- Virtual screening for novel Atg5-Atg16 complex inhibitors for autophagy modulation
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Two hit compounds (14 and 62) were identified using virtual high throughput screening (vHTS) inhibiting the autophagy process in A2780 ovarian cancer cells. The expression levels of the LC3-II and p62 autophagy marker proteins were monitored using Western blotting. Preliminary structure activity relationship (SAR) study of close structural analogues revealed another active compound 38. The three active compounds were tested in the MCF-7 human breast cancer cells and severe reduction of autophagosomes formation was observed confirming the activity of the inhibitors. The docking scaffold used for the vHTS was a lipophilic cleft on the Atg5 protein, which is occupied by a phenylalanine residue in the Atg16 polypeptide. To the best of our knowledge this is the first report on inhibitors that specifically modulate autophagy by directly inhibiting autophagy specific proteins, which is significant due the role autophagy plays in a number of morbid diseases such as cancer. This journal is
- Robinson, Elizabeth,Leung, Euphemia,Matuszek, Anna M.,Krogsgaard-Larsen, Niels,Furkert, Daniel P.,Brimble, Margaret A.,Richardson, Alan,Reynisson, Jhannes
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Read Online
- Efficient conversion of primary and secondary alcohols to primary amines
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A convenient single-vessel conversion of primary and secondary alcohols to primary amines is reported. Use of this method results in substantially cleaner crude products than similar procedures reported in the literature. A simple work-up also makes this procedure ideal for parallel synthesis.
- Sun, Weilin,Pelletier, Jeffrey C.
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Read Online
- Synthesis and antitumor activity of 5-(5-halogenated-2-oxo-1H-pyrrolo[2,3-b]pyridin-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamides
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We report herein the design and synthesis of a series of novel 5-halogenated-7-azaindolin-2-one derivatives containing a 2,4-dimethylpyrrole moiety. Nine target compounds with ≥70% inhibition against MCF-7 at 30 μM were further evaluated for their in vitro antitumor activity against seven human cancer cell lines by SRB assay. Results reveal that some compounds have potent antitumor activity, and the most active 13c7 (IC50s: 4.49-15.39 μM) was found to be more active than Sunitinib (IC50s: 4.70->30 μM) against all of the tested cancer cell lines.
- Wang, Minghua,Ye, Cheng,Liu, Mingliang,Wu, Zhaoyang,Li, Linhu,Wang, Chunlan,Liu, Xiujun,Guo, Huiyuan
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Read Online
- Design, synthesis, crystal structure, and herbicidal activity of novel pyrrolidine-2,4-dione derivatives incorporating an alkyl ether pharmacophore with natural tetramic acids as lead compounds
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In order to discover green herbicides with novel molecular scaffolds, natural tetramic acids were used as lead compounds to design and synthesize four pyrrolidine-2,4-dione derivatives incorporating a chainlike alkoxyalkyl moiety (4a-4d) and nineteen pyrrolidine-2,4-dione derivatives incorporating a substituted phenoxyethyl moiety (10a-10s)viasubstitution, acylation, cyclization, and acidification reactions. The synthesized target compounds were confirmed by FT-IR,1H NMR,13C NMR and HRMS spectral analyses. The single-crystal structure of compound10awas analyzed by X-ray diffraction, which revealed that the 1-hydroxyethylidene group links the third position of the pyrrolidine heterocycle through a double bond with theZ-configuration. The herbicidal activity was evaluated using barnyard grass (Echinochloa crus-galli) and rape (Brassica campestris) as model plants by a Petri dish culture method. Most target compounds were found to possess moderate to good inhibitory activities against the plant growth at 100 μg mL?1. Among them, the compounds10qand10nshowed the highest herbicidal activities against the roots of barnyard grass and rape seedlings with the corresponding inhibition rates of 65.6% and 84.0%, respectively. This result indicated that pyrrolidine-2,4-dione derivatives incorporating a substituted phenoxyethyl moiety are worthy of further structural optimization.
- Chen, Min,Geng, Chun-Wen,Han, Ling,Liu, Yu,Yu, Yong-Kai,Lu, Ai-Min,Yang, Chun-Long,Li, Guo-Hua
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p. 5621 - 5630
(2021/04/06)
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- Synthesis and Antichlamydial Activity of Molecules Based on Dysregulators of Cylindrical Proteases
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Chlamydia trachomatis is the most common sexually transmitted bacterial disease globally and the leading cause of infertility and preventable infectious blindness (trachoma) in the world. Unfortunately, there is no FDA-approved treatment specific for chlamydial infections. We recently reported two sulfonylpyridines that halt the growth of the pathogen. Herein, we present a SAR of the sulfonylpyridine molecule by introducing substituents on the aromatic regions. Biological evaluation studies showed that several analogues can impair the growth of C. trachomatis without affecting host cell viability. The compounds did not kill other bacteria, indicating selectivity for Chlamydia. The compounds presented mild toxicity toward mammalian cell lines. The compounds were found to be nonmutagenic in a Drosophila melanogaster assay and exhibited a promising stability in both plasma and gastric fluid. The presented results indicate this scaffold is a promising starting point for the development of selective antichlamydial drugs.
- Seleem, Mohamed A.,Rodrigues De Almeida, Nathalia,Chhonker, Yashpal Singh,Murry, Daryl J.,Guterres, Zaira Da Rosa,Blocker, Amanda M.,Kuwabara, Shiomi,Fisher, Derek J.,Leal, Emilse S.,Martinefski, Manuela R.,Bollini, Mariela,Monge, María Eugenia,Ouellette, Scot P.,Conda-Sheridan, Martin
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p. 4370 - 4387
(2020/05/22)
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- PYRIDIN-3-YL ACETIC ACID DERIVATIVES AS INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS REPLICATION
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Disclosed are compounds of Formula I, including pharmaceutically acceptable salts, pharmaceutical compositions comprising the compounds, methods for making the compounds and their use in inhibiting HIV integrase and treating those infected with HIV or AIDS.
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Page/Page column 237; 293; 294
(2020/01/11)
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- Corresponding amine nitrile and method of manufacturing thereof
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The invention relates to a manufacturing method of nitrile. Compared with the prior art, the manufacturing method has the characteristics of significantly reduced using amount of an ammonia source, low environmental pressure, low energy consumption, low production cost, high purity and yield of a nitrile product and the like, and nitrile with a more complex structure can be obtained. The invention also relates to a method for manufacturing corresponding amine from nitrile.
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- Identification of N-(2-Phenoxyethyl)imidazo[1,2-a]pyridine-3-carboxamides as New Antituberculosis Agents
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A series of imidazo[1,2-a]pyridine carboxamides (IPAs) bearing an N-(2-phenoxyethyl) moiety was designed and synthesized as new antitubercular agents. Seven 2,6-dimethyl IPAs demonstrated excellent in vitro activity (MIC: 0.025-0.054 μg/mL) against the drug susceptive H37Rv strain and two clinically isolated multidrug-resistant Mycobacterium tuberculosisstrains. Compound 10j displayed acceptable safety and pharmacokinetic properties, opening a new direction for further development.
- Wu, Zhaoyang,Lu, Yu,Li, Linhu,Zhao, Rui,Wang, Bin,Lv, Kai,Liu, Mingliang,You, Xuefu
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supporting information
p. 1130 - 1133
(2016/12/16)
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- Activity of Fluorine-Containing Analogues of WC-9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii
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Two obligate intracellular parasites, Trypanosoma cruzi, the agent of Chagas disease, and Toxoplasma gondii, an agent of toxoplasmosis, upregulate the mevalonate pathway of their host cells upon infection, which suggests that this host pathway could be a potential drug target. In this work, a number of compounds structurally related to WC-9 (4-phenoxyphenoxyethyl thiocyanate), a known squalene synthase inhibitor, were designed, synthesized, and evaluated for their effect on T. cruzi and T. gondii growth in tissue culture cells. Two fluorine-containing derivatives, the 3-(3-fluorophenoxy)- and 3-(4-fluorophenoxy)phenoxyethyl thiocyanates, exhibited half-maximal effective concentration (EC50) values of 1.6 and 4.9 μm, respectively, against tachyzoites of T. gondii, whereas they showed similar potency to WC-9 against intracellular T. cruzi (EC50values of 5.4 and 5.7 μm, respectively). In addition, 2-[3- (phenoxy)phenoxyethylthio]ethyl-1,1-bisphosphonate, which is a hybrid inhibitor containing 3-phenoxyphenoxy and bisphosphonate groups, has activity against T. gondii proliferation at sub-micromolar levels (EC50=0.7 μm), which suggests a combined inhibitory effect of the two functional groups.
- Chao, María N.,Li, Catherine,Storey, Melissa,Falcone, Bruno N.,Szajnman, Sergio H.,Bonesi, Sergio M.,Docampo, Roberto,Moreno, Silvia N. J.,Rodriguez, Juan B.
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p. 2690 - 2702
(2016/12/23)
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- HIV INTEGRASE INHIBITORS
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The present invention features compounds that are HIV integrase inhibitors and therefore are useful in the inhibition of HIV replication, the prevention and/or treatment of infection by HIV, and in the treatment of AIDS and/or ARC.
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- Highly Efficient Mechanochemical N-Arylation of Amino Alcohols and Diamines with Cu0 Powder
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Cu0-catalysed arylations have rightly acquired great importance over the last decade. This paper reports the N-arylation of amino alcohols and diamines with iodobenzene derivatives in a planetary ball mill and an investigation into the procedure. This newly developed solvent-free protocol is fast, efficient and occurs under the mechanochemical activation of metallic copper powder. It does not require additional ligands and gives excellent yields. This paper aims to broaden the scope of mechanochemical Cu0-activation and so a new one-pot, two-step synthesis that combines CuAAC and N-arylation has been successfully performed and reported herein.
- Martina, Katia,Rinaldi, Laura,Baricco, Francesca,Boffa, Luisa,Cravotto, Giancarlo
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p. 2789 - 2794
(2015/12/18)
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- AMINOETHYLATION PROCESS HAVING IMPROVED YIELD OF ARYLOXYALKYLENE AMINE COMPOUNDS AND REDUCED UREA BY-PRODUCTS
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Disclosed is a process for preparing an aryloxyalkylene amine compound via an aminoethylation reaction comprising: a) reacting an aromatic hydroxyl compound in the presence of a basic catalyst with a 2-oxazolidinone compound of the formula II to form an intermediate reaction product; wherein R3 is selected from the group consisting of hydrogen or lower alkyl having 1 to 6 carbon atoms, R4 is selected from the group consisting of hydrogen, straight or branched chain alkyl having from one to six carbon atoms, phenyl, alkaryl, or arylalkyl; and b) reacting the intermediate product of step a) with a polyalkylene polyamine.
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Paragraph 0062-0063
(2014/03/25)
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- New serotonin 5-HT1A receptor agonists endowed with antinociceptive activity in vivo
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We report the synthesis of new compounds 4-35 based on two different openings (A and B) of the chromane ring present in the previously identified 5-HT1A receptor (5-HT1AR) ligand 3. The synthesized compounds were assessed for binding affinity, selectivity, and functional activity at the 5-HT1AR. Selected candidates resulting from B opening were also evaluated for their potential antinociceptive effect in vivo and pharmacokinetic properties in vitro. Analogue 19 [2-(4-{[2-(2-ethoxyphenoxy) ethyl]amino}butyl)tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione] has been characterized as a high-affinity and potent 5-HT1AR agonist (K i = 2.3 nM; EC50 = 19 nM). Pharmacokinetic studies indicated that compound 19 displays a good metabolic stability in human liver microsomes (t1/2 ～ 3 h and CLint = 3.5 mL/min/kg, at 5 μM), and a low level of protein binding (25%, at 5 μM). Interestingly, 19 (3 mg/kg, ip, and 30 mg/kg, po) caused significant attenuation of formalin-induced behavior in early and late phases of the mouse intradermal formalin test of pain, and this in vivo effect was reversed by the selective 5-HT1AR antagonist WAY-100635. Thus, the new 5-HT1AR agonist identified in this work, 19, exhibits oral analgesic activity, and the results herein represent a step toward identifying new therapeutics for the control of pain.
- Valhondo, Margarita,Marco, Isabel,Martín-Fontecha, Mar,Vázquez-Villa, Henar,Ramos, José A.,Berkels, Reinhard,Lauterbach, Thomas,Benhamú, Bellinda,López-Rodríguez, María L.
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supporting information
p. 7851 - 7861
(2013/11/06)
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- A Synthesis of acetamidines
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The condensation of primary amine with N,N-dimethylacetamide dimethyl acetal yields amixture of acetamidine and imidate ester. The product distribution in this reaction depends on the temperature, solvent, and structure of the primary amine. It is possible to suppress the formation of imidate ester by performing the reaction in the presence of excess dimethyl amine, yielding acetamidine as the exclusive product. For acetamidines that cannot be purified either by crystallization or distillation, this new method is necessary for the generation of pure acetamidines in good yields.
- Harjani, Jitendra R.,Liang, Chen,Jessop, Philip G.
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experimental part
p. 1683 - 1691
(2011/05/12)
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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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- Design, synthesis, and pharmacological effects of structurally simple ligands for MT1 and MT2 melatonin receptors
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A series of phenoxyalkyl and phenylthioalkyl amides were prepared as melatoninergic ligands. Modulation of affinity of the newly synthesized compound by applying SARs around the terminal amide moiety, the alkyl chain, and the methoxy group on the aromatic ring provides compounds with nanomolar affinity for both melatonin receptor subtypes. Affinity towards MT1 and MT2 receptors were modulated also exploiting chirality. The investigation of intrinsic activity revealed that all the tested compounds behave as full or partial agonists.
- Carocci, Alessia,Catalano, Alessia,Lovece, Angelo,Lentini, Giovanni,Duranti, Andrea,Lucini, Valeria,Pannacci, Marilou,Scaglione, Francesco,Franchini, Carlo
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experimental part
p. 6496 - 6511
(2010/10/02)
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- Design and synthesis of highly potent and selective human peroxisome proliferator-activated receptor α agonists
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A combination of benzoxazole, phenoxyalkyl side chain, and phenoxybutyric acids was identified as a highly potent and selective human peroxisome proliferator-activated receptor α (PPARα) agonist. The synthesis, structure-activity relationship (SAR) studies, and in vivo activities of the representative compounds are described.
- Yamazaki, Yukiyoshi,Abe, Kazutoyo,Toma, Tsutomu,Nishikawa, Masahiro,Ozawa, Hidefumi,Okuda, Ayumu,Araki, Takaaki,Oda, Soichi,Inoue, Keisuke,Shibuya, Kimiyuki,Staels, Bart,Fruchart, Jean-Charles
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p. 4689 - 4693
(2008/02/11)
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- Phenoxypropanol connected with phenylpiperazine and phenoxyalkylamine terminal in its side chain
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The invention disclosed some 1,4-dihydropiridine derivative chemically have pharmacologically with adrenoceptor blocking and calcium channel blocker is now emerging. The compound of 1,4-dihydropiridine derivative wherein has the formula I, wherein R selected from four group as follow whetherin R present R1 selected from halogen(X), hydrogen(H), saturated C1-C6 alkyl chain, saturated C1-C6 alkyoxyl chain, R2 selected from R3 selected from halogen(X), hydrogen(H), saturated C1-C6 alkyl chain, saturated C1-C6 alkyoxyl chain, and O—(C1-C3)—CF3.
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- 1,3-Dioxolane-based ligands as a novel class of α1-adrenoceptor antagonists
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1,3-Dioxolane-based compounds (2-14) were synthesized, and the pharmacological profiles at α1-adrenoceptor subtypes were assessed by functional experiments in isolated rat vas deferens (α1A), spleen (α1B), and aorta (α1D). Compound 9, with a pA2 of 7.53, 7.36, and 8.65 at α1A, α1B, and α1D, respectively, is the most potent antagonist of the series, while compound 10 with a pA2 of 8.37 at α1D subtype and selectivity ratios of 162 (α1D/α1A) and 324 (α1D/α1B) is the most selective. Binding assays in CHO cell membranes expressing human cloned α1-adrenoceptor subtypes confirm the pharmacological profiles derived from functional experiments, although the selectivity values are somewhat lower. Therefore, it is concluded that 1,3-dioxolane-based ligands are a new class of α1-adrenoceptor antagonists.
- Brasili, Livio,Sorbi, Claudia,Franchini, Silvia,Manicardi, Massimo,Angeli, Piero,Marucci, Gabriella,Leonardi, Amedeo,Poggesi, Elena
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p. 1504 - 1511
(2007/10/03)
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- Reduction of azides to amines or amides with zinc and ammonium chloride as reducing agent
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Alkyl azides and acyl azides were reduced to the corresponding amines and amides with zinc and ammonium chloride as reducing agent under mild conditions in good to excellent yield.
- Lin, Wenqing,Zhang, Xiaomei,He, Ze,Jin, Yi,Gong, Liuzhu,Mi, Aiqiao
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p. 3279 - 3284
(2007/10/03)
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- Indium Mediated Reduction of Nitro and Azide Groups in the Presence of HCl in Aqueous Media
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Indium mediated reduction of azide and nitro groups in the presence of HCl (1.5 equiv based on indium) at room temperature in aqueous THF successfully provided the corresponding amine in high to quantitative yields. Under the some reaction conditions, selective reduction of azide and nitro group in the presence of vinyl group could be accomplished.
- Lee, Jung Gyu,Choi, Kyung Il,Koh, Hun Yeong,Kim, Youseung,Kang, Yonghan,Cho, Yong Seo
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- Relationships between conformational behaviour and binding affinity towards β1 and β2 adrenoceptors of some chiral phenoxypropanolamines with bulky N-substituents
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The optical isomers of a series of phenoxypropanolamine compounds with N-substituents bulkier than isopropyl have been synthesized, and their binding affinity towards β1 and β2-adrenoceptors has been determined. A computational study, including a Molecular Dynamics (MD) simulation and quenching in water and a GRID analysis provided some useful suggestions for possible interpretation patterns for the different affinity exhibited by the compounds studied.
- Villa,Villa,Pallavicini,Romeo,Valoti,Ferri,Iuliano,Brunello
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p. 643 - 658
(2007/10/03)
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- Preparation of phenoxyethanamines
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A process for preparing phenoxyethanamines from phenols and 2-oxazolines in quantitative yields was discovered. Phosphoric acid hydrolyzes the amide intermediate from the phenol/2-oxazoline reaction without cleaving the amide at the ether linkage and without undesired aromatic ring substitution. Thus, yield to the desired phenoxyethanamines is often 98% or better, requiring no subsequent purification. In contrast, sulfuric and hydrochloric acids give these undesired side reactions. Phenoxyethanamines are useful in thermosetting resins, pharmaceuticals and as surfactants.
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- Mechanistic Studies on Dopamine β-Monooxygenase Catalysis: N-Dealkylation and Mechanism-Based Inhibition by Benzylic-Nitrogen-Containing Compounds. Evidence for a Single-Electron-Transfer Mechanism
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Dopamine β-monooxygenase (DBM) readily catalyzes oxidative N-dealkylation of N-phenylethylenediamine (PEDA) and N-methyl-N-phenylethylenediamine (N-MePEDA) with the reaction characteriscics expected for a monooxygenase-catalyzed process.The products of this reaction have been quantitatively identified as aniline (or N-methylaniline for N-MePEDA) and 2-aminoacetaldehyde, the latter compound being successfully trapped by using NaBH4 reduction followed by N-succinimidyl p-nitriphenylacetate (SNPA) derivatization, and identified by HPLC and mass spectroscopy.In contrast, either analogues of PEDA, i.e. phenyl 2-aminoethyl ether (PAEE) and its p-hydroxy derivative (p-OHPAEE), as well as 2-phenoxycycloprpylamine are not substrates but are competitive inhibitors.Furthermore, 2-methyl-2-anilino-1-aminoethane (β-MePEDA) did not exhibit measurable substrate activity with DBM, in contrast to the excellent substrate activity of the sulfur analogue of β-MePEDA, 2-methyl-2-(phenylthio)-1-aminoethane (β-MePAES).DBM is inactivated during the N-dealkylation reaction in a time- and concentration-dependent manner, a phenomenon that has not, to our knowledge, been observed for any other oxygenase-catalyzed N-dealkylation reaction.Both PEDA and N-MePEDA, as well as β-MePEDA, inactivate DBM under turnover conditions.The inactivation exhibited pseudo-first-order saturable kinetics and expected protection by the DBM substrate, tyramine.No reappearance of enzyme activity was observed after extensive dialysis.Radioactive labeling experiments with ring-tritiated PEDA showed incorporation of nondialyzable radioactivity into DBM in the expected amount, consistent with covalent attachment of a reactive species derivd from PEDA to the DBM active site during enzyme inactivation.Although aniline, N-ethylaniline, N-(2-fluoroethyl)aniline, m- and p-anisidine, p-toluidine, and 5-hydroxyindole were found not to exhibit detectable DBM substrate activity, all of these inactivated the enzyme under turnover conditions.The isotope effect on partition ratio measured for dideuteriated PEDA was found to be a reflection of an isotope effect on Vmax and not on kinact.Our results provide a strong support for the conclusion that the initial nitrogen cation radical species is responsible for enzyme inactivation.Results with ring-deuteriated and ring-tritiated PEDA revealed that the amount of radioactivity incorporated into covalently inactivated DBM by ring-tritiated PEDA is in agreement with that expected for covalent attachment of the para carbon to the protein.An 18O labeling study was carried out to test for oxygen rebound into the aminoacetaldehyde product, and results demonstrated that the aldehyde oxygen of enzymatically produced 2-aminoacetaldehyde exchanges very rapidly with solvent water, in agreement with literature reports.On the basis ...
- Wimalasena, Kandatege,May, Sheldon W.
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p. 4036 - 4046
(2007/10/02)
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- METALLIC COPPER CATALYSIS OF N-ARYLATION OF AMINES BY TRIARYLBISMUTH DIACYLATES
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The N-arylation of aliphatic and aromatic amines by triarylbismuth diacylates under neutral conditions is strongly catalysed by copper powder at room temperature.
- Barton, Derek H. R.,Finet, Jean-Pierre,Khamsi, Jamal
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p. 3615 - 3618
(2007/10/02)
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