- Design, synthesis, anticancer activity, and solid lipid nanoparticle formulation of indole-and benzimidazole-based compounds as pro-apoptotic agents targeting bcl-2 protein
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Cancer is a multifactorial disease necessitating identification of novel targets for its treat-ment. Inhibition of Bcl-2 for triggered pro-apoptotic signaling is considered a promising strategy for cancer treatment. Within the current work, we aimed to design and synthesize a new series of benzimidazole-and indole-based derivatives as inhibitors of Bcl-2 protein. The market pan-Bcl-2 inhibitor, obatoclax, was the lead framework compound for adopted structural modifications. The obatoclax’s pyrrolylmethine linker was replaced with straight alkylamine or carboxyhydrazine methylene linkers providing the new compounds. This strategy permitted improved structural flexibility of synthesized compounds adopting favored maneuvers for better fitting at the Bcl-2 major hydrophobic pocket. Anti-cancer activity of the synthesized compounds was further investigated through MTT-cytotoxic assay, cell cycle analysis, RT-PCR, ELISA and DNA fragmentation. Cytotoxic results showed compounds 8a, 8b and 8c with promising cytotoxicity against MDA-MB-231/breast cancer cells (IC50 = 12.69 ± 0.84 to 12.83 ± 3.50 μM), while 8a and 8c depicted noticeable activities against A549/lung adenocarcinoma cells (IC50 = 23.05 ± 1.45 and 11.63 ± 2.57 μM, respectively). The signaling Bcl-2 inhibition pathway was confirmed by molecular docking where significant docking energies and interactions with key Bcl-2 pocket residues were depicted. Moreover, the top active compound, 8b, showed significant upregulated expression levels of pro-apoptotic/anti-apoptotic of genes; Bax, Bcl-2, caspase-3,-8, and-9 through RT-PCR assay. Improving the compound’s pharmaceutical profile was undertaken by introducing 8b within drug-solid/lipid nanoparticle formulation prepared by hot melting homogenization technique and evaluated for encapsulation efficiency, particle size, and zeta potential. Significant improvement was seen at the compound’s cytotoxic activity. In conclusion, 8b is introduced as a promising anti-cancer lead candidate that worth future fine-tuned lead optimization and development studies while exploring its potentiality through in-vivo preclinical investigation.
- Nagy, Manar I.,Darwish, Khaled M.,Kishk, Safaa M.,Tantawy, Mohamed A.,Nasr, Ali M.,Qushawy, Mona,Swidan, Shady A.,Mostafa, Samia M.,Salama, Ismail
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- Design, synthesis, and antimicrobial activity of certain new indole-1,2,4 triazole conjugates
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The increasing prevalence of microbial infections and the emergence of resistance to the currently available antimicrobial drugs urged the development of potent new chemical entities with eminent pharmacokinetic and/or pharmacodynamic profiles. Thus, a series of new indole-triazole conjugates 6a-u was designed and synthesized to be assessed as new antimicrobial candidates using the diameter of the inhibition zone and minimum inhibitory concentration assays against certain microbial strains. Their in vitro antibacterial evaluation revealed good to moderate activity against most of the tested Gram-negative strains with diameter of the inhibition zone (DIZ) values in the range of 11–15 mm and minimum inhibition concentration (MIC) values around 250 μg/mL. Meanwhile, their in vitro antifungal evaluation demonstrated a potent activity against Candida tropicalis with MIC value as low as 2 μg/mL for most of the tested compounds. Moreover, compound 6f is the most potent congener with an MIC value of 2 μg/mL against Candida albicans.
- Al-Mutairi, Maha S.,Al-Wabli, Reem I.,Alsulami, Mona A.,Attia, Mohamed I.,Bukhari, Sarah I.,Moubayed, Nadine M. S.
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- 4-Alkyl-1,2,4-triazole-3-thione analogues as metallo-β-lactamase inhibitors
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In Gram-negative bacteria, the major mechanism of resistance to β-lactam antibiotics is the production of one or several β-lactamases (BLs), including the highly worrying carbapenemases. Whereas inhibitors of these enzymes were recently marketed, they only target serine-carbapenemases (e.g. KPC-type), and no clinically useful inhibitor is available yet to neutralize the class of metallo-β-lactamases (MBLs). We are developing compounds based on the 1,2,4-triazole-3-thione scaffold, which binds to the di-zinc catalytic site of MBLs in an original fashion, and we previously reported its promising potential to yield broad-spectrum inhibitors. However, up to now only moderate antibiotic potentiation could be observed in microbiological assays and further exploration was needed to improve outer membrane penetration. Here, we synthesized and characterized a series of compounds possessing a diversely functionalized alkyl chain at the 4-position of the heterocycle. We found that the presence of a carboxylic group at the extremity of an alkyl chain yielded potent inhibitors of VIM-type enzymes with Ki values in the μM to sub-μM range, and that this alkyl chain had to be longer or equal to a propyl chain. This result confirmed the importance of a carboxylic function on the 4-substituent of 1,2,4-triazole-3-thione heterocycle. As observed in previous series, active compounds also preferentially contained phenyl, 2-hydroxy-5-methoxyphenyl, naphth-2-yl or m-biphenyl at position 5. However, none efficiently inhibited NDM-1 or IMP-1. Microbiological study on VIM-2-producing E. coli strains and on VIM-1/VIM-4-producing multidrug-resistant K. pneumoniae clinical isolates gave promising results, suggesting that the 1,2,4-triazole-3-thione scaffold worth continuing exploration to further improve penetration. Finally, docking experiments were performed to study the binding mode of alkanoic analogues in the active site of VIM-2.
- Gavara, Laurent,Legru, Alice,Verdirosa, Federica,Sevaille, Laurent,Nauton, Lionel,Corsica, Giuseppina,Mercuri, Paola Sandra,Sannio, Filomena,Feller, Georges,Coulon, Rémi,De Luca, Filomena,Cerboni, Giulia,Tanfoni, Silvia,Chelini, Giulia,Galleni, Moreno,Docquier, Jean-Denis,Hernandez, Jean-Fran?ois
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supporting information
(2021/06/15)
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- Synthesis of Indoles by Reductive Cyclization of Nitro Compounds Using Formate Esters as CO Surrogates
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Alkyl and aryl formate esters were evaluated as CO sources in the Pd- and Pd/Ru-catalyzed reductive cyclization of 2-nitrostyrenes to give indoles. Whereas the use of alkyl formates requires the presence of a ruthenium catalyst such as Ru3(CO)12, the reaction with phenyl formate can be performed by using a Pd/phenanthroline complex alone. Phenyl formate was found to be the most effective CO source and the desired products were obtained in excellent yields, often higher than those previously reported using pressurized CO. The reaction tolerates many functional groups, including sensitive ones like a free aldehydic group or a pendant pyrrole. Detailed experiments and kinetic studies allow to conclude that the activation of phenyl formate is base-catalyzed and that the metal doesn't play a role in the decarbonylation step. The reactions can be performed in a single thick-walled glass tube with as little as 0.2 mol-% palladium catalyst and even on a 2 g scale. The same protocol can be extended to other nitro compounds, affording different heterocycles.
- Ahmed Fouad, Manar,Ferretti, Francesco,Formenti, Dario,Milani, Fabio,Ragaini, Fabio
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p. 4876 - 4894
(2021/09/20)
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- Design, Synthesis and Characterization of Novel Isoxazole Tagged Indole Hybrid Compounds
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Sixteen new isoxazole tagged indole compounds have been synthesized via copper (I) catalyzed click chemistry of the aryl hydroxamoyl chloride and an indole containing alkyne moiety. The chemical structure of the synthesized compounds has been established using various physicochemical techniques. X-ray single crystal analysis of Ethyl 1-((3-phenylisoxazol-5-yl) methyl)-1H-indole-2-carboxylate (8a) has been analyzed. All compounds were tested for their antibacterial and anticancer activities. The activities for the new compounds were weak against both bacterial strains and the cancer cell lines.
- Al-Qawasmeh, Raed A.,Al-Nazer, Louy A.,Dawlat-Kari, Sarah A.,Abu-Qatouseh, Luay,Sabri, Salim S.,Aldamen, Murad A.,Sinnokrot, Mutasem
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p. 138 - 148
(2020/04/15)
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- Scaffold Hopping of Natural Product Evodiamine: Discovery of a Novel Antitumor Scaffold with Excellent Potency against Colon Cancer
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Inspired by the natural product evodiamine, a novel antitumor indolopyrazinoquinazolinone scaffold was designed by scaffold hopping. Structure-activity relationship studies led to the discovery of compound 15j, which shows low nanomolar inhibitory activity against the HCT116 cell line. Further antitumor mechanism studies indicated that compound 15j acted by the dual inhibition of topoisomerase 1 and tubulin and induced apoptosis with G2 cell-cycle arrest. The quaternary ammonium salt of compound 15j (compound 15js) exhibited excellent in vivo antitumor activity (TGI = 66.6%) in the HCT116 xenograft model with low toxicity. Indolopyrazinoquinazolinone derivatives represent promising multitargeting antitumor leads for the development of novel antitumor agents.
- Wang, Lei,Fang, Kun,Cheng, Junfei,Li, Yu,Huang, Yahui,Chen, Shuqiang,Dong, Guoqiang,Wu, Shanchao,Sheng, Chunquan
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p. 696 - 713
(2020/02/04)
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- Synthesis, biological evaluation and in silico studies of certain oxindole–indole conjugates as anticancer CDK inhibitors
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On account of their overexpression in a wide range of human malignancies, cyclin-dependent kinases (CDKs) are among the most validated cancer targets, and their inhibition has been featured as a valuable strategy for anticancer drug discovery. In this study, a hybrid pharmacophore approach was adopted to develop two series of oxindole–indole conjugates (6a–i and 9a–f) and carbocycle–indole conjugates (11a,b) as efficient antitumor agents with potential inhibitory action toward CDK4. All oxindole–indole conjugates, except 6i, 9b, and 9c efficiently affected the growth of the human breast cancer MCF-7 (IC50: 0.39 ± 0.05–21.40 ± 1.58 μM) and/or MDA-MB-231 (IC50: 1.03 ± 0.04–22.54 ± 1.67 μM) cell lines, whereas bioisosteric replacement of the oxindole nucleus with indane or tetralin rings (compounds 11a,b) diminished the anti-proliferative activity. In addition, hybrids 6e and 6f displayed effective cell cycle disturbance and proapoptotic capabilities in MCF-7 cells. Furthermore, the efficient anti-proliferative agents towards MCF-7 and/or MDA-MB-231 cell lines (6a–h, 9a, and 9e) were investigated for their potential inhibitory action toward CDK4. Hybrids 6a and 6e displayed good CDK4 inhibitory activity with IC50s equal 1.82 and 1.26 μM, respectively. The molecular docking study revealed that oxindole moiety is implicated in two H-bonding interactions via both (NH) and (C=O) groups with the key amino acids Glu94 and Val96, respectively, whereas the indole framework is stably accommodated in a hydrophobic sub-pocket establishing hydrophobic interactions with the amino acid residues of Ile12, Val20, and Gln98 lining this sub-pocket. Collectively, these results highlighted hybrids 6a and 6e as good leads for further optimization as promising antitumor drugs toward breast malignancy and CDK inhibitors.
- Abdel-Aziz, Hatem A.,Al-Ansary, Ghada H.,Al-Warhi, Tarfah,Aljaeed, Nada,Ayyad, Rezk R.,El Kerdawy, Ahmed M.,Eldehna, Wagdy M.,Ismael, Omnia E.
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- 4-Amino-1,2,4-triazole-3-thione-derived Schiff bases as metallo-β-lactamase inhibitors
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Resistance to β-lactam antibiotics in Gram-negatives producing metallo-β-lactamases (MBLs) represents a major medical threat and there is an extremely urgent need to develop clinically useful inhibitors. We previously reported the original binding mode of 5-substituted-4-amino/H-1,2,4-triazole-3-thione compounds in the catalytic site of an MBL. Moreover, we showed that, although moderately potent, they represented a promising basis for the development of broad-spectrum MBL inhibitors. Here, we synthesized and characterized a large number of 4-amino-1,2,4-triazole-3-thione-derived Schiff bases. Compared to the previous series, the presence of an aryl moiety at position 4 afforded an average 10-fold increase in potency. Among 90 synthetic compounds, more than half inhibited at least one of the six tested MBLs (L1, VIM-4, VIM-2, NDM-1, IMP-1, CphA) with Ki values in the μM to sub-μM range. Several were broad-spectrum inhibitors, also inhibiting the most clinically relevant VIM-2 and NDM-1. Active compounds generally contained halogenated, bicyclic aryl or phenolic moieties at position 5, and one substituent among o-benzoic, 2,4-dihydroxyphenyl, p-benzyloxyphenyl or 3-(m-benzoyl)-phenyl at position 4. The crystallographic structure of VIM-2 in complex with an inhibitor showed the expected binding between the triazole-thione moiety and the dinuclear centre and also revealed a network of interactions involving Phe61, Tyr67, Trp87 and the conserved Asn233. Microbiological analysis suggested that the potentiation activity of the compounds was limited by poor outer membrane penetration or efflux. This was supported by the ability of one compound to restore the susceptibility of an NDM-1-producing E. coli clinical strain toward several β-lactams in the presence only of a sub-inhibitory concentration of colistin, a permeabilizing agent. Finally, some compounds were tested against the structurally similar di-zinc human glyoxalase II and found weaker inhibitors of the latter enzyme, thus showing a promising selectivity towards MBLs.
- Baud, Damien,Bebrone, Carine,Becker, Katja,Benvenuti, Manuela,Cerboni, Giulia,Chelini, Giulia,Cutolo, Giuliano,De Luca, Filomena,Docquier, Jean-Denis,Feller, Georges,Fischer, Marina,Galleni, Moreno,Gavara, Laurent,Gresh, Nohad,Kwapien, Karolina,Legru, Alice,Mangani, Stefano,Mercuri, Paola,Pozzi, Cecilia,Sannio, Filomena,Sevaille, Laurent,Tanfoni, Silvia,Verdirosa, Federica,Berthomieu, Dorothée,Bestgen, Beno?t,Frère, Jean-Marie,Hernandez, Jean-Fran?ois
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supporting information
(2020/09/16)
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- A NaH-promoted N-detosylation reaction of diverse p-toluenesulfonamides
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A NaH-mediated detosylation reaction of various Ts-protected indoles, azaheterocycles, anilines and dibenzylamine was reported. The method features cheap reagent, convenient operations, mild reaction conditions and broad substrate scope. Moreover, this study revealed that the loading of NaH in tosylation reactions of nitrogen-containing compounds with NaH as a base in DMA or DMF should be controlled due to the possibility of adverse detosylation.
- Sun, Wanwan,Chen, Xiaobei,Hu, Ying,Geng, Huihui,Jiang, Yuanrui,Zhou, Yuxin,Zhu, Wenjing,Hu, Min,Hu, Haohua,Wang, Xingyi,Wang, Xinli,Zhang, Shilei,Hu, Yanwei
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supporting information
(2020/10/05)
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- Reusable, homogeneous water soluble photoredox catalyzed oxidative dehydrogenation of N-heterocycles in a biphasic system: Application to the synthesis of biologically active natural products
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Herein, a simple and efficient method for the oxidative dehydrogenation (ODH) of tetrahydro-β-carbolines, indolines and tetrahydro-(iso)quinolines is described using a reusable, homogeneous cobalt-phthalocyanine photoredox catalyst in a biphasic medium. A biphasic system offers an advantage of easy separation of the product and an efficient reusability of the homogeneous photoredox catalyst. Also, the current system significantly helps to overcome the solubility issue of the substrate and catalyst at room temperature. Its potential applications to organic transformations are demonstrated by the synthesis of various biologically active N-heterocycles such as indoles, (iso)quinolines and β-carbolines and natural products such as eudistomin U, norharmane, and harmane and precursors to perlolyrine and flazin. Without isolation and purification, the catalyst solution can be reused up to 5 times with almost comparable reactivity. Furthermore, the efficiency of the reaction was demonstrated on a gram scale. To the best of our knowledge, this is the first report on ODH reactions using a non noble, reusable and homogeneous cobalt photoredox catalyst under environmentally friendly conditions.
- Abinaya, R.,Baskar, B.,Mariappan, M.,Prasanth, Arun,Sridhar, R.,Srinath, S.
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p. 2575 - 2587
(2020/05/13)
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- Indole derivatives as multifunctional drugs: Synthesis and evaluation of antioxidant, photoprotective and antiproliferative activity of indole hydrazones
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Two series of indole derivatives 4–17, 20–22 were easily prepared and assayed for their radical-scavenging ability. Arylidene-1H-indole-2-carbohydrazones showed different extent antioxidant activity in DPPH, FRAP and ORAC assays. Good antioxidant activity is related to the number and position of hydroxyl groups on the arylidene moiety as well as to the presence of methoxy or 4-(diethylamino) group. On the contrary low antioxidant activity is showed by the isomeric 1H-indol-2-yl(methylene)-benzohydrazides. Furthermore, hydrazones 4–17 showed photoprotective capacities with satisfactory in vitro SPF as compared to the commercial PBSA sunscreen filter. The indole 16 and 17, showing the best antioxidant and photoprotective profile, were included in different formulation and their topical release was evaluated. Varying the formulation composition, it was possible to optimize skin adsorption and solubility of the active indole in the formulation. The antiproliferative effect of the hydrazones 4–17 was tested on human erythroleukemia K562 and melanoma Colo-38 cells. Hydrazones 11, 16 and 17 showed growth inhibition at sub micromolar concentrations on both cell lines. These results indicate indole hydrazones as potential multifunctional molecules especially in the treatment of neoplastic diseases being the good antioxidant properties of 16 and 17 correlated to their high antiproliferative activity.
- Demurtas, Monica,Baldisserotto, Anna,Lampronti, Ilaria,Moi, Davide,Balboni, Gianfranco,Pacifico, Salvatore,Vertuani, Silvia,Manfredini, Stefano,Onnis, Valentina
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p. 568 - 576
(2019/03/02)
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- Divergent synthesis of indole-2-carboxylic acid derivatives via ligand-free copper-catalyzed ullmann coupling reaction
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— This article describes a ligand-free copper-catalyzed Ullmami coupling reaction for the preparation of divergent indole-2-carboxylic acid derivatives including esters, amides and anhydrides. Various compounds 3, which could be synthesized from aldehydes conveniently, were used as substrate to provide the corresponding indole-2-carboxylic acid derivatives in moderate to good vields.
- Zhou, Jiadi,Chen, Yongjian,Huang, Junsong,Li, Jianjun
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p. 904 - 915
(2019/08/21)
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- RhCl3·3H2O-Catalyzed Regioselective C(sp2)-H Alkoxycarbonylation: Efficient Synthesis of Indole- and Pyrrole-2-carboxylic Acid Esters
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The C2-selective C-H alkoxycarbonylation of indoles with alcohols and CO catalyzed by RhCl3·3H2O is disclosed that offers convenient access to diverse indole-2-carboxylic esters. The rhodium-based catalysts outperformed all other precious-metal catalysts investigated. In addition, this protocal was found applicable to the synthesis of pyrrole-2-carboxylic esters, and allowed the C-H alkoxycarbonylation in an intramolecular fashion. Preliminary mechanistic studies indicate that C-H cleavage is not likely involved in the rate-determining step, and a five-membered rhodacycle might be an intermediate involved in the reaction.
- Zhao, Kang,Du, Rongrong,Wang, Bingyang,Liu, Jianhua,Xia, Chungu,Yang, Lei
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p. 5545 - 5551
(2019/06/18)
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- A highly selective ratiometric fluorescent probe for H2S based on new heterocyclic ring formation and detection in live cells
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A 3-indolylacrylate derivative, 3-IA, prepared by connecting an ethyl acrylate in 3-position of indole has been synthesised and characterised. Ethyl acrylate moiety acts as the Michael acceptor towards H2S, and the resultant addition product then participates in intramolecular cyclisation with the ester group at 2-position to form another new heterocyclic ring. Blue fluorescence of 3-IA turned into green in presence of H2S, leading to ratiometric behaviour of the fluorescent sensor with large stokes shift of 55 nm. Probe 3-IA has excellent selectivity towards H2S over other biothiols and other competing anions. Density function theory/time-dependent density function theory calculations were carried out to validate the reaction mechanism and the electronic properties of 3-IA. Importantly, the ratiometric probe 3-IA shows great promise in H2S detection by simple visual fluorescent inspection in filter paper-based protocol. The probe shows its excellent ability to detect H2S in different natural water samples. Furthermore, we have employed our probe to detect H2S for ratiometric imaging in live Vero cell.
- Samanta, Sandip Kumar,Ali, Syed Samim,Gangopadhyay, Ankita,Maiti, Kalipada,Pramanik, Ajoy Kumar,Guria, Uday Narayan,Ghosh, Aritri,Datta, Pallab,Mahapatra, Ajit Kumar
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p. 349 - 360
(2019/03/26)
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- Synthesis method for preparing 2-substituted indole derivative
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The invention relates to a synthesis method for preparing a 2-substituted indole derivative. The method includes the following steps: mixing aromatic amine compounds (I), ketone compounds (II) and a drying agent in an organic solvent; adding a palladium catalyst; and reacting in an aerobic weak acid environment to prepare the indole compounds (III). (I), (II) and (III) are as shown in the specification, wherein R1 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted phenyl, pyridyl and heterocyclic aryl; (I) can be pyridylamine, pyrimidylamine, pyridazinam or pyrazinamide which may further be substituted or unsubstituted; and the substituents are selected fromone or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, amino; and R2 is selected from C1-C6 alkyl, formate groups or C1-C6 alkylamide groups.
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Paragraph 0063-0066
(2019/05/28)
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- Efficient acceptorless photo-dehydrogenation of alcohols and: N -heterocycles with binuclear platinum(ii) diphosphite complexes
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Although photoredox catalysis employing Ru(ii) and Ir(iii) complexes as photocatalysts has emerged as a versatile tool for oxidative C-H functionalization under mild conditions, the need for additional reagents acting as electron donor/scavenger for completing the catalytic cycle undermines the practicability of this approach. Herein we demonstrate that photo-induced oxidative C-H functionalization can be catalysed with high product yields under oxygen-free and acceptorless conditions via inner-sphere atom abstraction by binuclear platinum(ii) diphosphite complexes. Both alcohols (51 examples), particularly the aliphatic ones, and saturated N-heterocycles (24 examples) can be efficiently dehydrogenated under light irradiation at room temperature. Regeneration of the photocatalyst by means of reductive elimination of dihydrogen from the in situ formed platinum(iii)-hydride species represents an alternative paradigm to the current approach in photoredox catalysis.
- Zhong, Jian-Ji,To, Wai-Pong,Liu, Yungen,Lu, Wei,Che, Chi-Ming
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p. 4883 - 4889
(2019/05/16)
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- A Reusable Cobalt Catalyst for Reversible Acceptorless Dehydrogenation and Hydrogenation of N-Heterocycles
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The development of robust catalytic systems based on base-metals for reversible acceptorless dehydrogenation (ADH) and hydrogenation of feedstock chemicals is very important in the context of ‘hydrogen storage’. Herein, we report a highly efficient reusable cobalt-based heterogeneous catalyst for reversible dehydrogenation and hydrogenation of N-heterocycles. Both the ADH and the hydrogenation processes operate under mild, benign conditions.
- Jaiswal, Garima,Subaramanian, Murugan,Sahoo, Manoj K.,Balaraman, Ekambaram
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p. 2449 - 2457
(2019/05/10)
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- Room temperature catalytic dehydrogenation of cyclic amines with the liberation of H2 using water as a solvent
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Catalytic dehydrogenation of cyclic amines, in particular partially saturated N-heterocycles to N-heterocyclic arenes, with the removal of molecular hydrogen as the sole byproduct in water is reported. This dehydrogenation reaction proceeds smoothly under very mild and benign conditions and operates at room temperature. This distinctive reactivity has been achieved under dual catalytic conditions by merging the visible-light active [Ru(bpy)3]2+ as the photoredox catalyst and a newly synthesized cobalt complex as the proton-reduction catalyst. A detailed mechanistic study (control experiments, electrochemical studies, UV-visible experiments) is presented for the present dual catalysis.
- Sahoo, Manoj K.,Balaraman, Ekambaram
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supporting information
p. 2119 - 2128
(2019/04/26)
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- A Bu4N[Fe(CO)3(NO)]-Catalyzed Hemetsberger–Knittel Indole Synthesis
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The nucleophilic Fe complex Bu4N[Fe(CO)3(NO)] (TBA[Fe]) catalyzes the direct intramolecular amination of aryl vinyl azides to give the corresponding indole derivatives in good to excellent yields.
- Baykal, Aslihan,Plietker, Bernd
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supporting information
(2020/02/20)
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- Rational modifications on a benzylidene-acrylohydrazide antiviral scaffold, synthesis and evaluation of bioactivity against Chikungunya virus
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Chikungunya virus is a re-emerging arbovirus transmitted to humans by Aedes mosquitoes, responsible for an acute febrile illness associated with painful and debilitating arthralgia, which can persist for several months or become chronic. Over the past few years, infection with this virus has spread worldwide with a previously unknown virulence. No specific antiviral treatments nor vaccines are currently available against this important pathogen. Starting from the structure of a class of selective anti-CHIKV agents previously identified in our research group, different modifications to this scaffold were rationally designed, and 69 novel small-molecule derivatives were synthesised and evaluated for their inhibition of Chikungunya virus replication in Vero cells. Further structure-activity relationships associated with this class of antiviral agents were elucidated for the original scaffolds, and novel antiviral compounds with EC50 values in the low micromolar range were identified. This work provides the foundation for further investigation of these new structures as antivirals against Chikungunya virus.
- Giancotti, Gilda,Cancellieri, Michela,Balboni, Andrea,Giustiniano, Mariateresa,Novellino, Ettore,Delang, Leen,Neyts, Johan,Leyssen, Pieter,Brancale, Andrea,Bassetto, Marcella
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supporting information
p. 56 - 68
(2018/03/06)
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- Temperature-modulated diastereoselective transformations of 2-vinylindoles to tetrahydrocarbazoles and tetrahydrocycloheptadiindoles
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Direct and expedient access to densely substituted tetrahydrocarbazoles and tetrahydrocycloheptadiindoles bearing multiple contiguous stereocentres has been achieved via a two-fold divergent diastereoselective (dr up to >99:1) transformation of 2-vinylindoles. The high-yielding conversions (yield up to 87%) that are amenable for a wide range of substituted 2-vinylindoles proceed through Lewis acid-catalyzed [4 + 2] and [4 + 3] cyclization-aromatization cascade reactions, respectively, involving a heretofore-unprecedented reversal of the polarity (umpolung) of 2-vinylindoles. The two synthetic routes are effortlessly transposable into each other by merely modulating the temperature to furnish the corresponding products in a selective and exclusive fashion. In addition, another novel synthetic route to tetrahydroindolocarbazoles has been developed that advances via a formal [4 + 2] cyclization of 4-vinylindoles involving sequential C3 Michael addition-dearomatization-aromatization cascade reactions.
- Wani, Imtiyaz Ahmad,Bhattacharyya, Aditya,Sayyad, Masthanvali,Ghorai, Manas K.
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p. 2910 - 2922
(2018/05/03)
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- Design, synthesis, in vitro antiproliferative activity and apoptosis-inducing studies of 1-(3′,4′,5′-trimethoxyphenyl)-3-(2′-alkoxycarbonylindolyl)-2-propen-1-one derivatives obtained by a molecular hybridisation approach
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Inhibition of microtubule function using tubulin targeting agents has received growing attention in the last several decades. The indole scaffold has been recognized as an important scaffold in the design of novel compounds acting as antimitotic agents. Indole-based chalcones, in which one of the aryl rings was replaced by an indole, have been explored in the last few years for their anticancer potential in different cancer cell lines. Eighteen novel (3′,4′,5′-trimethoxyphenyl)-indolyl-propenone derivatives with general structure 9 were synthesized and evaluated for their antiproliferative activity against a panel of four different human cancer cell lines. The highest IC50 values were obtained against the human promyelocytic leukemia HL-60 cell line. This series of chalcone derivatives was characterized by the presence of a 2-alkoxycarbonyl indole ring as the second aryl system attached at the carbonyl of the 3-position of the 1-(3′,4′,5′-trimethoxyphenyl)-2-propen-1-one framework. The structure–activity relationship (SAR) of the indole-based chalcone derivatives was investigated by varying the position of the methoxy group, by the introduction of different substituents (hydrogen, methyl, ethyl or benzyl) at the N-1 position and by the activity differences between methoxycarbonyl and ethoxycarbonyl moieties at the 2-position of the indole nucleus. The antiproliferative activity data of the novel synthesized compounds revealed that generally N-substituted indole analogues exhibited considerably reduced potency as compared with their parent N-unsubstituted counterparts, demonstrating that the presence of a hydrogen on the indole nitrogen plays a decisive role in increasing antiproliferative activity. The results also revealed that the position of the methoxy group on the indole ring is a critical determinant of biological activity. Among the synthesized derivatives, compound 9e, containing the 2-methoxycarbonyl-6-methoxy-N-1H-indole moiety exhibited the highest antiproliferative activity, with IC50 values of 0.37, 0.16 and 0.17 μM against HeLa, HT29 and MCF-7 cancer cell lines, respectively, and with considerably lower activity against HL-60 cells (IC50: 18 μM). This derivative also displayed cytotoxic properties (IC50 values ~1 μM) in the human myeloid leukemia U-937 cell line overexpressing human Bcl-2 (U-937/Bcl-2) via cell cycle progression arrest at the G2-M phase and induction of apoptosis. The results obtained also demonstrated that the antiproliferative activity of this molecule is related to inhibition of tubulin polymerisation. The presence of a methoxy group at the C5- or C6-position of the indole nucleus, as well as the absence of substituents at the N-1-indole position, contributed to the optimal activity of the indole-propenone-3′,4′,5′-trimethoxyphenyl scaffold.
- Preti, Delia,Romagnoli, Romeo,Rondanin, Riccardo,Cacciari, Barbara,Hamel, Ernest,Balzarini, Jan,Liekens, Sandra,Schols, Dominique,Estévez-Sarmiento, Francisco,Quintana, José,Estévez, Francisco
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p. 1225 - 1238
(2018/09/04)
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- Method for preparing perindopril despinner and intermediate thereof
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The invention discloses a method for preparing perindopril despinner and an intermediate thereof. The method comprises the following steps: halogenating N-propionyl indole-2-carboxylic acid under theaction of a halogenation reagent so as to obtain a halogenation product, and further carrying out amine substitution and catalytic hydrogenation reduction on the obtained halogenation product, therebyobtaining the perindopril despinner. Compared with the prior art, the method is cheap and easy in reaction raw material, has a total yield as high as 64%, is high in product purity and is applicableto industrial production.
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Paragraph 0011; 0024; 0025; 0027; 0038; 0042-0044
(2018/11/22)
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- A new and efficient method for the synthesis of 3-(2-nitrophenyl)pyruvic acid derivatives and indoles based on the Reissert reaction
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The formation of 3-(2-nitrophenyl)pyruvic acid and its amide and ester derivatives – key compounds for the Reissert indole synthesis – was achieved under various reaction conditions via the acid catalyzed hydrolysis of 5-(2-nitrobenzyliden)-2,2-dimethyl-1,3-oxazolidin-4-one, which is readily available from 3-(2-nitrophenyl)oxirane-2-carboxamide. A new and highly efficient method for the synthesis of indole-2-carboxylic acid derivatives via the intramolecular reductive cyclization of o-nitrophenylpyruvic acid and its amide and ester derivatives was developed using Na2S2O4 in dioxane/water at reflux.
- Mamedov, Vakhid A.,Mamedova, Vera L.,Syakaev, Victor V.,Khikmatova, Gul'naz Z.,Korshin, Dmitry E.,Kushatov, Temur A.,Latypov, Shamil K.
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supporting information
p. 3923 - 3925
(2018/10/02)
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- Carboxylic Acid-Promoted Single-Step Indole Construction from Simple Anilines and Ketones via Aerobic Cross-Dehydrogenative Coupling
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The cross-dehydrogenative coupling (CDC) reaction is an efficient strategy for indole synthesis. However, most CDC methods require special substrates, and the presence of inherent groups limits the versatility for further transformation. A carboxylic acid-promoted aerobic catalytic system is developed herein for a single-step synthesis of indoles from simple anilines and ketones. This versatile system is featured by the broad substrate scope and the use of ambient oxygen as an oxidant and is convenient and economical for both laboratory and industry applications. The existence of the labile hydrogen at C-3 and the highly transformable carbonyl at C-2 makes the indoles versatile building blocks for organic synthesis in different contexts. Computational studies based on the density functional theory (DFT) suggest that the rate-determining step is carboxylic acid-assisted condensation of the substrates, rather than the functionalization of aryl C-H. Accordingly, a pathway via imine intermediates is deemed to be the preferred mechanism. In contrast to the general deduction, the in situ formed imine, instead of its enamine isomer, is believed to be involved in the first ligand exchange and later carbopalladation of the α-Me, which shed new light on this indolization mechanism.
- Ren, Long,Nan, Guanglei,Wang, Yongcheng,Xiao, Zhiyan
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supporting information
p. 14472 - 14488
(2018/11/23)
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- Gold(0) catalyzed dehydrogenation of N-heterocycles
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Gold nanoclusters are good catalyst precursors for the catalytic dehydrogenation of indolines, tetrahydroquinazolines, and related N-heterocycles. The catalytically active species is presumably Au(0) nanoparticles.
- Kumaran, Elumalai,Leong, Weng Kee
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supporting information
p. 3958 - 3960
(2018/10/02)
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- Synthesis of N-Heterocycles by Reductive Cyclization of Nitro Compounds using Formate Esters as Carbon Monoxide Surrogates
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A series of alkyl and aryl formate esters were evaluated as CO sources in the Pd- and Pd/Ru-catalyzed reductive cyclization of substituted nitro compounds to afford heterocycles, especially indoles. Phenyl formate was found to be the most effective, and it allowed the desired products to be obtained in excellent yields, often higher than those previously reported with pressurized CO. Through detailed experiments and kinetic studies, we were able to discern between metal-catalyzed and base-mediated activation of phenyl formate and confirmed that just the base was effective in catalyzing its decarbonylation.
- Formenti, Dario,Ferretti, Francesco,Ragaini, Fabio
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p. 148 - 152
(2017/12/04)
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- From Cells to Mice to Target: Characterization of NEU-1053 (SB-443342) and Its Analogues for Treatment of Human African Trypanosomiasis
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Human African trypanosomiasis is a neglected tropical disease that is lethal if left untreated. Existing therapeutics have limited efficacy and severe associated toxicities. 2-(2-(((3-((1H-Benzo[d]imidazol-2-yl)amino)propyl)amino)methyl)-4,6-dichloro-1H-indol-1-yl)ethan-1-ol (NEU-1053) has recently been identified from a high-throughput screen of >42,000 compounds as a highly potent and fast-acting trypanocidal agent capable of curing a bloodstream infection of Trypanosoma brucei in mice. We have designed a library of analogues to probe the structure-activity relationship and improve the predicted central nervous system (CNS) exposure of NEU-1053. We report the activity of these inhibitors of T. brucei, the efficacy of NEU-1053 in a murine CNS model of infection, and identification of the target of NEU-1053 via X-ray crystallography.
- Devine, William G.,Diaz-Gonzalez, Rosario,Ceballos-Perez, Gloria,Rojas, Domingo,Satoh, Takashi,Tear, Westley,Ranade, Ranae M.,Barros-álvarez, Ximena,Hol, Wim G. J.,Buckner, Frederick S.,Navarro, Miguel,Pollastri, Michael P.
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p. 225 - 236
(2017/04/21)
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- Graphene Oxide: An Efficient Acid Catalyst for the Construction of Esters from Acids and Alcohols
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Graphene oxide was found to be an efficient and reusable acid catalyst for the esterification reaction. A wide range of aliphatic and aromatic acids and alcohols were compatible with the standard conditions and afforded the corresponding products in good yields. The heterogeneous catalyst can be easily recovered and recycled in dichloro-ethane solvent with good catalytic activity.
- Chen, Zhengwang,Wen, Yuelu,Fu, Yejuan,Chen, Hai,Ye, Min,Luo, Guotian
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supporting information
p. 981 - 985
(2017/05/05)
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- 1,2,4-Triazole-3-thione Compounds as Inhibitors of Dizinc Metallo-β-lactamases
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Metallo-β-lactamases (MBLs) cause resistance of Gram-negative bacteria to β-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We previously identified the original binding mode of 4-amino-2,4-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione (compound IIIA) within the dizinc active site of the L1 MBL. Herein we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB (1,2-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione). Unexpectedly, the binding mode of IIIB was similar but reverse to that of IIIA. The 3 D structures suggested that the triazole–thione scaffold was suitable to bind to the catalytic site of dizinc metalloenzymes. On the basis of these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC50 values in the micromolar range toward at least one of five representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM-2, and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial dinuclear zinc-dependent hydrolases belonging to the MBL-fold superfamily (i.e., endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. Whereas the bacterial tRNases were not inhibited, the best IC50 values toward plasmodial glyoxalase II were in the 10 μm range.
- Sevaille, Laurent,Gavara, Laurent,Bebrone, Carine,De Luca, Filomena,Nauton, Lionel,Achard, Maud,Mercuri, Paola,Tanfoni, Silvia,Borgianni, Luisa,Guyon, Carole,Lonjon, Pauline,Turan-Zitouni, Gülhan,Dzieciolowski, Julia,Becker, Katja,Bénard, Lionel,Condon, Ciaran,Maillard, Ludovic,Martinez, Jean,Frère, Jean-Marie,Dideberg, Otto,Galleni, Moreno,Docquier, Jean-Denis,Hernandez, Jean-Fran?ois
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p. 972 - 985
(2017/06/27)
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- Substituted indole - 2 - formic acid (by machine translation)
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This invention relates to a substituted indole - 2 - carboxylic acid synthesis method, is to replace the phenyl hydrazine hydrochloride or arylhydrazines as raw materials, through with pyruvic acid ethyl ester cheng zong, Fischer indole synthesis by reaction of substituted indole - 2 - carboxylic acid ethyl ester, hydrolysis to obtain the substituted - 2 - carboxylic acid. Product purity is greater than 97%, the reaction yield is 64%. Synthesis method of the invention with non-harsh conditions, the operation is simple, and environmental friendliness, it has certain economic benefits. It is a kind of raw materials are easy, simple operation, three wastes, high yield of indole - 2 - carboxylic acid synthesis method. (by machine translation)
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Paragraph 0035; 0037; 0057
(2017/10/28)
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- Photochemistry of ortho -Azidocinnamoyl Derivatives: Facile and Modular Synthesis of 2-Acylated Indoles and 2-Substituted Quinolines under Solvent Control
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The light-promoted potential of ortho -azidocinnamoyl compounds is evaluated for heterocycle synthesis. Depending on the nature of the solvent, 2-acylated indoles were obtained under aprotic conditions, whereas the use of a protic medium led to 2-substituted quinolines. The synthetic significance of this metal-free method is that, by simply changing the solvent, the reaction outcome can be directed towards different key heterocyclic scaffolds.
- Chaabouni,Pinkerton,Abid,Galaup,Chassaing
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supporting information
p. 2614 - 2618
(2017/10/06)
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- Organo-Photoredox Catalyzed Oxidative Dehydrogenation of N-Heterocycles
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We report here for the first time the catalytic oxidative dehydrogenation of N-heterocycles by a visible-light organo-photoredox catalyst with low catalyst loading (0.1–1 mol %). The reaction proceeds efficiently under base- and additive-free conditions with ambient air at room temperature. The utility of this benign approach is demonstrated by the synthesis of various pharmaceutically relevant N-heteroarenes such as quinoline, quinoxaline, quinazoline, acridine, and indole.
- Sahoo, Manoj K.,Jaiswal, Garima,Rana, Jagannath,Balaraman, Ekambaram
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supporting information
p. 14167 - 14172
(2017/10/16)
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- Cu nanoparticles immobilized on montmorillonite by biquaternary ammonium salts: a highly active and stable heterogeneous catalyst for cascade sequence to indole-2-carboxylic esters
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Copper nanoparticles immobilized on montmorillonite (MMT) by biquaternary ammonium salts (N1,N6-dibenzyl-N1,N1,N6,N6-tetramethylheptane-1,6-diaminium bromide, Q) were prepared by cation-exchange and impregnation-reduction and designated Cu-Q-MMT. The material was extensively characterized by various characterization techniques such as FTIR, XRD, XPS, SEM, TEM, and N2 adsorption-desorption. The Cu-Q-MMT could be used as a highly active heterogeneous catalyst for cascade sequence to indole-2-carboxylic esters from ortho-bromobenzaldehydes with ethyl acetamidoacetate. Even for inactive chlorobenzaldehydes, a good yield could be obtained. In addition, the catalyst can be reused six times without any significant loss of activity. The high activity and stability of the Cu-Q-MMT catalyst is mainly attributed to the excellent synergistic effects of biquaternary ammonium salts, Cu nanoparticles and the nanospace structure of MMT.
- Lang, Wencheng,Yang, Qin,Song, Xueping,Yin, Mengyun,Zhou, Limei
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p. 13754 - 13759
(2017/03/11)
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- Design, synthesis and evaluation of indole-2-carboxamides with pan anti-mycobacterial activity
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Current treatment regimens for non-tuberculous mycobacteria (NTM) and tuberculosis (TB) generally require long duration of therapy with multiple drugs, some of which are broad spectrum antibiotics. Despite some advances in antimicrobial compounds, there remains a need in therapy for antibiotics with specific mycobacterial targets. It has been shown that MmpL3 is an essential transporter required for the translocation of mycolic acids to the mycobacterial cell envelope. Here, we synthesized a series of indole-2-carboxamides that inhibit MmpL3 and have potent pan-activity against mycobacterial species. The compounds were tested against several fast and slow-growing Mycobacterium species, including M. abscessus, M. massiliense, M. bolletii, M. chelonae, M. tuberculosis, M. avium, M. xenopi and M. smegmatis. The target of these indole-based compounds makes them selective for mycobacteria, while showing no clinically relevant bactericidal activity against S. aureus or P. aeruginosa. These compounds were tested against THP-1, a human-cell line, and showed minimal in vitro cytotoxicity and good selectivity indices. The data shown and discussed suggest that lead indole-2-carboxamides are strong contenders for further preclinical testing as NTM therapeutics.
- Franz, Nicholas D.,Belardinelli, Juan Manuel,Kaminski, Michael A.,Dunn, Louis C.,Calado Nogueira de Moura, Vinicius,Blaha, Michael A.,Truong, Dan D.,Li, Wei,Jackson, Mary,North, E. Jeffrey
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p. 3746 - 3755
(2017/06/13)
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- Identification of indole scaffold-based dual inhibitors of NOD1 and NOD2
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NOD1 and NOD2 are important members of the pattern recognition receptor family and play a crucial role within the context of innate immunity. However, overactivation of NODs, especially of NOD1, has also been implicated in a number of diseases. Surprisingly, NOD1 remains a virtually unexploited target in this respect. To gain additional insight into the structure–activity relationships of NOD1 inhibitors, a series of novel analogs has been designed and synthesized and then screened for their NOD1-inhibitory activity. Selected compounds were also investigated for their NOD2-inhibitory activity. Two compounds 4 and 15, were identified as potent mixed inhibitors of NOD1 and NOD2, displaying a balanced inhibitory activity on both targets in the low micromolar range. The results obtained have enabled a deeper understanding of the structural requirements for NOD1 and NOD2 inhibition.
- Ke?ek Ple?ec, Kaja,Urban?i?, Dunja,Gobec, Martina,Peko?ak, Aleksandra,Toma?i?, Tihomir,Anderluh, Marko,Mlinari?-Ra??an, Irena,Jakopin, ?iga
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p. 5221 - 5234
(2016/10/24)
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- Synthesis of novel 5-[(1,2,3-triazol-4-yl)methyl]-1-methyl-3H-pyridazino[4,5-b]indol-4-one derivatives by click reaction and exploration of their anticancer activity
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A series of pyridazino[4,5-b]indole derivatives containing alkyl-, benzyl- and phenacyl-substituted 1,2,3-triazolylmethyl units was synthesized using click chemistry approach. All 30 compounds of the series were screened in vitro against four cancer cell lines, viz. breast cancer cells MDA-MB-231 and MCF 7, human primary glioblastoma U-87 and human neuroblastoma IMR-32 cell lines. Most of the compounds exhibited potent cancer cell growth inhibition activity at very low micromolar concentrations. The IC50 value of compounds 7v and 7x against human neuroblastoma IMR-32 cell line is 0.07 and 0.04 μM, respectively. Among the tested compounds, ten compounds showed IC50 value less than 1 μM against MDA-MB-231 cells, whereas against IMR-32 cells, nine compounds and, against U-87 cells, six compounds showed similar inhibition activity. Further, these molecules exhibited prominent binding affinity and docking scores in the molecular simulation study with the target enzyme PI3 kinase. Graphical Abstract: This paper illustrates the synthesis of new fused indole-pyridazinone derivatives containing substituted 1,2,3-triazoles via click chemistry approach. Most of the compounds exhibited potent cancer cell growth inhibition activity at very low micromolar concentrations. [Figure not available: see fulltext.]
- Panathur, Naveen,Gokhale, Nikhila,Dalimba, Udayakumar,Koushik, Pulla Venkat,Yogeeswari, Perumal,Sriram, Dharmarajan
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p. 135 - 148
(2016/01/25)
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- Rh(II)-catalyzed intramolecular annulation of N-sulfonyl 1,2,3-triazoles with indole derivatives: A new method for synthesis pyranoindoles
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A direct and highly stereoselective approach for the synthesis of Z-alkenyl-pyranoindoles had been developed by utilizing Rh(II)-catalyzed intramolecular cyclization of N-sulfonyl-1,2,3-triazoles with indole derivatives. A variety of pyranoindoles were obtained in 44-93% yields. Moreover, a more convenient synthesis of pyranoindoles starting from terminal alkyne was realized via a Cu-Rh sequentially catalyzed one-pot cascade reaction.
- Xie, Hui,Yang, Jian-Xin,Bora, Pranjal Protim,Kang, Qiang
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supporting information
p. 3014 - 3021
(2016/05/19)
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- SYNTHESIS OF INDOLES FROM ACETOACETIC ESTERS
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The present invention relates to a synthesizing method of indole using acetoacetic ester and, more specifically, to a synthesizing method of indole which induces reduction of a nitro group into an amine group and aromatic cyclization with a ketone group through hydrogenation using a metal catalyst in a 2-nitrobenzyl ketone compound, after synthesizing the 2-nitrobenzyl ketone compound through deacetylation using a manganese (III) / cobalt (II) catalyst in a 2-nitrobenzyl acetone compound obtained by adding an acetoacetic ester compound in a 2-nitrobenzyl bromide compound.COPYRIGHT KIPO 2016
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Paragraph 0028; 0052; 0072-0076
(2021/05/29)
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- Synthesis of Indole-2-carboxylate Derivatives via Palladium-Catalyzed Aerobic Amination of Aryl C-H Bonds
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A direct oxidative C-H amination affording 1-acetyl indolecarboxylates starting from 2-acetamido-3-arylacrylates has been achieved. Indole-2-carboxylates can be targeted with a straightforward deacetylation of the initial reaction products. The C-H amination reaction is carried out using a catalytic Pd(II) source with oxygen as the terminal oxidant. The scope and application of this chemistry is demonstrated with good to high yields for numerous electron-rich and electron-poor substrates. Further reaction of selected products via Suzuki arylation and deacetylation provides access to highly functionalized indole structures.
- Clagg, Kyle,Hou, Haiyun,Weinstein, Adam B.,Russell, David,Stahl, Shannon S.,Koenig, Stefan G.
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p. 3586 - 3589
(2016/08/16)
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- Development of indole sulfonamides as cannabinoid receptor negative allosteric modulators
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Existing CB1 negative allosteric modulators (NAMs) fall into a limited range of structural classes. In spite of the theoretical potential of CB1 NAMs, published in vivo studies have generally not been able to demonstrate the expected therapeutically-relevant CB1-mediated effects. Thus, a greater range of molecular tools are required to allow definitive elucidation of the effects of CB1 allosteric modulation. In this study, we show a novel series of indole sulfonamides. Compounds 5e and 6c (ABD1075) had potencies of 4 and 3?nM respectively, and showed good oral exposure and CNS penetration, making them highly versatile tools for investigating the therapeutic potential of allosteric modulation of the cannabinoid system.
- Greig, Iain R.,Baillie, Gemma L.,Abdelrahman, Mostafa,Trembleau, Laurent,Ross, Ruth A.
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p. 4403 - 4407
(2016/08/25)
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- Bismuth Acetate as a Catalyst for the Sequential Protodeboronation of Di- and Triborylated Indoles
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Bismuth(III) acetate is a safe, inexpensive, and selective facilitator of sequential protodeboronations, which when used in conjunction with Ir-catalyzed borylations allows access to a diversity of borylated indoles. The versatility of combining Ir-catalyzed borylations with Bi(III)-catalyzed protodeboronation is demonstrated by selectively converting 6-fluoroindole into products with Bpin groups at the 4-, 5-, 7-, 2,7-, 4,7-, 3,5-, and 2,4,7-positions and the late-stage functionalization of sumatriptan.
- Shen, Fangyi,Tyagarajan, Sriram,Perera, Damith,Krska, Shane W.,Maligres, Peter E.,Smith, Milton R.,Maleczka, Robert E.
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supporting information
p. 1554 - 1557
(2016/05/02)
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- Safe generation and use of bromine azide under continuous flow conditions-selective 1,2-bromoazidation of olefins
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Bromine azide (BrN3), a useful but extremely toxic and explosive reagent for the preparation of vicinal 1,2-bromine azide compounds, was safely generated and reacted in situ with alkenes in a continuous flow photoreactor. BrN3 was generated by a novel procedure from NaBr and NaN3 in water, and efficiently extracted into an organic phase containing the alkene thus avoiding decomposition. The resulting addition products have been used for the preparation of several useful building blocks.
- Cantillo, David,Gutmann, Bernhard,Oliver Kappe
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supporting information
p. 853 - 857
(2016/01/15)
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- Organocatalytic Synthesis of Fused Bicyclic 2,3-Dihydro-1,3,4-oxadiazoles through an Intramolecular Cascade Cyclization
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Hydrazone-carboxylic acids undergo intramolecular cyclization in the presence of pivaloyl chloride, iPr2NEt, and catalytic DABCO to form a range of substituted fused tricyclic 2,3-dihydro-1,3,4-oxadiazoles in high yields.
- Fugard, Alison J.,Thompson, Bethany K.,Slawin, Alexandra M. Z.,Taylor, James E.,Smith, Andrew D.
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supporting information
p. 5824 - 5827
(2015/12/11)
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- Intramolecular Gold-Catalyzed and NaH-Supported Cyclization Reactions of N-Propargyl Indole Derivatives with Pyrazole and Pyrrole Rings: Synthesis of Pyrazolodiazepinoindole, Pyrazolopyrazinoindole, and Pyrrolopyrazinoindole
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Gold-catalyzed and NaH-supported intramolecular cyclization of N-propargyl indole derivatives with pyrazole and pyrrole units attached to indole is described. An efficient route to the synthesis of pyrazolodiazepinoindole, pyrazolopyrazinoindole, and pyrrolopyrazinoindole has been established. First, N-propargyl 2-(1H-pyrazol-5-yl)-1H-indole and 2-(1H-pyrrol-2-yl)-1H-indole were synthesized. Introduction of various substituents into the alkyne functionality was accomplished by Sonogashira cross-coupling reaction. Gold-catalyzed cyclization of pyrazoles having a terminal alkyne afforded the 6-exo-dig cyclization product. However, exclusive formation of 7-endo-dig cyclization products was observed with internal alkynes. On the other hand, cyclization with NaH only resulted in the formation of 6-exo-dig cyclization products regardless of the substitution of the alkyne functionality. Allenic intermediates were postulated for this outcome.
- Basceken, Sinan,Kaya, Serdal,Balci, Metin
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p. 12552 - 12561
(2016/01/09)
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- PAIN RELIEF COMPOUNDS
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The present invention relates to the use of compounds for the treatment or prevention of pain in mammals, in particularly in human beings, and also to a process for preparing these compounds.
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Paragraph 0493
(2015/02/19)
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- Piperazine analogs of naphthyridine-3-carboxamides and indole-2-carboxamides: Novel 5-HT3 receptor antagonists with antidepressant-like activity
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Series of piperazine analogs of naphthyridine-3-carboxamides and indole-2-carboxamides were designed using a ligand-based approach with consideration of the pharmacophoric requirements for 5-HT3 receptor antagonists. The title carboxamides were synthesized using appropriate synthetic routes. Initially, the 5-HT3 receptor antagonistic activity of all the compounds was determined on isolated guinea pig ileum tissue against the 5-HT3 agonist, 2-methyl-5-hydroxytryptamine, which was denoted in the form of pA2 values. The structure-activity relationship regarding the influence of the aromatic part and basic moiety as features in the 5-HT3 pharmacophore was derived. Among all the compounds screened, the piperazine derivatives of indole-2-carboxamide 13i and naphthyridine-3-carboxamide 8h exhibited prominent 5-HT3 receptor antagonism with pA2 values of 7.5 and 7.3, respectively. Subsequent investigation of the antidepressant activities of selected compounds in the mouse forced swim test (FST) led to the identification of the piperazine analogs of indole-2-carboxamide 13i and naphthyridine-3-carboxamide 8h as the most promising compounds. Both 13i and 8h demonstrated significant reduction in the duration of immobility as compared to the control. Importantly, none of the tested compounds affected the baseline locomotion of mice at the tested dose levels.
- Dhar, Arghya K.,Mahesh, Radhakrishnan,Jindal, Ankur,Bhatt, Shvetank
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- Indole-3-carbinol and 1,3,4-oxadiazole hybrids: Synthesis and study of anti-proliferative and anti-microbial activity
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In the present study, molecular hybrids of indole-3-carbinol and 1,3,4-oxadiazole-2-thiols have been designed and synthesized. The thiol analogues consisted of diversely substituted benzyl and alkyl groups with different electronic properties. The structures of all the newly synthesized scaffolds and target compounds were ascertained using 1H NMR, 13C NMR, mass spectrometry, and elemental analyses. All the final compounds were screened in vitro for their anti-proliferative and anti-microbial activity. Three compounds showed excellent anti-proliferative activity with more than 70% cell growth inhibition against three cancer cell lines, HepG2 (human liver hepatocellular carcinoma), HeLa (human cervix carcinoma), and MCF-7 (human breast carcinoma). In the anti-microbial studies, compounds with electron-withdrawing fluoro or nitro substituent displayed appreciable activity similar to that of standard drugs. Also, the final compounds are non-toxic to non-cancerous Vero cell line.
- Gokhale, Nikhila,Panathur, Naveen,Dalimba, Udayakumar,Kumsi, Manjunatha
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p. 1603 - 1613
(2015/10/20)
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- Tandem catalytic oxidative deacetylation of acetoacetic esters and heteroaromatic cyclizations
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One pot syntheses of furan, thiophene, and pyrrole were accomplished by oxidative deacetylation using Mn(iii)/Co(ii) catalysts and the Paal-Knorr reaction from 1,5-dicarbonyl compounds, which are prepared from the conjugate addition of ethyl acetoacetate to α,β-unsaturated carbonyl compounds. The oxidative deacetylation and reductive cyclization of β-ketoesters derived from ethyl acetoacetate and o-nitrobenzyl bromides efficiently produced diversely substituted indoles. This journal is
- Ju, Yeming,Miao, Di,Yu, Ruiyang,Koo, Sangho
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p. 2588 - 2599
(2015/04/21)
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- Three consecutive steps over the chirally modified Pt surface: Asymmetric catalytic cascade reaction of 2-nitrophenylpyruvates
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The influence of the reaction conditions on the asymmetric heterogeneous cascade reaction of 2-nitrophenylpyruvates over Pt catalysts modified with cinchonidine leading to (R)-3-hydroxy-3,4-dihydroquinolin-2(1H)-one derivatives has been studied. Results of studies on the amount of acetic acid or catalyst, nature of the Pt support, kinetic examinations, effect of H2 pressure, and modifier and substrate concentrations showed that all three steps of this catalytic cascade take place on the Pt surface, with the nitro group reduction immediately following the enantioselective hydrogenation of the keto group, whereas the final intramolecular amidation was preceded by desorption after complete reduction of the substrate and re-adsorption of the corresponding intermediate.
- Szollosi, Gy?rgy,Kovcs, Lenke,Makra, Zsolt
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p. 697 - 704
(2015/02/19)
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