- Conformationally restricted homotryptamines. Part 6: Indole-5-cycloalkyl methylamines as selective serotonin reuptake inhibitors
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Racemic 5-(trans-2-aminomethylcyclopropyl)indoles, 5-(trans-2- aminomethylcyclopentyl) indoles, and 5-(cis-2-aminomethylcyclopentyl)indoles were synthesized and evaluated as selective serotonin reuptake inhibitors. These analogs followed SAR trends similar to those previously reported for 3-cycloalkyl substituted indoles. The most potent analogs exhibited single digit nanomolar inhibition at the human serotonin transporter but were 10-fold less active than the previously reported compounds.
- Ditta, Jonathan L.,Denhart, Derek J.,Deskus, Jeffrey A.,Epperson, James R.,Meng, Zhaoxing,Gao, Qi,Mattson, Gail K.,Lapaglia, Mellissa A.,Taber, Matthew T.,Molski, Thaddeus F.,Lodge, Nicholas J.,Mattson, Ronald J.,MacOr, John E.
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Read Online
- Discovery of Phytoalexin Camalexin and Its Derivatives as Novel Antiviral and Antiphytopathogenic-Fungus Agents
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In response to the invasion of plant viruses and pathogenic fungi, higher plants produce defensive allelochemicals. Finding candidate varieties of botanical pesticides based on allelochemicals is one of the important ways to create efficient and green pes
- Liao, Ancai,Li, Lin,Wang, Tienan,Lu, Aidang,Wang, Ziwen,Wang, Qingmin
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p. 2554 - 2563
(2022/03/02)
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- 1,2,4-Oxadiazole Topsentin Analogs with Antiproliferative Activity against Pancreatic Cancer Cells, Targeting GSK3β Kinase
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A new series of topsentin analogs, in which the central imidazole ring of the natural lead was replaced by a 1,2,4-oxadiazole moiety, was efficiently synthesized. All derivatives were pre-screened for antiproliferative activity against the National Cancer Institute (NCI-60) cell lines panel. The five most potent compounds were further investigated in various pancreatic ductal adenocarcinoma (PDAC) cell lines, including SUIT-2, Capan-1, and Panc-1 cells, eliciting EC50 values in the micromolar and sub-micromolar range, associated with significant reduction of cell migration. These remarkable results might be explained by the effects of these new topsentin analogues on epithelial-to-mesenchymal transition markers, including SNAIL-1/2 and metalloproteinase-9. Moreover, flow cytometric analysis after Annexin V-FITC and propidium iodide staining demonstrated that these derivatives enhanced apoptosis of PDAC cells. Keeping with these data, the PathScan intracellular signaling and ELISA array revealed cleavage of caspase-3 and PARP and a significant inhibition of GSK3β phosphorylation, suggesting this kinase as a potential downstream target of our novel compounds. This was further supported by a specific assay for the evaluation of GSK3β activity, showing IC50 values for the most active compounds against this enzyme in the micromolar range.
- Carbone, Daniela,Parrino, Barbara,Cascioferro, Stella,Pecoraro, Camilla,Giovannetti, Elisa,Di Sarno, Veronica,Musella, Simona,Auriemma, Giulia,Cirrincione, Girolamo,Diana, Patrizia
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p. 537 - 554
(2020/12/01)
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- Chemoselective Cu-catalyzed synthesis of diverseN-arylindole carboxamides, β-oxo amides andN-arylindole-3-carbonitriles using diaryliodonium salts
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Chemoselective copper-catalyzed synthesis of diverseN-arylindole-3-carboxamides, β-oxo amides andN-arylindole-3-carbonitriles from readily accessible indole-3-carbonitriles, α-cyano ketones and diaryliodonium salts has been developed. DiverseN-arylindole-3-carboxamides and β-oxo amides were successfully achieved in high yields under copper-catalyzed neutral reaction conditions, and the addition of an organic base (DIPEA) resulted in a completely different selectivity pattern to produceN-arylindole-3-carbonitriles. Moreover, the importance of the developed methodology was realized by the synthesis of indoloquinolones andN-((1H-indol-3-yl)methyl)aniline and by a single-step gram-scale synthesis of the naturally occurring cephalandole A analogue.
- Kumar Mehra, Manish,Malik, Monika,Kumar, Bintu,Kumar, Dalip
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supporting information
p. 1109 - 1114
(2021/02/16)
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- Efficient construction of diverse 3-cyanoindoles under novel tandem catalysis
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A novel and rapid construction of 3-cyanoindoles by palladium-catalyzed tandem reactions has been developed. "N-H"free unprotected, N-alkyl and N-aryl 3-cyanoindoles are obtained with good to excellent yields. The usefulness of this synthetic approach is further demonstrated by the successful synthesis of practical compounds such as the therapeutic estrogen receptor ligand A precursor. Mechanism study shows that the tandem catalysis exploits a Suzuki cross-coupling with subsequent base-induced isoxazole fragmentation, followed by the aldimine condensation.
- Wu, Jun,Liu, Jiabin,Zhou, Kerui,He, Zhenni,Wang, Qian,Wu, Fen,Miao, Tingting,Qian, Jinjie,Shi, Qian
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supporting information
p. 12660 - 12663
(2020/11/02)
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- Imidazo[2,1-b] [1,3,4]thiadiazoles with antiproliferative activity against primary and gemcitabine-resistant pancreatic cancer cells
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A new series of eighteen imidazo [2,1-b] [1,3,4]thiadiazole derivatives was efficiently synthesized and screened for antiproliferative activity against the National Cancer Institute (NCI-60) cell lines panel. Two out of eighteen derivatives, compounds 12a and 12h, showed remarkably cytotoxic activity with the half maximal inhibitory concentration values (IC50) ranging from 0.23 to 11.4 μM, and 0.29–12.2 μM, respectively. However, two additional compounds, 12b and 13g, displayed remarkable in vitro antiproliferative activity against pancreatic ductal adenocarcinoma (PDAC) cell lines, including immortalized (SUIT-2, Capan-1, Panc-1), primary (PDAC-3) and gemcitabine-resistant (Panc-1R), eliciting IC50 values ranging from micromolar to sub-micromolar level, associated with significant reduction of cell-migration and spheroid shrinkage. These remarkable results might be explained by modulation of key regulators of epithelial-to-mesenchymal transition (EMT), including E-cadherin and vimentin, and inhibition of metalloproteinase-2/-9. High-throughput arrays revealed a significant inhibition of the phosphorylation of 45 tyrosine kinases substrates, whose visualization on Cytoscape highlighted PTK2/FAK as an important hub. Inhibition of phosphorylation of PTK2/FAK was validated as one of the possible mechanisms of action, using a specific ELISA. In conclusion, novel imidazothiadiazoles show potent antiproliferative activity, mediated by modulation of EMT and PTK2/FAK.
- Cascioferro, Stella,Petri, Giovanna Li,Parrino, Barbara,Carbone, Daniela,Funel, Niccola,Bergonzini, Cecilia,Mantini, Giulia,Dekker, Henk,Geerke, Daan,Peters, Godefridus J.,Cirrincione, Girolamo,Giovannetti, Elisa,Diana, Patrizia
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- Optimization, Structure-Activity Relationship, and Mode of Action of Nortopsentin Analogues Containing Thiazole and Oxazole Moieties
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Plant diseases seriously endanger plant health, and it is very difficult to control them. A series of nortopsentin analogues were designed, synthesized, and evaluated for their antiviral activities and fungicidal activities. Most of these compounds displayed higher antiviral activities than ribavirin. Compounds 1d, 1e, and 12a, with excellent antiviral activities, emerged as novel antiviral lead compounds, among which 1e was selected for further antiviral mechanism research. The mechanism research results indicated that these compounds may play an antiviral role by aggregating viral particles to prevent their movement in plants. Further fungicidal activity tests revealed that nortopsentin analogues displayed broad-spectrum fungicidal activities. Compounds 2p and 2f displayed higher antifungal activities against Alternaria solani than the commercial fungicides carbendazim and chlorothalonil. Current research has laid a foundation for the application of nortopsentin analogues in plant protection.
- Guo, Jincheng,Hao, Yanan,Ji, Xiaofei,Wang, Ziwen,Liu, Yuxiu,Ma, Dejun,Li, Yongqiang,Pang, Huailin,Ni, Jueping,Wang, Qingmin
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p. 10018 - 10031
(2019/10/05)
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- 2,6-Disubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives as potent staphylococcal biofilm inhibitors
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A class of 36 new 2-(6-phenylimidazo[2,-1-b][1,3,4]thiadiazol-2-yl)-1H-indoles was efficiently synthesized and evaluated for their anti-biofilm properties against the Gram-positive bacterial reference strains Staphylococcus aureus ATCC 25923, S. aureus ATCC 6538 and Staphylococcus epidermidis ATCC 12228, and the Gram-negative strains Pseudomonas aeruginosa ATCC 15442 and Escherichia coli ATCC 25922. Many of these new compounds, were able to inhibit biofilm formation of the tested staphylococcal strains showing BIC50 lower than 10 μg/ml. In particular, derivatives 9c and 9h showed remarkable anti-biofilm activity against S. aureus ATCC 25923 with BIC50 values of 0.5 and 0.8 μg/ml, respectively, whereas compound 9aa was the most potent against S. aureus ATCC 6538, with a BIC50 of 0.3 μg/ml. Remarkably, these compounds showed effects in the early stages of the biofilm formation without affecting the mature biofilm of the same strains and the viability of the planktonic form. Their ability in counteracting a virulence factor (biofilm formation) without interfering with the bacterial growth in the free life form make them novel valuable anti-virulence agents.
- Cascioferro, Stella,Parrino, Barbara,Petri, Giovanna Li,Cusimano, Maria Grazia,Schillaci, Domenico,Di Sarno, Veronica,Musella, Simona,Giovannetti, Elisa,Cirrincione, Girolamo,Diana, Patrizia
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p. 200 - 210
(2019/02/19)
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- New thiazole nortopsentin analogues inhibit bacterial biofilm formation
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New thiazole nortopsentin analogues were conveniently synthesized and evaluated for their activity as inhibitors of biofilm formation of relevant Gram-positive and Gram-negative pathogens. All compounds were able to interfere with the first step of biofilm formation in a dose-dependent manner, showing a selectivity against the staphylococcal strains. The most active derivatives elicited IC50 values against Staphylococcus aureus ATCC 25923, ranging from 0.40–2.03 μM. The new compounds showed a typical anti-virulence profile, being able to inhibit the biofilm formation without affecting the microbial growth in the planktonic form.
- Carbone, Anna,Parrino, Barbara,Cusimano, Maria Grazia,Spanò, Virginia,Montalbano, Alessandra,Barraja, Paola,Schillaci, Domenico,Cirrincione, Girolamo,Diana, Patrizia,Cascioferro, Stella
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- Stable and reusable nanoscale Fe2O3-catalyzed aerobic oxidation process for the selective synthesis of nitriles and primary amides
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The sustainable introduction of nitrogen moieties in the form of nitrile or amide groups in functionalized molecules is of fundamental interest because nitrogen-containing motifs are found in a large number of life science molecules, natural products and materials. Hence, the synthesis and functionalization of nitriles and amides from easily available starting materials using cost-effective catalysts and green reagents is highly desired. In this regard, herein we report the nanoscale iron oxide-catalyzed environmentally benign synthesis of nitriles and primary amides from aldehydes and aqueous ammonia in the presence of 1 bar O2 or air. Under mild reaction conditions, this iron-catalyzed aerobic oxidation process proceeds to synthesise functionalized and structurally diverse aromatic, aliphatic and heterocyclic nitriles. Additionally, applying this iron-based protocol, primary amides have also been prepared in a water medium.
- Murugesan, Kathiravan,Senthamarai, Thirusangumurugan,Sohail, Manzar,Sharif, Muhammad,Kalevaru, Narayana V.,Jagadeesh, Rajenahally V.
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supporting information
p. 266 - 273
(2018/01/12)
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- Aromatic heterocyclic compound and a method of producing aminonitrile
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PROBLEM TO BE SOLVED: To provide a novel method of turning an aromatic heterocyclic compound into nitrile, by which a raw material having high toxicity is not needed, the amount of a byproduct can be reduced and structural restriction of a usage raw material is reduced.SOLUTION: In the method of turning the aromatic heterocyclic compound into the nitrile, a nitrogen-containing aromatic heterocyclic compound represented by general formula (1), a silicon compound represented by general formula (2) and a nitromethane are reacted in the presence of one or more zinc catalysts selected from the group consisting of zinc sulfonate, zinc sulfonamide and a zinc halide to obtain the nitrile compound of the aromatic heterocyclic compound represented by general formula (3).
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Paragraph 0077; 0078
(2017/06/02)
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- Zinc-catalyzed direct cyanation of indoles and pyrroles: Nitromethane as a source of a cyano group
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With nitromethane and diphenylsilane (Ph2SiH2), zinc triflate behaves as a Lewis acid catalyst for the cyanation of nitrogen-containing heteroarenes such as indoles and pyrroles. This is the first realization of the Lewis acid-catalyzed direct cyanation of a C(aryl)-H bond with no CN group-containing cyanating agent.
- Nagase, Yuta,Sugiyama, Tetsuya,Nomiyama, Shota,Yonekura, Kyohei,Tsuchimoto, Teruhisa
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supporting information
p. 347 - 352
(2014/05/20)
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- Copper-mediated C3-cyanation of indoles by the combination of amine and ammonium
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A copper-promoted C3-cyanation of both the free N-H and N-protected indoles by N,N,N′,N′-tetramethyl-ethane-1,2-diamine (TMEDA) and ammonium is achieved. The iminium ion acts as the intermediate in this transformation, which is sequentially electrophilically attacked by indole and H2O followed by hydrolyzation to form the aldehyde. Then the reaction between the aldehyde and ammonium afforded nitriles. The reaction employs O2 as a clean oxidant with good efficiency and functional group tolerance. Thus, it represents a facile and safe procedure leading to 3-cyano indoles. The Royal Society of Chemistry 2014.
- Liu, Bin,Wang, Jiehui,Zhang, Bo,Sun, Yang,Wang, Lei,Chen, Jianbin,Cheng, Jiang
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supporting information
p. 2315 - 2317
(2014/03/21)
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- Indole cyanation via CH bond activation under catalysis of Ru(III)-exchanged NaY zeolite (RuY) as a recyclable catalyst
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Selective 3-cyanation of indoles was achieved under heterogeneous catalysis of Ru(III)-exchanged NaY zeolite (RuY) as a recyclable catalyst, in combination with K4[Fe(CN)6] as a nontoxic, slow cyanide releasing agent. Under the aforementioned conditions, good yields of the desired products were obtained.
- Khorshidi, Alireza
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experimental part
p. 903 - 906
(2012/08/28)
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- Synthesis and in-vitro anticancer activity of 3,5-bis(indolyl)-1,2,4- thiadiazoles
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A series of 3,5-bis(indolyl)-1,2,4-thiadiazoles were synthesized and evaluated for their cytotoxicity against selected human cancer cell lines. The reaction of indole-3-thiocarboxamide 3 with iodobenzene diacetate underwent oxidative dimerization to give 3,5-bis(indolyl)-1,2,4-thiadiazoles 4a-n. Among the synthesized bis(indoly)-1,2,4-thiadiazoles, the compound 4h with 4-chlorobenzyl and methoxy substituents showed the most potent activity.
- Kumar, Dalip,Kumar, N. Maruthi,Chang, Kuei-Hua,Gupta, Ritika,Shah, Kavita
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scheme or table
p. 5897 - 5900
(2011/10/18)
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- Pd(OAc)2-catalyzed C-H activation of indoles: a facile synthesis of 3-cyanoindoles
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Indoles undergo smooth cyanation with CuCN in the presence of 20 mol % Pd(OAc)2 and 40 mol % CuBr2 in DMF to produce a wide range of the corresponding 3-cyanoindoles in good yields with high regioselectivity.
- Subba Reddy,Begum, Zubeda,Jayasudhan Reddy,Yadav
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experimental part
p. 3334 - 3336
(2010/07/06)
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- 3-Amino-1-arylpropyl indoles and aza-substituted indoles and uses thereof
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The present invention provides compounds of the formula: or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein p, Ar, R1, R2, R3, Ra, Rb, Rc, Rd and Re are defined herein. Also provided are pharmaceutical compositions, methods of using, and methods of preparing the compounds.
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Page/Page column 70
(2008/06/13)
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- Calcitonin gene related peptide receptor antagonists
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The present invention relates to compounds of Formula (I) as antagonists of calcitonin gene-related peptide receptors (“CGRP-receptor”), pharmaceutical compositions comprising them, methods for identifying them, methods of treatment using them and their use in therapy for treatment of neurogenic vasodilation, neurogenic inflammation, migraine and other headaches, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), and other conditions the treatment of which can be effected by the antagonism of CGRP-receptors.
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- SUBSTITUTED (AMINOIMINOMETHYL OR AMINOMETHYL) BENZOHETEROARYL COMPOUNDS
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This invention is directed to an (aminoiminomethyl or aminomethyl) benzoheteroaryl compound of formula I which is useful for inhibiting the activity of Factor Xa by combining said compound with a composition containing Factor Xa. The present invention is also directed to compositions containing compounds of the formula I, methods for their preparation, their use, such as in inhibiting the formation of thrombin or for treating a patient suffering from, or subject to, a disease state associated with a physiologically detrimental excess amount of thrombin.
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- A concise synthesis of topsentin A and nortopsentins B and D.
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[reaction: see text] A concise synthesis of topsentin A (R(1) = R(2) = H) and nortopsentins B (R(1) = Br, R(2) = H) and D (R(1) = R(2) = H) is described from oxotryptamine 5 via reduction of acyl cyanide 4. Regiospecific bromination of 3-cyanoindole afforded 6-bromo-3-cyanoindole (10) as the major product.
- Miyake,Yakushijin,Horne
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p. 2121 - 2123
(2007/10/03)
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- Syntheses and cytotoxicity evaluation of bis(indolyl)thiazole, bis(indolyl)pyrazinone and bis(indolyl)pyrazine: Analogues of cytotoxic marine bis(indole) alkaloid
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2,4-Bis(3'-indolyl)thiazoles, 3,5-bis(3'-indolyl)-2(1H)pyrazinone and 3,6-bis(3'-indolyl)pyrazine were synthesized and evaluated for cytotoxic activity against diverse human cancer cell lines by the National Cancer Institute. These compounds demonstrated significant inhibitory effects in the growth of a range of cancer cell lines. 2,4-Bis(3'-indolyl)thiazole displayed selective cytotoxicity against certain leukemia cell lines with GI50 values in the low micromolar range while the substituted derivatives showed a broad spectrum of cytotoxic activity. 3,5-Bis(3'-indolyl)-2(1H)pyrazinone and 3,6- bis[3'-(N-methyl-indolyl)]pyrazine possessed strong inhibitory activity against a wide range of human tumor cell lines. The mechanism of action remained unknown. The results suggested that 2,4-bis(3'-indolyl)thiazoles, 3,5-bis(3'-indolyl)-2(1H)pyrazinone and 3,6-bis[3'-(N-methyl-indolyl)] pyrazine offer potential as lead compounds for the discovery of anticancer agents. (C) 2000 Elsevier Science Ltd.
- Jiang, Biao,Gu, Xiao-Hui
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p. 363 - 371
(2007/10/03)
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