- Design, synthesis, and antitumor activity of PLGA nanoparticles incorporating a discovered benzimidazole derivative as EZH2 inhibitor
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Purpose: Targeting enhancer of zeste homolog 2 (EZH2) can represent a hopeful strategy for oncotherapy. Also, the use of PLGA-based nanoparticles as a novel and rate-controlling carrier system was of our concern. Methods: Benzimidazole derivatives were synthesized, and their structures were clarified. In vitro antitumor activity was evaluated. Then, a modeling study was performed to investigate the ability of the most active compounds to recognize EZH2 active sites. Compound 30 (Drug) was selected to conduct pre-formulation studies and then it was incorporated into polymeric PLGA nanoparticles (NPs). NPs were then fully characterized to select an optimized formula (NP4) that subjected to further evaluation regarding antitumor activity and protein expression levels of EZH2 and EpCAM. Results: The results showed the antitumor activity of some synthesized derivatives. Docking outcomes demonstrated that Compound 30 was able to identify EZH2 active sites. NP4 exhibited promising findings and proved to keep the antitumor activity of Compound 30. HEPG-2 was the most sensitive for both Drug and NP4. Protein analysis indicated that Drug and NP4 had targeted EZH2 and the downstream signaling pathway leading to the decline of EpCAM expression. Conclusions: Targeting EZH2 by Compound 30 has potential use in the treatment of cancer especially hepatocellular carcinoma.
- Elkot, Hoda A.,Ragab, Ibrahim,Saleh, Noha M.,Amin, Mohamed N.,Al-Rashood, Sara T.,El-Messery, Shahenda M.,Hassan, Ghada S.
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- Synthesis of novel amides with antiradical capacity from 2-mercaptobenzimidazole and cinnamic acids: Evaluation through donor-acceptor maps and QSAR
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The structures of thioethers I-III and the new amidic compounds 1(a-f)-3(a-f) derived from 2-mercaptobenzimidazole (MBZ) and cinnamic acids were confirmed by NMR and elemental analysis. Antioxidant activity was evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH●) radical scavenging assay and 2,2-azinobis (3-ethyl benzothiazoline-6-sulfonic acid) ABTS●+ radical cation decolorization method. Besides, donor-acceptor maps (DAM) and electrophilicity were calculated using DFT/B3LYP method with a 6-311G(d,p) basis set. MBZ, I-III and (1a-3a) compounds showed higher activity in vitro antioxidant assays, confirming with in silico studies that they are the best candidates. The findings found in antiradical activity suggest that these compounds could be promising in the development of new antitumor and antimicrobial agents. QSAR Molecular properties and topological descriptors of the synthesized compounds 1(a-f)-3(a-f) were calculated. The QSAR model indicates that the size and molecular shape are relevant for the antiradical activity for this family of compounds.
- Benicio, Fernando Obledo,Gami?o, José Antonio Valcárcel,Hernández, Carlos Eduardo Macías,Martínez, Francisco J. Martínez,Martínez, María Teresa Sumaya,Ramos-Organillo, ángel,Rodríguez, Omar Alejandro Ramos,Sánchez, Juan Pablo Mojica,Sandoval, Zeferino Gómez
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- Metal-Free Aminomethylation of Aromatic Sulfones Promoted by Eosin Y
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A metal-free α-aminomethylation of heteroaryls promoted by eosin Y under green light irradiation is reported. A large variety of α-trimethylsilylamines as precursor of α-aminomethyl radical species were engaged to functionalize sulfonyl-heteroaryls following a Homolytic Aromatic Substitution (HAS) pathway. This method has provided a range of α-aminoheteroaryl compounds including a functionalized natural product. The mechanism of this late-stage functionalization of aryls was investigated and suggests the formation of a sulfonyl radical intermediate over a reductive quenching cycle.
- Thierry, Thibault,Pfund, Emmanuel,Lequeux, Thierry
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supporting information
p. 14826 - 14830
(2021/10/01)
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- Methylenation for Aldehydes and Ketones Using 1-Methylbenzimidazol-2-yl Methyl Sulfone
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The methylenation reagent 1-methylbenzimidazol-2-yl methyl sulfone 2 reacts with various aldehydes and ketones in the presence of t-BuOK (room temperature, 1 h) in dimethylformamide to give the corresponding terminal alkenes generally in high yields. For sensitive substrates, the reaction is better carried out at low temperature using sodium hexamethyldisilazide in 1,2-dimethoxyethane. The byproduct is easily removed from the products, and the reaction conditions are mild and practical. Reagent 2 can be easily prepared from commercially available 2-mercaptobenzimidazole 5 in 95% yield without any expensive reagents.
- Ando, Kaori,Oguchi, Mai,Kobayashi, Takahisa,Asano, Haruka,Uchida, Nariaki
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p. 9936 - 9943
(2020/09/04)
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- Synthesis and antidiabetic evaluation of benzimidazole-tethered 1,2,3-triazoles
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Some novel benzimidazole-tethered 1,2,3-triazole derivatives (4a–r) were synthesized by a click reaction between 2-substituted 1-(prop-2-yn-1-yl)-1H-benzo[d]imidazole and in situ azide. The structures of the synthesized compounds were confirmed by spectroscopic studies (one- and two-dimensional nuclear magnetic resonance, Fourier transform infrared, and high-resolution mass spectra). The synthesized compounds were evaluated for their antidiabetic activity. Compounds 4a–r exhibited a good-to-moderate α-amylase and α-glucosidase inhibitory activity, with IC50 values ranging from 0.0410 to 0.0916 μmol/ml and 0.0146 to 0.0732 μmol/ml, respectively. Compounds 4e, 4g, and 4n were found to be most active. Furthermore, the binding conformation of the most active compounds was ascertained by docking studies.
- Deswal, Laxmi,Verma, Vikas,Kumar, Devinder,Kaushik, Chander?P.,Kumar, Ashwani,Deswal, Yogesh,Punia, Suman
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- S-Benzimidazolyl (SBiz) Imidates as a Platform for Oligosaccharide Synthesis via Active-Latent, Armed-Disarmed, Selective, and Orthogonal Activations
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This article describes the development of S-benzimidazolyl (SBiz) imidates as versatile building blocks for oligosaccharide synthesis. The SBiz imidates have been originally developed as a new platform for active-latent glycosylations. This article expands upon the utility of these compounds. The application to practically all common concepts for the expeditious oligosaccharide synthesis including selective, chemoselective, and orthogonal strategies is demonstrated. The strategy development was made possible thanks to our enhanced understanding of the reaction mechanism and the modes by which SBiz imidates interact with various promoters of glycosylation.
- Hasty, Scott J.,Bandara, Mithila D.,Rath, Nigam P.,Demchenko, Alexei V.
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p. 1904 - 1911
(2017/03/01)
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- An environmentally benign and selective electrochemical oxidation of sulfides and thiols in a continuous-flow microreactor
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A practical and environmentally benign electrochemical oxidation of thioethers and thiols in a commercially-available continuous-flow microreactor is presented. Water is used as the source of oxygen to enable the oxidation process. The oxidation reaction utilizes the same reagents in all scenarios and the selectivity is solely governed by the applied potential. The procedure exhibits a broad scope and good functional group compatibility providing access to various sulfoxides (15 examples), sulfones (15 examples) and disulfides (6 examples). The use of continuous flow allows the optimal reaction parameters (e.g. residence time, applied voltage) to be rapidly assessed, to avoid mass- and heat-transfer limitations and to scale the electrochemistry.
- Laudadio, Gabriele,Straathof, Natan J. W.,Lanting, Menno D.,Knoops, Benny,Hessel, Volker,No?l, Timothy
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supporting information
p. 4061 - 4066
(2017/09/07)
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- Highly efficient tandem syntheses of unsymmetrically substituted isomeric S,N-disubstituted-2-mercaptobenzimidazoles
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Highly efficient tandem syntheses of unsymmetrically substituted isomeric S,N-disubstituted-2-mercaptobenzimidazoles have been developed. The structures of 6a-d and isomeric compounds 9a-d have been synthesized from 2-mercaptobenzimidazole using tandem synthesis. The structures of 6a-d and isomeric compounds 9a-d have been established by spectral and analytical data, and by unambiguous syntheses.
- Rao, S. Srinivas,Reddy, Ch Venkata Ramana,Dubey
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p. 829 - 832
(2015/06/30)
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- Cyanuric chloride as promoter for the oxidation of sulfides and deoxygenation of sulfoxides
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This Letter discusses the use of cyanuric chloride as an efficient promoter for the chemoselective oxidation of sulfides to the corresponding sulfones in the presence of H2O2 as the terminal oxidant. Sulfoxides were also found to undergo deoxygenation to sulfides with cyanuric chloride and potassium iodide system. The reaction is broad in scope and easy to perform.
- Bahrami, Kiumars,Khodaei, Mohammad M.,Sohrabnezhad, Samira
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experimental part
p. 6420 - 6423
(2011/12/21)
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- Ionic liquids - Promoted S-methylation of thiols utilizing dimethyl carbonate
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Convenient and efficient S-methylation of mercaptans or thiophenols occurs with dimethyl carbonate (DMC) in room temperature ionic liquids (RTILs) [Bmim]Cl. [Bmim]Cl can be recycled in four subsequent runs with only a gradual decrease in activity. A possible mechanism of this transformation is also discussed. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. Copyright Taylor & Francis Group, LLC.
- Xie, Jiangang,Wu, Chengyao,Christopher, Branford White,Quan, Jing,Zhu, Limin
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experimental part
p. 31 - 37
(2011/04/22)
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- S-methylation of N-containing heterocyclic thiols with conjugated acids of methoxy groups
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2-Mercaptopyridine-3-carboxylic acid reacts with methanol under acidic conditions to afford the corresponding S-methylated methyl ester, methyl 2-methylthiopyridine-2-carboxylate. Such S-methylation occurred for various N-containing heterocyclic thiols wi
- Shimizu, Masao,Shimazaki, Teruaki,Kon, Yoshihiro,Konakahara, Takeo
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experimental part
p. 413 - 420
(2010/09/05)
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- An easy and fast ultrasonic selective S-alkylation of hetaryl thiols at room temperature
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A series of 2-alkylthio derivatives of hetaryl thiols were synthesized by selective S-alkylation with alkyl halides (bromides and iodides) with ultrasonic irradiation at room temperature. The reaction was found to be generally applicable to hetaryl thiol derivatives with different substituents in the aromatic nucleus and various alkyl halides. The reaction gives high to excellent yields of products with high purity.
- Deligeorgiev, Todor,Kaloyanova, Stefka,Lesev, Nedyalko,Vaquero, Juan J.
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experimental part
p. 783 - 788
(2011/10/09)
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- Enzymatic synthesis of novel chiral sulfoxides employing Baeyer-villiger monooxygenases
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Optically active sulfoxides are compounds of high interest in organic chemistry. Herein, we report the preparation of a set of chiral heteroaryl alkyl, cyclohexyl alkyl, and alkyl alkyl sulfoxides by using enantioselective sulfoxidation reactions employing three Baeyer-Villiger monooxygenases (BVMOs). Careful selection of the reaction conditions, starting sulfide, and biocatalyst can be used to achieve good to excellent enantiomeric excess values. Thus, valuable chiral synthons can be obtained by performing the reactions under mild and environmentally friendly conditions. The most promising biotransformations that employ a BVMO cell-free extract preparation have been developed on a 250-mg scale to give the chiral sulfoxides in high yields in most of the reactions. Copyright
- Rioz-Martinez, Ana,De Gonzalo, Gonzalo,Pazmino, Daniel E. Torres,Fraaije, Marco W.,Gotor, Vicente
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experimental part
p. 6409 - 6416
(2011/02/24)
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- Discovery of small molecule benzimidazole antagonists of the chemokine receptor CXCR3
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High-throughput screening identified a low molecular weight antagonist of CXCR3 displaying micromolar activity in a membrane filtration-binding assay. Systematic modification of the benzimidazole core and tethered acetophenone moiety established tractable SAR of analogs with improved physicochemical properties and sub-micromolar activity across both human and murine receptors.
- Hayes, Martin E.,Wallace, Grier A.,Grongsaard, Pintipa,Bischoff, Agnieszka,George, Dawn M.,Miao, Wenyan,McPherson, Michael J.,Stoffel, Robert H.,Green, David W.,Roth, Gregory P.
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p. 1573 - 1576
(2008/09/21)
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- A new method of synthesis of triazolobenzimidazole
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Condensation between dipole 1,3 and 2-alkylthiobenzimidazole was studied. We obtained some compounds derived from triazolobenzimidazole. All the molecules were characterized by 1H NMR, IR, mass and X-rays.
- Zniber, Rachid,Moussaif, Ahmed,Achour, Redouane,Ghoul, Mostafa E.L.,Hakam, Asmae,Souhassou, Mohamed
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p. 157 - 161
(2007/10/03)
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- A practical one pot synthesis of 2-[2-(pridylmethyl)-thio]-1H-benzimidazoles
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A combination of Et3N and pTSCl was found to be far superior than pTSCl or benzene sulfonyl chloride alone in convert ing substituted 2-picoline-N-oxides to the corresponding 2-chloromethylpyridines and has been exploited for the synthesis of a variety of 2-[2-(pyridylmethyl)-thio]-1H-benzimidazoles, key intermediates in the manufacture of H+/K+-ATPase inhibitors in a single pot.
- Rane,Pathak,Kaushik,Prasad Rao,Kumar, Ashok
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p. 1211 - 1217
(2007/10/03)
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- Heterocyclic substituted 2-methyl-benzimidazole antiviral agents
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The present invention concerns antiviral compounds, their methods of preparation and their compositions, and use in the treatment of viral infections. More particularly, the invention provides heterocyclic substituted 2-methylbenzimidazole derivatives for the treatment of respiratory syncytial virus infection.
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- An efficient method for the N-debenzylation of aromatic heterocycles
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The treatment of N-benzylated heterocycles with potassium tert-butoxide/DMSO and oxygen at room temperature cleanly affords N-debenzylated products in high yield. This procedure can be utilized on a variety of functionalized nitrogen-containing heterocycles such as imidazoles, benzimidazoles, pyrazoles, indazoles, carbazoles, and indoles.
- Haddach, Aubrey A.,Kelleman, Audrey,Deaton-Rewolinski, Melissa V.
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p. 399 - 402
(2007/10/03)
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- Synthesis and antiparasitic activity of 1H-benzimidazole derivatives.
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Compounds 1-18 have been synthesized and tested in vitro against the protozoa Giardia lamblia, Entamoeba histolytica and the helminth Trichinella spiralis. Inhibition of rat brain tubulin polymerization was also measured and compared for each compound. Results indicate that most of the compounds tested were more active as antiprotozoal agents than Metronidazole and Albendazole. None of the compounds was as active as Albendazole against T. spiralis. Although only compounds 3, 9 and 15 (2-methoxycarbonylamino derivatives) inhibited tubulin polymerization, these were not the most potent antiparasitic compounds.
- Valdez, Juan,Cedillo, Roberto,Hernandez-Campos, Alicia,Yepez, Lilian,Hernandez-Luis, Francisco,Navarrete-Vazquez, Gabriel,Tapia, Amparo,Cortes, Rafael,Hernandez, Manuel,Castillo, Rafael
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p. 2221 - 2224
(2007/10/03)
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- Preparation of new imidacloprid analogues
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A 3-step synthesis of the biologically active metabolites (2 and 3) of imidacloprid from aminoacetaldehyde diethyl acetal or ethylenediamine was developed. A series of new imidacloprid analogues were also prepared.
- Novak, Lajos,Hornyanszky, Gabor,Kiraly, Imre,Rohaly, Janos,Kolonits, Pal,Szantay, Csaba
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- 2-mercapto-N-(azolyl)benzenesulphonamides IV. syntheses of some 4-chloro-2-mercapto-5-methyl-N-(benzimidazol-2-yl)benzenesulphonamides derivatives with potential anticancer and anti-HIV activities
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Syntheses of 4-chloro-2-mercapto-5-methyl-N-(5-R1-6-R2-benzimidazol-2 -yl)benzenesulphonamides [II-V], their disulfides [IIa-IVa] and S,N-substituted derivatives [VI-IX] were described. The probable mechanism for the reactions was suggested. The moderate anticancer activity was observed in vitro for compounds [II-IV].
- Pomarnacka, Elzbieta,Brzozowski, Zdzislaw
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p. 215 - 221
(2007/10/03)
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- Synthesis and structure-activity relationship of new piperidinyl and piperazinyl derivatives as antiallergics
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A series of piperazinebenzothiazoles 3-5, piperazinebenzimidazoles 6-12, piperidinobenzothiazoles 14-45, piperidinobenzoxazoles 46-52 and piperidinobenzimidazoles 53-129 has been synthesized and their antiallergic activity evaluated by means of the passive cutaneous anaphylaxis (PCA) assay. Structure-activity relationships are discussed and related to classical antihistaminics. Piperidino derivatives with an aryl group linked to the nitrogen atom by an ethyl chain are the most active compounds, with ID50 1 mg/kg po. Some of these compounds are more potent antiallergics than astemizole and terfenadine.
- Orjales,Bordell,Rubio
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p. 707 - 718
(2007/10/02)
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- Synthesis of Novel 1-, 1,4- and 1,7-Substituted 2-Mercapto- and 2-Methylmercapto- Benzimidazoles: Acyclic Analogues of the HIV-1 RT Inhibitor, TIBO
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Synthetic approaches towards acyclic analogues of the HIV-1 RT inhibitor TIBO ring system, lacking either the diazepine C7 methylene, C5-N6 bond or the N1-N6 two-carbon bridge, are reported, utilizing ring opening reactions of 2-methylaziridines.A number of isomeric 2-methylmercaptobenzimidazole analogues have also been prepared, and the regiochemistry of 2-methylmercaptobenzimidazole alkylations is discussed, as a convenient route to 1,2,7-trifunctionalized benzimidazoles.
- Gardiner, John M.,Loyns, Colin R.
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p. 11515 - 11530
(2007/10/02)
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- A New Synthetic Method for the 2-Substitution of N-Unsubstituted Benzimidazoles: Formaldehyde as a Versatile Protecting Agent for Heterocyclic NH
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N-Unsubstituted benzimidazoles 1 are readily converted in a one-pot sequence into 2-substituted derivatives 2 with good overall yields.N-Protection with formaldehyde and lithiation with lithium N,N-diisopropylamide (LDA), n-butyllithium, or tert-butyllithium gives the dilithiohemiaminals 6, which readily react with a range of electrophiles at the 2-carbon.The 2-substituted 1-(lithioxymethyl)benzimidazoles 7 undergo smooth acid-catalyzed dehydroxymethylation under mild conditions to give N-unsubstituted 2-substituted benzimidazoles 2.
- Katritzky, Alan R.,Akutagawa, Kunihiko
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p. 2949 - 2952
(2007/10/02)
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- ALTERNATIVE SYNTHESES OF 3-HYDRAZINO-1,2,4-TRIAZINOBENZIMIDAZOLE: EVIDENCE FOR THE DIHYDRAZINO INTERMEDIATE
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2-S-methyl-mercapto-benzimidazole and 2-chloro-1-methoxycarbonylmethyl-benzimidazole were utilized as starting materials for the two independent synthesis of 3-Hydrazino-1,2,4-triazinobenzimidazole.The probability of the formation of a dihydrazino compound as the key intermediate in these syntheses as well as in the previously reported synthesis has been confirmed.
- Venkataratnam, R. V.,Sujatha, K.
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p. 805 - 810
(2007/10/02)
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- REACTIONS OF 1-VINYLBENZIMIDAZOLE-2-THIONE WITH ALCOHOLS AND PHENOL
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1-(α-Alkoxyethyl)- and 1-(α-phenoxyethyl)benzimidazole-2-thiones were obtained in the reaction of 1-vinylbenzimidazole-2-thione with alcohols and phenol in the presence of gaseous hydrogen chloride.It was established that partial hydrolysis of the 1-(α-alkoxyethyl)benzimidazole-2-thiones to benzimidazole-2-thione with subsequent alkylation with excess alcohol at the exocyclic sulfur atom occurs under the conditions of the investigated reaction.A convenient method for the alkylation of thiones was proposed, and a number of 2-alkylthiobenzimidazoles were synthesized.
- Abramova, N. D.,Skvortsova, G. G.,Trzhtsinskaya, B. V.
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p. 656 - 658
(2007/10/02)
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- SYNTHESIS AND VIBRATIONAL PROPERTIES OF SOME BENZAZOLE-2-SELENONES. A COMPARISON WITH THE CORRESPONDING AZOLIDINE DERIVATIVES
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Several benzazole-2-selenone compounds have been prepared and the syntheses are discussed together with those of the corresponding azolidine-2-selenones.The comparisons of the infrared spectra of each selenonic compound with the thionic isologue differ in the low frequency region, while they are very similar in the fingerprint region.This similarity can be used as a diagnostic aid in confirming the analogy in structure between sulphur and selenium compounds.
- Cristiani, Franco,Devillanova, Francesco A.,Diaz, Angelo,Verani, Gaetano
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p. 231 - 240
(2007/10/02)
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- Methylathion of Heterocyclic Compounds Containing NH, SH and/or OH Groups by Means of N,N-Dimethylformamide Dimethyl Acetal
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Methylations of heterocyclic systems, such as benzimidazole, naphthimidazole, imidazopyridine, purine, pyridine, pyrimidine, pyridazine and s-triazolopyridazine, which bore SH, NH and/or OH groups, were carried out with dimethylformamide dimethyl acetal to give the corresponding S-, N- and/or O-methyl derivatives in high yields.Selective methylation of some compounds containing both SH and NH groups took place to give first the S-methyl and subsequently the S,N-dimethyl derivatives.No side reactions, such as C-methylation, were observed.
- Stanovnik, Branko,Tisler, Miha,Hribar, Alenka,Barlin, Gordon B.,Brown, Desmond J.
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p. 1729 - 1738
(2007/10/02)
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