- Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2-EED Interaction
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Disruption of EZH2-embryonic ectoderm development (EED) protein-protein interaction (PPI) is a new promising cancer therapeutic strategy. We have previously reported the discovery of astemizole, a small-molecule inhibitor targeting the EZH2-EED PPI. Herein, we report the cocrystal structure of EED in complex with astemizole at 2.15 ?. The structure elucidates the detailed binding mode of astemizole to EED and provides a structure-guided design for the discovery of a novel EZH2-EED interaction inhibitor, DC-PRC2in-01, with an affinityKdof 4.56 μM. DC-PRC2in-01 destabilizes the PRC2 complex, thereby leading to the degradation of PRC2 core proteins and the decrease of global H3K27me3 levels in cancer cells. The proliferation of PRC2-driven lymphomas cells is effectively inhibited, and the cell cycle is arrested in the G0/G1 phase. Together, these data demonstrate that DC-PRC2in-01 could be an effective chemical probe for investigating the PRC2-related physiology and pathology and providing a promising chemical scaffold for further development.
- Du, Daohai,Xu, Dandan,Zhu, Licheng,Stazi, Giulia,Zwergel, Clemens,Liu, Yanli,Luo, Zhongyuan,Li, Yuanqing,Zhang, Yuanyuan,Zhu, Kongkai,Ding, Yiluan,Liu, Jingqiu,Fan, Shijie,Zhao, Kaiyan,Zhang, Naixia,Kong, Xiangqian,Jiang, Hualiang,Chen, Kaixian,Zhao, Kehao,Valente, Sergio,Min, Jinrong,Duan, Wenhu,Luo, Cheng
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supporting information
p. 8194 - 8207
(2021/06/28)
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- 1,2-Disubstituted Benzimidazoles by the Iron Catalyzed Cross-Dehydrogenative Coupling of Isomeric o-Phenylenediamine Substrates
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Benzimidazoles are common in nature, medicines, and materials. Numerous strategies for preparing 2-arylbenzimidazoles exist. In this work, 1,2-disubstituted benzimidazoles were prepared from various mono- and disubstituted ortho-phenylenediamines (OPD) by iron-catalyzed oxidative coupling. Specifically, O2 and FeCl3·6H2O catalyzed the cross-dehydrogenative coupling and aromatization of diarylmethyl and dialkyl benzimidazole precursors. N,N′-Disubstituted-OPD substrates were significantly more reactive than their N,N-disubstituted isomers, which appears to be relative to their propensity for complexation and charge transfer with Fe3+. The reaction also converted N-monosubstituted OPD substrates to 2-substituted benzimidazoles; however, electron-poor substrates produce 1,2-disubstituted benzimidazoles by intermolecular imino-transfer. Kinetic, reagent, and spectroscopic (UV-vis and EPR) studies suggest a mechanism involving metal-substrate complexation, charge transfer, and aerobic turnover, involving high-valent Fe(IV) intermediates. Overall, comparative strategies for the relatively sustainable and efficient synthesis of 1,2-disubstituted benzimidazoles are demonstrated.
- Foss, Frank W.,Palacios, Philip M.,Pierce, Brad S.,Thapa, Pawan,Tran, Tam
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p. 1991 - 2009
(2020/03/13)
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- Synthesis of Structurally Diverse Benzotriazoles via Rapid Diazotization and Intramolecular Cyclization of 1,2-Aryldiamines
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An operationally simple method has been developed for the preparation of N-unsubstituted benzotriazoles by diazotization and intramolecular cyclization of a wide range of 1,2-aryldiamines under mild conditions, using a polymer-supported nitrite reagent and p-tosic acid. The functional group tolerance of this approach was further demonstrated with effective activation and cyclization of N-alkyl, -aryl, and -acyl ortho-aminoanilines leading to the synthesis of N1-substituted benzotriazoles. The synthetic utility of this one-pot heterocyclization process was exemplified with the preparation of a number of biologically and medicinally important benzotriazole scaffolds, including an α-amino acid analogue.
- Faggyas, Réka J.,Sloan, Nikki L.,Buijs, Ned,Sutherland, Andrew
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p. 5344 - 5353
(2019/05/21)
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- Design, synthesis, and biological evaluation of 4-phenoxyquinoline derivatives as potent c-Met kinase inhibitor
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A series of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydro-quinoxaline moiety were synthesized and evaluated for their antiproliferative activity against five human cancer cell lines (A549, H460, HT-29, MKN-45 and U87MG) in vitro. Most of the tested compounds exhibited more potent inhibitory activities than the positive control foretinib. Compound 1b, 1s and 1t were further examined for their inhibitory activity against c-Met kinase. The most promising compound 1s (with c-Met IC50 value of 1.42 nM) showed remarkable cytotoxicity against A549, H460, HT-29, MKN45 and U87MG cell lines with IC50 values of 0.39 μM, 0.18 μM, 0.38 μM, 0.81 μM, respectively. Their preliminary structure-activity relationships (SARs) study indicated that the replacement of the aromatic ring with the cyclohexane improved their antiproliferative activity.
- Yang, Yifeng,Li, Yingxiu,Hou, Yunlei,Qin, Mingze,Gong, Ping,Liu, Ju,Zhao, Yanfang
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- Discovery of Benzimidazole–Quinolone Hybrids as New Cleaving Agents toward Drug-Resistant Pseudomonas aeruginosa DNA
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A series of benzimidazole–quinolone hybrids as new potential antimicrobial agents were designed and synthesized. Bioactive assays indicated that some of the prepared compounds exhibited potent antibacterial and antifungal activities. Notably, 2-fluorobenzyl derivative 5 b (ethyl 7-chloro-6-fluoro-1-[[1-[(2-fluorophenyl)methyl]benzimidazol-2-yl]methyl]-4-oxo-quinoline-3-carboxylate) showed remarkable antimicrobial activity against resistant Pseudomonas aeruginosa and Candida tropicalis isolated from infected patients. Active molecule 5 b could not only rapidly kill the tested strains, but also exhibit low toxicity toward Hep-2 cells. It was more difficult to trigger the development of bacterial resistance of P. aeruginosa against 5 b than that against norfloxacin. Molecular docking demonstrated that 5 b could effectively bind with topoisomerase IV–DNA complexes, and quantum chemical studies theoretically elucidated the good antimicrobial activity of compound 5 b. Preliminary experimental reaction mechanism exploration suggested that derivative 5 b could not intercalate into DNA isolated from drug-resistant P. aeruginosa, but was able to cleave DNA effectively, which might further block DNA replication to exert powerful bioactivities. In addition, compound 5 b is a promising antibacterial agent with membrane disruption abilities.
- Wang, Ya-Nan,Bheemanaboina, Rammohan R. Yadav,Gao, Wei-Wei,Kang, Jie,Cai, Gui-Xin,Zhou, Cheng-He
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p. 1004 - 1017
(2018/04/30)
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- Novel purine benzimidazoles as antimicrobial agents by regulating ROS generation and targeting clinically resistant Staphylococcus aureus DNA groove
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A novel series of purine benzimidazole hybrids were designed and synthesized for the first time with the aim to circumvent the increasing antibiotic resistance. Hexyl appended hybrid 3c gave potent activities against most of the tested bacteria and fungi especially against multidrug-resistant strains Staphylococcus aureus (MIC = 4 μg/mL). Structure-activity relationships revealed that the benzimidazole fragment at the 9-position of purine played an important role in exerting potentially antibacterial activity. Both cell toxicity and ROS generation assays indicated that the purine derivative 3c showed low cytotoxicity and could be used as a safe agent. Molecular modeling suggested that hybrid 3c could bind with the residues of Topo IA through hydrogen bonds and electrostatic interactions. Quantum chemical studies were also performed on the target compound 3c to understand the structural features essential for activity. The active molecule 3c could effectively interact with S. aureus DNA to form 3c–DNA complex through groove binding mode, which might block DNA replication to display their powerful antimicrobial activity.
- Wang, Ya-Nan,Bheemanaboina, Rammohan R. Yadav,Cai, Gui-Xin,Zhou, Cheng-He
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supporting information
p. 1621 - 1628
(2018/03/29)
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- Astemizole analogues with reduced hERG inhibition as potent antimalarial compounds
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Astemizole is a H1-antagonist endowed with antimalarial activity, but has hERG liabilities. Systematic structural modifications of astemizole led to the discovery of analogues that display very potent activity as inhibitors of the growth of the Plasmodium parasite, but show a decreased hERG inhibition, when compared to astemizole. These compounds can be used as starting point for the development of a new class of antimalarials.
- Tian, Junjun,Vandermosten, Leen,Peigneur, Steve,Moreels, Lien,Rozenski, Jef,Tytgat, Jan,Herdewijn, Piet,Van den Steen, Philippe E.,De Jonghe, Steven
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p. 6332 - 6344
(2017/10/23)
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- Discovery of membrane active benzimidazole quinolones-based topoisomerase inhibitors as potential DNA-binding antimicrobial agents
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A series of novel benzimidazole quinolones as potential antimicrobial agents were designed and synthesized. Most of the prepared compounds exhibited good or even stronger antimicrobial activities in comparison with reference drugs. The most potent compound 15m was membrane active and did not trigger the development of resistance in bacteria. It not only inhibited the formation of biofilms but also disrupted the established Staphylococcus aureus and Escherichia coli biofilms. It was able to inhibit the relaxation activity of E. coli topoisomerase IV at 10 μM concentration. Moreover, this compound also showed low toxicity against mammalian cells. Molecular modeling and experimental investigation of compound 15m with DNA suggested that this compound could effectively bind with DNA to form a steady 15m-DNA complex which might further block DNA replication to exert the powerful bioactivities.
- Zhang, Ling,Addla, Dinesh,Ponmani, Jeyakkumar,Wang, Ao,Xie, Dan,Wang, Ya-Nan,Zhang, Shao-Lin,Geng, Rong-Xia,Cai, Gui-Xin,Zhou, Cheng-He,Li, Shuo
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p. 160 - 182
(2018/05/17)
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- Synthesis and biological evaluation of 2,3-dihydroimidazo[1,2-a] benzimidazole derivatives against Leishmania donovani and Trypanosoma cruzi
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A high-throughput (HTS) and high-content screening (HCS) campaign of a commercial library identified 2,3-dihydroimidazo[1,2-a]benzimidazole analogues as a novel class of anti-parasitic agents. A series of synthetic derivatives were evaluated for their in vitro anti-leishmanial and anti-trypanosomal activities against Leishmania donovani and Trypanosoma cruzi, which have been known as the causative parasites for visceral leishmaniasis and Chagas disease, respectively. In the case of Leishmania, the compounds were tested in both intracellular amastigote and extracellular promastigote assays. Compounds 4 and 24 showed promising anti-leishmanial activity against intracellular L. donovani (3.05 and 5.29 μM, respectively) and anti-trypanosomal activity against T. cruzi (1.10 and 2.10 μM, respectively) without serious cytotoxicity toward THP-1 and U2OS cell lines.
- Oh, Sangmi,Kim, Sungbum,Kong, Sunju,Yang, Gyongseon,Lee, Nakyung,Han, Dawoon,Goo, Junghyun,Siqueira-Neto, Jair L.,Freitas-Junior, Lucio H.,Song, Rita
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p. 395 - 403
(2014/08/05)
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- Synthesis and biological evaluation of 2,3-dihydroimidazo[1,2-a] benzimidazole derivatives against Leishmania donovani and Trypanosoma cruzi
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A high-throughput (HTS) and high-content screening (HCS) campaign of a commercial library identified 2,3-dihydroimidazo[1,2-a]benzimidazole analogues as a novel class of anti-parasitic agents. A series of synthetic derivatives were evaluated for their in vitro anti-leishmanial and anti-trypanosomal activities against Leishmania donovani and Trypanosoma cruzi, which have been known as the causative parasites for visceral leishmaniasis and Chagas disease, respectively. In the case of Leishmania, the compounds were tested in both intracellular amastigote and extracellular promastigote assays. Compounds 4 and 24 showed promising anti-leishmanial activity against intracellular L. donovani (3.05 and 5.29 μM, respectively) and anti-trypanosomal activity against T. cruzi (1.10 and 2.10 mM, respectively) without serious cytotoxicity toward THP-1 and U2OS cell lines.
- Oh, Sangmi,Kim, Sungbum,Kong, Sunju,Yang, Gyongseon,Lee, Nakyung,Han, Dawoon,Goo, Junghyun,Siqueira-Neto, Jair L.,Freitas-Junior, Lucio H.,Song, Rita
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p. 395 - 403
(2015/03/13)
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- Sustainable synthesis of diverse privileged heterocycles by palladium-catalyzed aerobic oxidative isocyanide insertion
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Heterocycles containing a guanidine moiety are of great importance in medicinal chemistry (Scheme 1).[1] As a result, several methods for the synthesis of these "privileged scaffolds" have been reported.[2, 3] Classical approaches, such as the addition of diamines to isothiocyanates followed by condensation and the coupling of diamines with cyanogen bromide,[2, 4] have some clear limitations, such as the availability and toxicity of reagents. Moreover, these procedures suffer from poor atom and/or step efficiency, thus making them unattractive from a sustainability point of view.
- Vlaar, Tj?stil,Cioc, Razvan C.,Mampuys, Pieter,Maes, Bert U. W.,Orru, Romano V. A.,Ruijter, Eelco
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supporting information
p. 13058 - 13061
(2013/02/26)
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- Synthesis, biological evaluation and SAR studies of benzimidazole derivatives as H1-antihistamine agents
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A series of benzimidazole derivatives have been designed, synthesized and evaluated for H1 antihistamine activity. Six compounds have showed potent antihistamine H1 activity. The primary SAR analysis indicated that benzyl or benzylidinyl substituted on the exo-nitrogen atom and C2 of the benzimidazole were significant. Further experiments indicated that compound 17d displayed excellent activity to reduce mast cell degranulation, moderate anti-PAF activity and decreased potency on hERG compared to astermizole. Hence compound 17d could serve as anti-allergic agent for further development.
- Wang, Xiao Jian,Xi, Mei Yang,Fu, Ji Hua,Zhang, Fu Rong,Cheng, Gui Fang,Yin, Da Li,You, Qi Dong
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scheme or table
p. 707 - 710
(2012/07/03)
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- Discovery of novel, orally available benzimidazoles as melanin concentrating hormone receptor 1 (MCHR1) antagonists
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Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays role in several disorders such as obesity, stress, depression and anxiety. The synthesis and biological evaluation of novel benzimidazole derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified.
- Sasmal, Pradip K.,Sasmal, Sanjita,Rao, P. Tirumala,Venkatesham,Roshaiah,Abbineni, Chandrasekhar,Khanna, Ish,Jadhav, Vikram P.,Suresh,Talwar, Rashmi,Muzeeb, Syed,Receveur, Jean-Marie,Frimurer, Thomas M.,Rist, ?ystein,Elster, Lisbeth,H?gberg, Thomas
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scheme or table
p. 5443 - 5448
(2011/01/03)
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- Chemoselective reductions of nitroarenes: Bromoethanol-assisted phthalocyanatoiron/NaBH4 reductions
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Porphyrinatoiron/NaBH4 and a novel phthalocyanatoiron/NaBH4 catalyst systems were investigated for the reductions of nitroarenes. The phthalocyanatoiron/NaBH4 system was superior to the porphyrinatoiron/NaBH4 system. The reductions were performed in good yields and excellent chemoselectivities. The rate of reduction by the PcFe/NaBH4 system increased upon the addition of 2-bromoethanol.
- Wilkinson,Tanoury, Gerald J.,Wald, Stephen A.,Senanayake, Chris H.
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p. 167 - 170
(2007/10/03)
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- Derivatives of terbutylphenyl-1-amino-4-hydroxybutane their preparation processes and the pharmaceutical compositions containing them
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STR1 The present invention concerns (4-substituted phenyl)4-oxy 1-aminobutane of the general formula (I) in which X is a nitrogen atom or >CH--CH, and R is a cyclic substituent chosen from the group comprising a) a xanthic substituent, b) a benzimidazolic substituent, as well as salts and optic isomers of the compounds of formula (I). The invention also concerns processes for obtaining the compounds of formula (I) and pharmaceutical compositions containing, as antihistamine ingredient, at least one compound of formula (I) or one of its salts with a mineral or organic acid.
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