, Mohammad Reza,Lamei, Navid,Nedaie, Hasan Ali
-
p. 183 - 190
(2014/02/14)
-
- Catalytic intermolecular haloamidation of simple alkenes with N-halophthalimide as both nitrogen and halogen source
-
A simple, efficient, and highly atom economic haloamidation of simple alkenes has been developed, using AgBF4 or InBr3/AgBF 4 (1:3) as catalyst and N-halophthalimide as both nitrogen and halogen source. A broad range of olefins can be applied to afford vicinal haloamines in good yields and with high regioselectivity and diastereoselectivity.
- Song, Lu,Luo, Sanzhong,Cheng, Jin-Pei
-
supporting information
p. 5702 - 5705
(2013/12/04)
-
- A mesogenic triphenylene-perylene-triphenylene triad
-
A straightforward synthesis of triphenylene-perylene-triphenylene triad structures has been achieved by using versatile triphenylene intermediates bearing a single oxyalkyl amine side chain. Among these, PBITP10 showed a stable columnar mesophase implying favorably matched core-core separations in the structure. Importantly, the triad can be used as a vehicle for doping columnar triphenylene matrices with functional but incompatible perylene units and a mixture of hexahexyloxytriphenylene matrix doped with 0.1% PBITP10 is homogeneous and liquid crystalline.
- Kong, Xiangfei,He, Zhiqun,Zhang, Yinning,Mu, Linping,Liang, Chunjun,Chen, Bo,Jing, Xiping,Cammidge, Andrew N.
-
supporting information; experimental part
p. 764 - 767
(2011/04/24)
-
- Pore formation in phospholipid bilayers by amphiphilic cavitands
-
Five new cavitands were prepared that have four pendant n-undecyl chains and "headgroups" connected by 2-carbon spacers. The headgroups were ～OCH2CONH-Ala-OCH3, 1; ～OCH2CONH-Phe- OCH3, 2; ～OCH2CONH-Ala-OH, 3; ～OCH 2CONH-Phe-OH, 4; and ～OCH2CONHCH2CH 2-thyminyl, 5. Pore formation by each cavitand was studied by use of the planar bilayer conductance experiment. All five compounds were found to form pores in asolectin bialyer membranes. Compounds 1-3 behaved in a generally similar fashion and exhibited open-close dynamics. Compounds 4 and 5 formed pores more rapidly, were more dynamic, and led more quickly to membrane rupture. Differences in the ion transport activity are rationalized in terms of structure and aggregate cavitand assemblies.
- Elidrisi, Iman,Negin, Saeedeh,Bhatt, Pralav V.,Govender, Thavendran,Kruger, Hendrick G.,Gokel, George W.,Maguire, Glenn E. M.
-
experimental part
p. 4498 - 4506
(2011/07/30)
-
- Synthesis of several MPP derivatives for 99mTc-labelling and evaluated as potential 5-HT1A receptor imaging agents
-
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
-
experimental part
p. 1148 - 1154
(2012/04/04)
-
- Synthesis, biological evaluation of 9-N-substituted berberine derivatives as multi-functional agents of antioxidant, inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid-β aggregation
-
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
-
experimental part
p. 5885 - 5893
(2012/01/04)
-
- COMPOUNDS AND METHODS FOR INHIBITING NHE-MEDIATED ANTIPORT IN THE TREATMENT OF DISORDERS ASSOCIATED WITH FLUID RETENTION OR SALT OVERLOAD AND GASTROINTESTINAL TRACT DISORDERS
-
The present disclosure is directed to corn- pounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders. The methods generally comprise administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that is designed to be substantially active in the gastrointestinal (GI) tract to inhibit NHE-mediated antiport of sodium ions and hydrogen ions therein. More particularly, the method comprises administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that inhibits NHE-3, -2 and/ or -8 mediated antiport of sodium and/or hydrogen ions in the GI tract and is designed to be substantially impermeable to the layer of epithelial cells, or more specifically the epithelium of the GI tract. As a result of the compound being substantially impermeable, it is not absorbed and is thus essentially systemically non-bioavailable, so as to limit the exposure of other internal organs (e.g., liver, heart, brain, etc.) thereto. The present disclosure is still further directed to a method wherein a mammal is administered such a compound with a fluid-absorbing polymer, such that the combination acts as described above and further provides the ability to sequester fluid and/or salt present in the GI tract
- -
-
Page/Page column 147
(2010/08/04)
-
- N-alkylation of imides using phase transfer catalysts under solvent-free conditions
-
(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
-
scheme or table
p. 1371 - 1375
(2009/04/07)
-
- Arylpiperazinylalkylpyridazinones and analogues as potent and orally active antinociceptive agents: Synthesis and studies on mechanism of action
-
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
-
p. 7826 - 7835
(2008/02/02)
-
- N-VINYLFORMAMIDE DERIVATIVES, POLYMERS FORMED THEREFROM AND SYNTHESIS THEREOF
-
A method of synthesizing a compound having the formula (I), comprising the step of: reacting a N-vinylformamide salt having the formula (II), with a compound having the formula XRR1; wherein X is Br, CI or I, M is an alkali metal or an alkali earth metal, R1 is a C0-C25 alkylene group, a C0-C25 fluroalkylene group or a C0-C25 perfluoro alkylene group, R2 is H, provided R1 is not absent, an alkyl group, a fluroalkyl group, a perfluoroalkyl group, an aryl group, a hydroxy group, a polyether group, a heterocyclic group of 5 or 6 atoms wherein at least one of the atoms is not a carbon and is N, O, or S, -OR3, wherein, R3 is an alkyl group, a fluoroalkyl group, a perfluoroalkyl group, or an aryl group, -C(O)R4, -C(O)OR4, -OC(O)R4, wherein R4 is an H, an alkyl group, a fluoroalkyl group, a perfluoroalkyl group, or an aryl group, a phthalimide group or NR5R5 wherein R5 and R5 are independently H, -C(O)R4, an alkyl, a fluoroalkyl group, a perfluoroalkyl group or an aryl group.
- -
-
-
- Design and synthesis of N-nonpolar nucleobase dipeptides: Application of the Ugi reaction for the preparation of dipeptides havingfluoroarylalkyl groups appended to the nitrogen atom
-
A single-step one-pot synthesis based on the Ugi four-component condensation of previously unknown dipeptides, 2,3,4 and 5, having afluoroaromatic group appended to the nitrogen atom, is described. The series of dipeptides produced here can be viewed as nonpolar nucleobase dipeptides since the difluorotoluene nucleoside 1 is a well known nonpolar analogue of natural thymidine. A mixture of N-protected amino acids 7, fluorophenethylamines 6, isocyanides 8, and acetone or paraformaldehyde are stirred in methanol in the presence of 3 A molecular sieves to furnish the N-fluoroarylethyl-Aib- or -Gly-containing dipeptides 2 or 3, in moderate yields. The dipeptides 2d and 3b, having a cyclohex-1-enamide moiety, are deprotected readily with 3 M HCl in THF to a3ord the free dipeptides in high yields. The N-fluoroarylmethyl-Aib- or -Gly-containingβ-alanyl dipeptides 4 or 5, designed based on the structure of 2′,5′-linked isoDNA, are also synthesized in a similar fashion to the preparation of 2, in moderate to good yields as both protected and free dipeptides.
- Das, Biplab Kumar,Shibata, Norio,Takeuchi, Yoshio
-
p. 197 - 206
(2007/10/03)
-
- Development of a new class of nonimidazole histamine H3 receptor ligands with combined inhibitory histamine N-methyltransferase activity
-
In search of novel ways to enhance histaminergic neurotransmission in the central nervous system, a new class of nonimidazole histamine H3 receptor ligands were developed that simultaneously possess strong inhibitory activity on the main histamine metabolizing enzyme, histamine N-methyltransferase (HMT). The novel compounds contain an aminoquinoline moiety, which is an important structural feature for HMT inhibitory activity, connected by different spacers to a piperidino group (for H3 receptor antagonism). Variation of the spacer structure provides two different series of compounds. One series, having only an alkylene spacer between the basic centers, led to highly potent HMT inhibitors with moderate to high affinity at human histamine H3 receptors. The second series possesses a p-phenoxypropyl spacer, which may be extended by another alkylene chain. This latter series also showed strong inhibitory activity on HMT, and in most cases, the H3 receptor affinity even surpassed that of the first series. One of the most potent compounds with this dual mode of action is 4-(4-(3-piperidinopropoxy)phenylamino)quinoline (34) (hH3, Ki = 0.09 nM; HMT, IC50 = 51 nM). This class of compounds showed high antagonist potency and good H3 receptor selectivity in functional assays in guinea pig on H1, H2, and H3 receptors. Because of low or missing in vivo activity of two selected compounds, the proof of concept of these valuable pharmacological tools for the supposed superior overall enhancing effect on histaminergic neurotransmission failed to appear hitherto.
- Apelt, Joachim,Ligneau, Xavier,Pertz, Heinz H.,Arrang, Jean-Michel,Ganellin, C. Robin,Schwartz, Jean-Charles,Schunack, Walter,Stark, Holger
-
p. 1128 - 1141
(2007/10/03)
-
- -
-
New initiators 1-7, analogues of tetra-acetylethylenediamine, have been prepared and their use in the in situ generation of peroxyacids by reaction with sodium peroxycarbonate described. The kinetics of perhydrolysis of these initiators in aqueous solutio
- Lion, Claude,Da Conceicao, Louis,Hedayatullah, Mir
-
-
- Phenylacetamide derivatives
-
A phenylacetamide derivative of formula (I) have potent analgesic and anti-inflammatory activities and exhibit less irritability and toxicity: STR1 wherein, X, Y, W, n, m and Ar are as defined in the specification.
- -
-
-
- Synthesis of phosphinico analogues of pantetheine
-
The synthesis of phosphinico analogues 9a-c of pantetheine is described where the carbonyl group of one of the amide linkage is replaced by a methyl-, ethyl-, or phenylphosphinoyl group.
- Neidlein,Li
-
p. 1570 - 1576
(2007/10/02)
-
- Syntheses of Phosphonic- and Phosphinic Analogues of Pantothenic Acid Ethyl Ester and of the Phosphonic Analogue of Pantetheine
-
The replacement of amino acids in peptides by phosphono-analogous (aminoalkyl)phosphonic acids 1, (2-aminoethyl)phosphonic acid (2) and substituted derivatives has been an important aspect of peptides research in the last years.In pantothenic acid (3), there is a peptide linkage between (2R)-2,4-dihydroxy-3,3-dimethylbutyric acid and the amino group of β-alanine, and in pantetheine (4), there is a second peptide linkage between the β-alanine and cysteamine.The synthesis of phosphono and phosphino analogues of pantothenic acid ethyl ester, where the β-alanine is replaced by the diethyl ester of (2-aminoethyl)phosphonic acid and the ethyl ester of (2-aminoethyl)methylphosphonic acid, respectively, and the syntheses of the phosphono analogue of pantetheine, where the β-alanine is replaced by (2-aminoethyl)phosphonic acid, are described.
- Neidlein, Richard,Greulich, Peter
-
p. 2545 - 2552
(2007/10/02)
-
- Studies on hypotensive agents. Synthesis of 1-substituted 3-(2-chlorophenyl)-6-ethoxycarbonyl-5,7-dimethyl-2,4(1H,3H)- quinazolinediones
-
3-(2-Chlorophenyl)-6-ethoxycarbonyl-5,7-dimethyl-2,4(1H,3H)- quinazolinedione was newly prepared. 1-Hydrogen atoms of the compound were variously substituted in order to test for their hypotensive activities on relaxing effects of the blood vessels. The compounds with 2-(1-pyrrolidinyl ethyl, 2-(1-piperidinyl)ethyl, 3-(dimethylamino)propyl, and 3-(N-benzyl-N-methylamino)propyl moieties showed significant activity. The 2-(1-piperidinyl)ethyl compound possessed activity approximately 23 times more potent than papaverine, however, it was less potent than cinnarizine.
- Eguchi,Sasaki,Sugimoto,Ebisawa,Ishikawa
-
p. 1753 - 1759
(2007/10/02)
-
