- Bisulfite Addition Compounds as Substrates for Reductive Aminations in Water
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Highly valued products resulting from reductive aminations utilizing shelf-stable bisulfite addition compounds of aldehydes can be made under aqueous micellar catalysis conditions. Readily available α-picolineborane serves as the stoichiometric hydride source. Recycling of the aqueous reaction medium is easily accomplished, and several applications to targets in the pharmaceutical industry are documented.
- Bailey, J. Daniel,Iyer, Karthik S.,Leahy, David K.,Li, Xiaohan,Lipshutz, Bruce H.,Thakore, Ruchita R.
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supporting information
p. 7205 - 7208
(2021/09/22)
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- Synthesis, in vitro antiprotozoal activity, molecular docking and molecular dynamics studies of some new monocationic guanidinobenzimidazoles
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A series of monocationic new guanidinobenzimidazole derivatives were prepared in a four step process starting from 2-nitro-1,4-phenylendiamine. Their antiparasitic activity against Plasmodium falciparum, Trypanosoma brucei rhodesiense, Trypanosoma cruzi and Leishmania donovani were evaluated in vitro. Two out of 20 tested monocationic compounds (7, 14) showed close activity with reference drug chloroquine against P. Falciparum. To understand the interactions between DNA minor groove and in vitro active compounds (7, 14) molecular docking studies were carried out. Stability and binding energies of DNA-ligand complexes formed by DNA with compounds 7 and 14 were measured by molecular dynamics simulations throughout 200 ns time. Root mean square deviation (RMSD) values of the ligands remained stable below 0.25 mm and root mean square fluctuation (RMSF) values of the active site residues with which it interacted decreased compared to the apo form. All compounds exhibited theoretical absorption, distribution, metabolism and excretion (ADME) profiles conforming to Lipinski's and Ghose's restrictive rules.
- Brun, Reto,Celik, Ismail,Doganc, Fatima,Eren, Gokcen,Goker, Hakan,Kaiser, Marcel
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- High-yield DL-mandelic acid synthesis process
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The invention provides a high-yield DL-mandelic acid synthesis process. The synthesis process specifically comprises the following steps: 1, treating benzaldehyde by using sodium hydrogen sulfite to obtain benzaldehyde sodium hydrogen sulfite; 2, extracting the benzaldehyde sodium hydrogen sulfite by using an organic solvent, recovering unreacted benzaldehyde in the benzaldehyde sodium hydrogen sulfite, and adding sodium cyanide after the extraction is completed to prepare mandelonitrile; 3, adding an inorganic acid, and then carrying out heating and pressure maintaining treatment to hydrolyze the mandelonitrile so as to obtain mandelic acid; and 4, purifying the mandelic acid. According to the method, the step of extracting the p-benzaldehyde sodium hydrogen sulfite salt is added, so that the probability that the product purity is reduced due to benzoin condensation is reduced, the recycled benzaldehyde can be returned to the raw material for use, and the yield can be increased in multiple rounds of reactions; and the hydrolysis process of the mandelonitrile adopts heating and pressure maintaining treatment, so that consumption of inorganic acid can be reduced, and the hydrolysis efficiency is improved.
- -
-
Paragraph 0021-0025
(2021/09/04)
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- Benzimidazole derivatives as potent and isoform selective tumor-associated carbonic anhydrase IX/XII inhibitors
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We describe the synthesis of a series of 2-arylbenzimidazole derivatives bearing sulfonamide functionality (4a–d, 7a–c and 10) as well as hydroxamic acid (15a–b), carboxylic acid (16a–b), carboxamide (17a–b) and boronic acid (22a–b and 26) functionalities, which act as human carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors. The newly synthesized benzimidazole derivatives were evaluated against 4 physiologically relevant CA isoforms (hCA I, II, IX, and XII), and especially the sulfonamide-containing benzimidazoles demonstrated intriguing inhibitory activity against tumor associated CA IX and XII with KI values in the range of 5.2–29.3 nM and 9.9–41.7 nM, respectively. Notably, compound 4c was the most potent and selective CA IX (KI = 6.6 nM) and XII (KI = 9.9 nM) inhibitor with a significant selectivity ratio over cytosolic CA I and II isoforms in the range of 3.4–25.2. In addition, compounds having hydroxamic acid (15a-b) or carboxylic acid (16a-b) functionalities resulted in greater selectivity ratios for CA IX/XII over CAI/II in the range of 4.1–121.5 although with KI values in lower micromolar potency (KIs = 0.36–0.85 μM for CA IX/XII).
- ?al??kan, Burcu,Banoglu, Erden,Gür Maz, Tu??e,Nocentini, Alessio,Supuran, Claudiu T.,Uslu, Azize Gizem
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- An efficient NaHSO3-promoted protocol for chemoselective synthesis of 2-substituted benzimidazoles in water
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An efficient protocol for chemoselective synthesis of 2-substituted benzimidazoles from a variety of aliphatic/aromatic/ heteroaryl aldehydes and o-phenylenediamine derivatives promoted by NaHSO3 in water had been developed. The amount of NaHSO3 had a great effect on the reaction selectivity of 2-substituted benzimidazole and 1,2-disubstituted benzimidazole when the reaction was carried out in water. When the amount of the NaHSO3 was more than 11 equivalents, the 2-substituted benzimidazole could be highly selectively formed as the sole product. NaHSO3 was firstly reacted with aldehyde to form the aldehyde sodium bisulfite, which reacted with o-phenylenediamine to form the 2-substituted benzimidazole and inhibited the formation of 1,2-disubstituted benzimidazole. This protocol solved the poor selectivity problem appearing in traditional method when cyclocondensation between o-phenylenediamine and aldehydes. The method also had advantage of simple work up by filtrating the single 2-substituted benzimidazole precipitates from reaction mixture at the end of the reaction without further purification. In addition, the method was applicable to both electron-rich and electron-poor starting materials, which was successfully used for synthesizing nine novel 2-substituted benzimidazole derivatives containing a 1,2,3-triazole moiety. They were characterized by NMR, IR and HRMS spectrum. Moreover, this method had been applied to a large scale synthesis of 2-substituted benzimidazole derivatives.
- Jiang, Yu-Qin,Jia, Shu-Hong,Li, Xi-Yong,Sun, Ya-Min,Li, Wei,Zhang, Wei-Wei,Xu, Gui-Qing
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p. 1265 - 1276
(2019/01/28)
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- Facile utilisation of aldehyde bisulfite adducts: Synthesis of (E)-1,2- diphenylethenes
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Background: A one-pot coupling reaction of aldehyde bisulfite adducts was developed for McMurry reaction using Zn-TiCl4 in 1,4-dioxane solvent medium. The treatment of sodium hydroxy(phenyl)methane sulfonate (2a) with TiCl4 in 1,4-dioxane favoured the deprotection of the bisulfite adduct 2a, and the in situ regeneration of benzaldehyde (1a) underwent reductive coupling to afford stilbene 3a in a relatively good yield, thus leading to an improved synthesis of a series of (E)-1,2- diphenylethenes 3. The present approach provides a new solution to the inherent instability of aldehydes and also provides a direct access to C'C bond formation for the synthesis of 1,2-diphenylethenes from aryl aldehyde bisulfite adducts. Methods: All reactions were performed at 70-80o and the synthesized compounds were characterized by IR, 1H NMR, 13C NMR, and mass spectrometric techniques. Results: The present approach provides a new solution to the instability of aldehydes and also provides a direct access to C'C bond formation for the synthesis of 1,2-diphenylethenes from aryl aldehyde bisulfite adducts. Conclusion: In the present work, we have reported an efficient method for the synthesis of 1,2- diphenylethene derivatives. Aldehydes are commonly used as the starting materials in the McMurry reaction, which affords the stilbene derivatives, the core skeleton of various valuable compounds. To increase the stability of the aldehydes, bisulfite adducts are usually employed, but the deprotection process causes loss of process efficiency. To address this issue, we developed a method based on the single-pot reaction of aromatic bisulfite adduct using TiCl4/Zn in 1,4-dioxane.
- Vinay Kumar,Jaganmohan,Sandeep Reddy,Mohanty, Sandeep,Kumar, Jaydeep,Rao, Venkateswara
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p. 109 - 114
(2017/04/03)
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- Antituberculosis agents bearing the 1,2-disubstituted benzimidazole scaffold
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Abstract: The emergence of drug-resistant strains in recent years has fueled the epidemic of tuberculosis. This necessitates the development of new chemical scaffolds to curb resistant tuberculosis for effective control of this disease. In this study, we have designed and synthesized two series of benzimidazole derivatives. Their antimycobacterial activities were initially evaluated using Mycobacterium tuberculosis H37RV strains. The most potent analog (6h) was further assessed using various drug-resistant M. tuberculosis strains. This report described the importance of benzimidazoles as new antitmycobacterial agents targeting both the M. tuberculosis H37RV as well as the drug-resistant-tuberculosis strains. The trifluoromethyl group which was essential for antimycobacterial activity was also highlighted. Graphical Abstract: Two series of benzimidazole derivatives and their antimycobacterial activities were evaluated using M. tuberculosis H37RV (MTB-H37RV) strains. Compound 6h was identified as the most potent among all synthesized compounds. The most potent analog was further assessed using various drug-resistant MTB strains. In addition, the trifluoromethyl was identified as an important substitution in giving good antimycobacterial effect. [InlineMediaObject not available: see fulltext.]
- Yeong, Keng Yoon,Ang, Chee Wei,Ali, Mohamed Ashraf,Osman, Hasnah,Tan, Soo Choon
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p. 770 - 778
(2017/03/06)
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- Synthesis of 3-Formylbenzenesulfonyl Chloride Derivatives
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A synthetic route to 3-formylbenzenesulfonyl chloride derivatives from the corresponding benzaldehydes has been developed. The key step in this procedure is the conversion of aldehyde bisulfite adducts to target compounds via a two-stage reaction in the presence of Na 2 SO 4. A series of 3-formylbenzenesulfonyl chloride derivatives were prepared by this method and identified by chemical derivatization method.
- Bao, Xuefei,Liu, Ziao,Liang, Xinjie,Song, Dake,Shi, Tao,Zhao, Xuan,Bao, Changshun,Chen, Guoliang
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p. 3165 - 3170
(2017/07/12)
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- Liquid-Liquid Extraction Protocol for the Removal of Aldehydes and Highly Reactive Ketones from Mixtures
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The reaction of the bisulfite ion with aldehydes to form charged bisulfite adducts is a well-established method for the purification of aldehydes. This reaction has been modified to create a convenient liquid-liquid extraction method for the removal of aldehydes from mixtures. The use of a water-miscible solvent allows the reaction to occur during a simple 30 s shaking protocol by increasing the contact between the bisulfite ion and the aldehyde. The introduction of an immiscible solvent allows for the extraction of the uncharged organic components away from the bisulfite adduct. The developed protocol is applicable to a wide range of aldehydes, including sterically hindered neopentyl aldehydes. Sterically unhindered cyclic and linear ketones, as well as highly electrophilic ketones, are also removed using this protocol. The mild conditions tolerate a wide range of functional groups, allowing for excellent aldehyde contaminant removal rates with high levels of recovery of the desired component.
- Boucher, Maria M.,Furigay, Maxwell H.,Quach, Phong K.,Brindle, Cheyenne S.
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p. 1394 - 1403
(2017/09/23)
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- The Development of an Effective Synthetic Route of Belinostat
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A practical synthetic route of belinostat is reported. Belinostat was obtained via a five-step process starting from benzaldehyde and including addition reaction with sodium bisulfite, sulfochlorination with chlorosulfonic acid, sulfonamidation with aniline, Knoevenagel condensation, and the final amidation with hydroxylamine. Key to the strategy is the preparation of 3-formylbenzenesulfonyl chloride using an economical and practical protocol. The main advantages of the route include inexpensive starting materials and acceptable overall yield. The scale-up experiment was carried out to provide 169 g of belinostat with 99.6% purity in 33% total yield.
- Bao, Xuefei,Song, Dake,Qiao, Xuejun,Zhao, Xuan,Chen, Guoliang
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p. 1482 - 1488
(2016/08/30)
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- Potent sirtuin inhibition with 1,2,5-trisubstituted benzimidazoles
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Two series of compounds were synthesized based on the benzimidazole scaffold. The compounds were subsequently screened for their SIRT1, SIRT2 and SIRT3 activities. Three of the compounds showed good inhibitory activity against SIRT2 in this study with the most potent compound (5i) having an IC50 value of 2.9 μM. Molecular docking analysis demonstrated that 5i was able to inhibit SIRT2 by displacing the co-factor NAD+ in the active site. This was further confirmed experimentally by ligand-NAD+ competitive assay.
- Yoon,Osman,Choon
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p. 2094 - 2099
(2016/11/18)
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- Quantitative and highly selective sensing of sodium houttuyfonate via long-aliphatic chains hydrophobic assembly and aggregation-induced emission
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A new α-cyanostilbene derivative, CDB-DMA12, was designed and synthesized as a supramolecular chemosensor for the detection of sodium houttuyfonate (SH) via aggregation-induced emission enhancement (AIEE), which could efficiently bind with SH, then induce an obvious fluorescence enhancement and visible absorption red-shifting (by the naked eye). Accordingly, a linear relationship was found when plotting the fluorescence intensity at 558 nm against SH concentration, with an estimated detection limit of 8.5 μM. Interestingly, morphology changes from nanoparticles to sheet, scroll and tube-shaped aggregates were observed on CDB-DMA12 after the addition of SH. Moreover, CDB-DMA12 showed high selectivity to SH among other sulfonyl containing species, which is attributed to the synergistic effect of its quaternary ammonium, the hydrogen bonding of the active group sites and the twelve carbon containing long-aliphatic chain units. In addition, the results paved a new way for the detection/recognition of amphiphilic natural products in aqueous solution with high sensitivity and selectivity. Besides, it provided a possible approach for the preparation of new fluorescent micro/nano-scaled architectures through the solution self-assembly of oppositely-charged amphiphiles.
- Yu, Feifei,Yang, Yunxu,Wang, Aizhi,Hu, Biwei,Luo, Xiaofei,Sheng, Ruilong,Dong, Yajun,Fan, Weiping
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p. 9743 - 9751
(2015/12/01)
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- Reduction of Weinreb amides to aldehydes under ambient conditions with magnesium borohydride reagents Dedicated to the memory of Professor Sheldon Shore
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Chloromagnesium dimethylaminoborohydride (ClMg+ [H3BNMe2]-, MgAB) is an analogue of the versatile lithium dialkylaminoborohydrides (LAB reagents), prepared by the reaction of dimethylamine-borane with methylmagnesium chloride. MgAB is a partial reducing agent for Weinreb amides under ambient conditions and is complementary to the commonly utilized lithium aluminum hydride (LiAlH4) and diisobutylaluminum hydride (DIBAL) reagents, while exhibiting enhanced chemoselectivity. To prevent over-reduction, the aldehyde products are readily isolated in good yields by forming the sodium bisulfite adducts. Aldehyde products can both be stored and later used as the bisulfite adducts, or can be regenerated from the bisulfite adducts by treatment with aqueous formaldehyde.
- Bailey, Christopher L.,Clary, Jacob W.,Tansakul, Chittreeya,Klabunde, Lucas,Anderson, Christopher L.,Joh, Alexander Y.,Lill, Alexander T.,Peer, Natalie,Braslau, Rebecca,Singaram, Bakthan
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supporting information
p. 706 - 709
(2015/01/30)
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- Synthesis and evaluation of antimycobacterial activity of new benzimidazole aminoesters
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Abstract A total of 51 novel benzimidazoles were synthesized by a 4-step reaction starting from basic compound 4-fluoro-3-nitrobenzoic acid under relatively mild reaction conditions. The structure of the novel benzimidazoles was confirmed by mass spectra as well as 1H NMR spectroscopic data. Out of the 51 novel synthesized compounds, 42 of them were screened for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain using BacTiter-Glo Microbial Cell Viability (BTG) method. Results of activity screened using Alamar Blue method was also provided for comparison purposes. Two of the novel benzimidazoles synthesized showed moderately good activity with IC50 of less than 15 μM. Compound 5g, ethyl 2-(4-(trifluoromethyl)phenyl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazole-5-carboxylate, was found to be the most active with IC50 of 11.52 μM.
- Yoon, Yeong Keng,Ali, Mohamed Ashraf,Wei, Ang Chee,Choon, Tan Soo,Ismail, Rusli
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p. 614 - 624
(2015/03/18)
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- Direct reductive alkylation of amine hydrochlorides with aldehyde bisulfite adducts
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A mild procedure for the direct reaction of aromatic and aliphatic aldehyde bisulfite adducts with primary and secondary amine hydrochlorides in the presence of sodium cyanoborohydride in methanol is reported.
- Barniol-Xicota, Marta,Turcu, Andreea L.,Codony, Sandra,Escolano, Carmen,Vázquez, Santiago
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supporting information
p. 2548 - 2550
(2014/05/06)
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- Phosphoryl chloride mediated synthesis of 5-arylidene-2,4- thiazolidinediones derivatives via aromatic bisulfite adducts
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The carbon-carbon bond formation by the condensation of bisulfite adduct of aromatic aldehydes with thiazolidine-2, 4-dione to furnish 5-arylidene-2,4- thiazolidinedione's has been investigated. This novel methodology was applied to convert substituted aryl bisulfite adducts to corresponding 5-arylidene-2,4-thiazolidinedione's with POCl3 in less-polar solvents such as toluene, chlorobenzene and o-xylene. 5-(4-methoxybenzylidene) thiazolidine-2,4-dione and 5-(4-ethoxybenzylidene)thiazolidine-2,4-dione were obtained in good yields.
- Mohanty, Sandeep,Reddy. G, Sandeep,Karmakar, Arun Chandra
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p. 197 - 202
(2014/05/20)
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- Synthesis and evaluation of novel benzimidazole derivatives as sirtuin inhibitors with antitumor activities
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A total of 15 novel benzimidazole derivatives were designed, synthesized and evaluated for their SIRT1 and SIRT2 inhibitory activity. All compounds showed better inhibition on SIRT2 as compared to SIRT1. Among these, compound 5j displayed the best inhibitory activity for SIRT1 (IC50 = 58.43 μM) as well as for SIRT2 (IC50 = 45.12 μM). Cell cytotoxicity assays also showed that compound 5j possesses good antitumor activity against two different cancer cell lines derived from breast cancer (MCF-7 and MDA-MB-468). A simple structure-activity-relationship (SAR) study of the newly synthesized benzimidazole derivatives was also discussed.
- Yoon, Yeong Keng,Ali, Mohamed Ashraf,Wei, Ang Chee,Choon, Tan Soo,Osman, Hasnah,Parang, Keykavous,Shirazi, Amir Nasrolahi
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p. 703 - 710
(2014/01/23)
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- Counterion effects in the preparation of aldehyde-bisulfite adducts
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The identification and development of an aldehyde-bisulfite adduct as an isolable starting material in the synthesis of the CETP inhibitor Evacetrapib are described. The physical properties of the sodium and potassium analogs are compared, and the extension of the scope of this study to include an investigation into the solid state properties of a range of sodium and potassium bisulfite adducts of commonly encountered aldehydes is discussed.
- Kissane, Marie G.,Frank, Scott A.,Rener, Gregory A.,Ley, Christopher P.,Alt, Charles A.,Stroud, Paul A.,Vaid, Radhe K.,Boini, Sathish K.,McKee, Laura A.,Vicenzi, Jeffrey T.,Stephenson, Gregory A.
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supporting information
p. 6587 - 6591
(2013/11/19)
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- Direct reductive amination of aldehyde bisulfite adducts induced by 2-picoline borane: Application to the synthesis of a DPP-IV inhibitor
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Aldehyde-bisulfite adducts dervied from unstable parent aldehydes were reductively alkylated in a direct fashion with a variety of amines. This approach features the use of 2-picoline borane as the reducing agent and a protic solvent for the reaction media and has been successfully applied to the synthesis of a DPP-IV inhibitor and a variety of other amines.
- Faul, Margaret,Larsen, Rob,Levinson, Adam,Tedrow, Jason,Vounatsos, Filisaty
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p. 1655 - 1659
(2013/03/28)
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- Synthesis, p38 kinase inhibitory and anti-inflammatory activity of new substituted benzimidazole derivatives
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P38 mitogen activated protein kinases have been found to involve in the production and release of unwarranted levels of pro-inflammatory cytokines including TNFα and IL-1β in numerous inflammatory diseases. A new series of molecules, 5-substituted benzoylamino-2-substituted phenylbezimidazoles has been synthesized from 4-nitro-1, 2-diaminobenzene. The synthesized compounds were characterized by FTIR, 1HNMR and Mass. The final compounds were screened for in vitro p38 kinase inhibitory and in vivo anti-inflammatory activity. Three compounds from the series demonstrated nearly 50percent inhibition of p38 kinase in the in vitro screening method at 10 μM concentration and two molecules exhibited greater than 75percent inhibition of paw oedema volume during the first hour. The docking study of synthesized molecule revealed a new binding pose in ATP binding pocket.
- Kulkarni, Ravindra G.,Laufer, Stefan A.,Chandrashekhar,Garlapati, Achaiah
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- Benzimidazole derivatives: Synthesis, leishmanicidal effectiveness, and molecular docking studies
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Leishmanolysin GP63 is a zinc metalloprotease, expressed at the surface of Leishmania promastigotes. Studies on this protein are hindered as only a limited number of effective non-toxic inhibitors of this drug target are known. Present study describes the identification of a variety of 2-aryl- and 5-nitro-2-arylbenzimidazoles as new GP63 inhibitors. All the compounds were tested for in vitro activity against the promastigote form of Leishmania major and showed very good activity. 2-(Thiophen-2-yl)-1H-benzimidazole (19) and 2-(1H-indol-3-yl)-5-nitro-1H-benzimidazole (34) with IC50 value of 0.62 μg/mL were identified as lead of this library. Molecular docking studies were performed on binding site of GP63 to study the binding mode of compounds. The results of both in vitro and in silico studies clearly indicated that benzimidazoles may serve as new drug candidates in the combat against leishmaniasis.
- Shaukat, Awais,Mirza, Hira M.,Ansari, Amna H.,Yasinzai, Masoom,Zaidi, Sohail Z.,Dilshad, Sana,Ansari, Farzana L.
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p. 3606 - 3620
(2013/07/26)
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- Synthesis, characterization, and molecular docking analysis of novel benzimidazole derivatives as cholinesterase inhibitors
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Two series of novel acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors containing benzimidazole core structure were synthesized by a four-step reaction pathway starting from 4-fluoro-3-nitrobenzoic acid as the basic compound. The structure of the novel benzimidazoles was characterized and confirmed by the elemental and mass spectral analyses as well as 1H NMR spectroscopic data. Of the 34 novel synthesized compounds, three benzimidazoles revealed AChE inhibition with IC50 10 lM. The highest inhibitory activity (IC50 = 5.12 lM for AChE and IC50 = 8.63 lM for BChE) corresponds to the compound 5IIc (ethyl 1-(3-(1H-imidazol-1-yl)propyl)-2- (4-nitrophenyl)-1H-benzo[d]imidazole-5-carboxylate). The relationship between lipophilicity and the chemical structures as well as their limited structure-activity relationship was discussed.
- Yoon, Yeong Keng,Ali, Mohamed Ashraf,Wei, Ang Chee,Choon, Tan Soo,Khaw, Kooi-Yeong,Murugaiyah, Vikneswaran,Osman, Hasnah,Masand, Vijay H.
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- Microwave-assisted synthesis of sec/tert-butyl 2-arylbenzimidazoles and their unexpected antiproliferative activity towards ER negative breast cancer cells
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A new series of N-sec/tert-butyl 2-arylbenzimidazole derivatives was synthesised in 85-96% yields within 2-3.5min by condensing ethyl 3-amino-4-butylamino benzoate with various substituted metabisulfite adducts of benzaldehyde under focused microwave irradiation. The benzimidazole analogues were characterised using 1H NMR, 13C NMR, high resolution MS and melting points. Evaluation of antiproliferative activity of the benzimidazole analogues against MCF-7 and MDA-MB-231 revealed several compounds with unexpected selective inhibitions of MDA-MB-231 in micromolar range. All analogues were found inactive towards MCF-7. The most potent inhibition against MDA-MB-231 human breast cancer cell line came from the unsubstituted 2-phenylbenzimidazole 10a.
- Abdul Rahim, Aisyah Saad,Muhamad Salhimi, Salizawati,Arumugam, Natarajan,Pin, Lim Chung,Yee, Ng Shy,Muttiah, Nithya Niranjini,Keat, Wong Boon,Abd. Hamid, Shafida,Osman, Hasnah,Mat, Ishak B.
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p. 1255 - 1260
(2013/12/04)
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- 5-Acetyl-2-arylbenzimidazoles as antiviral agents. Part 4
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Within a project aimed at discovering new Flaviviridae inhibitors, new variously substituted 2-phenylbenzimidazoles were synthesized and evaluated in cell-based assays for cytotoxicity and antiviral activity against viruses representatives of the three genera of the Flaviviridae family, i.e.: Pestivirus (BVDV), Flavivirus (YFV) and Hepacivirus (HCV). Title compounds were also tested against RNA viruses representative of other single-stranded, positive-sense (ssRNA+) negative-sense (RNA-), or double-stranded (dsRNA) genomes, as well as against representatives of two DNA virus families. Nine compounds showed activity against BVDV (EC50 = 0.8-8.0 μM), compound 31 being the most potent (EC50 = 0.80 μM) and selective (SI = CC50/EC50 = >100). When tested in an HCV replicon assay, compound 31 resulted again the most potent, displaying an EC50 value of 1.11 μM and an SI of 100. Besides inhibiting BVDV, two compounds (35 and 38) showed a moderate activity also against YFV (EC 50 = 13 μM). Interestingly, 35 was moderately active also against RSV (EC50 = 25 μM).
- Vitale, Gabriella,Corona, Paola,Loriga, Mario,Carta, Antonio,Paglietti, Giuseppe,Giliberti, Gabriele,Sanna, Giuseppina,Farci, Pamela,Marongiu, Maria Elena,La Colla, Paolo
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body text
p. 83 - 97
(2012/08/08)
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- Straightforward synthesis of novel 1-(2'-α-O-D-glucopyranosyl ethyl) 2-arylbenzimidazoles
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A series of novel 1-(2'-α-O-D-glucopyranosyl ethyl) 2-arylbenzimidazoles has been prepared via one-pot glycosylation of ethyl-1-(2'-hydroxyethyl)-2-arylbenzimidazole- 5-carboxylate derivatives. Synthesis of the 2-arylbenzimidazole aglycones from 4-fluoro-3- nitrobenzoic acid was accomplished in four high-yielding steps. The reduction and cyclocondensation steps for the aglycone synthesis proceeded efficiently under microwave irradiation to afford the appropriate benzimidazoles in excellent yields within 2-3 min. Glycosylation of the hydroxyethyl aglycones with the perbenzylated 1-hydroxyglucopyranose, pretreated with the Appel-Lee reagent, followed by catalytic hydrogenolysis delivered the desired 1-(2'-α-O-D- glucopyranosyl ethyl) 2-arylbenzimidazoles in a simple and straightforward manner.
- Arumugam, Natarajan,Rahim, Aisyah Saad Abdul,Hamid, Shafida Abd,Osman, Hasnah
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p. 9887 - 9899
(2012/11/13)
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- Novel clarithromycin analogs with C-4′′ 2-arylbenzimidazolyl bishydrazide side chain: Synthesis and antibacterial evaluation
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A series of novel 4′′-O-2-arylbenzimidazolyl derivatives of clarithromycin were synthesized and evaluated. These 4′′-O-2- arylbenzimidazolyl derivatives demonstrated excellent activity against erythromycin-susceptible strains and showed remarkably improved activity against erythromycin-resistant strains compared with the references. In particular, compound 7c, which possesses the terminal 2-(2-methoxyphenyl)benzimidazolyl group on the C-4′′ bishydrazide side chain, not only presented the most potent activity against erythromycin-susceptible Streptococcus pneumoniae ATCC49619 and Staphylococcus aureus ATCC25923, exhibiting 4-fold and 4-fold higher efficacy than the parent clarithromycin, but also displayed the highest activity against erythromycin-resistant Streptococcus pneumoniae expressing the mef gene and the erm gene, which was 133-fold and 32-fold better than clarithromycin or azithromycin, respectively.
- Qi, Yunkun,Ma, Ruixin,Li, Xin,Hu, Yue,Ma, Siti,Cong, Chao,Ma, Xiaodong,Cui, Wenping,Ma, Shutao
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experimental part
p. 966 - 971
(2012/07/01)
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- Expedient reductive animation of aldehyde bisulfite adducts
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A novel, one-pot protocol for the direct reductive animation of aldehyde bisulfite adducts is reported. Bisulfite adducts of aliphatic and aromatic aldehydes, on treatment with an organic base under non-aqueous conditions liberate the aldehyde in situ, which then undergoes efficient reductive amination with amines in the presence of sodium triacetoxyborohydride.
- Pandit, Chennagiri R.,Mani, Neelakandha S.
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experimental part
p. 4032 - 4036
(2010/03/24)
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- Complete switch of migratory aptitude in aluminum-catalyzed 1,2-rearrangement of differently α,α-disubstituted a-siloxy aldehydes
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(Chemical Equation Presented) Control of the migration tendency: The regiodivergent 1,2-rearrangement of asiloxy aldehydes bearing α-aryl and α-alkyl substituents into α-siloxy ketones has been realized by using different aluminum Lewis acid catalyst/solvent systems (see scheme). The scope of this unprecedented protocol has been investigated with various substrates and clearly demonstrates its utility for the selective synthesis of two structural isomers from one substrate.
- Ohmatsu, Kohsuke,Tanaka, Takayuki,Ooi, Takashi,Maruoka, Keiji
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supporting information; experimental part
p. 5203 - 5206
(2009/04/11)
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- A novel and efficient synthesis of 3-aryl and 3-heteroaryl substituted-1H-indazoles and their Mannich derivatives
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A general and highly convenient procedure for the synthesis of 3-heteroaryl and 3-aryl substituted-1H-indazoles has been developed. These compounds (3a-f) were synthesized in good yield by refluxing the NaHSO3 adduct of heteroaromatic and aromatic aldehyde and phenyl hydrazine in DMF. This procedure is more general and shorter than earlier methods. Five new 3-hetero-aryl substituted-1H-indazoles were synthesized and characterized. New Mannich derivatives of 3-(1H-pyrrol-2-yl)-1H-indazole (3a) and 3-(1H-indol-3-yl)-1H-indazole (3b) were prepared from morpholine and formaldehyde.
- Servi, Sueleyman,Akguen, Z. Ruestem
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p. 3399 - 3405
(2007/10/03)
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- The efficient synthesis of 2-arylamino-2-imidazolines, 2-heteroaryl- substituted benzimidazoles, and their morpholin-4-ylmethyl derivatives
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2-Heteroaryl-substituted 1H-benzimidazoles were synthesized in good yields by heating the HSO3 adducts of heteroaromatic aldehydes with o-phenylenediamine in DMF under reflux. This procedure is more general and shorter than earlier methods. 2-Arylamino-2-imidazolines were prepared by heating dimethyl aryldithioimidocarbonates and ethylenediamine under reflux. The imine-enamine tautomerization of 2-arylamino-2-imidazolines was investigated by means of 1H-NMR spectroscopy. Morpholin-4-ylmethyl derivatives of the benzimidazole and imidazoline products were synthesized regioselectively by treatment with morpholine and formaldehyde.
- Servi, Sueleyman
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p. 119 - 123
(2007/10/03)
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- Synthese d'α-Hydroxysulfinates
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α-hydroxysulfinates 1 (table 1) are synthesized (path b, Fig. 1), by slowly adding aldehydes 3 to the mixture sodium dithionite 4 - sodium hydroxide.Owing to their limited stability the products 1 are readily separated from sodium sulfite 5 and isolated.They are easily distinguished (table 2) from their oxydation counterparts 2.
- Mulliez, Michel,Naudy, Carole
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p. 2469 - 2476
(2007/10/02)
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- Kinetics, Thermodynamics, and Mechanism of the Formation of Benzaldehyde-S(IV) Adducts
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The kinetics and mechanism of the formation of α-hydroxyphenylmethanesulfonate (HPMS) by the addition of bisulfite to benzaldehyde were studied at low pH.A three-term rate law was observed as d/dt = (k1α2 + (k2 + k3KH- (H+))α1)t where α1 = ->/, α2 = 2->/, and KH is the proton association constant of benzaldehyde.The rate-limiting steps of each term appeared to be the nucleophilic attack of SO32- on the carbonyl carbon of benzaldehhyde, the attack of HSO3- on the carbonyl carbon, and the attack by HSO3- on the protonated carbon of the carbocation, C6H5C+H(OH), respectively.Over the pH range of most natural systems, only the k1 and k2 steps contribute to adduct formation while the k3 term becomes important for pH 1 = (2.15 +/- 0.09) * 104 M-1 s-1, k2 = (0.71 +/- 0.03) M-1 s-1, k3 ca./= 2.5 * 107 M-1 s-1.Para-substitution on the benzaldehyde ring resulted in a slight increase in reactivity for p-NO2- and p-Cl-, and a decrease for p-OH-, p-OCH3-, and p-CH3-C6H5CHO.The equilibrium association constant, K = ->/-> , at 25 deg C was determined to be 4.8 (+/-0.8) * 103 at μ = 0.1 M and 0.98 (+/-0.11) * 103 M-1 at μ = 1.0 M. ΔH deg and ΔS deg were determined to be -64.6 kJ mol-1 and -146 J mol-1 deg-1, respectively.
- Olson, Terese M.,Boyce, Scott D.,Hoffmann, Michael R.
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p. 2482 - 2488
(2007/10/02)
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- Metabolites of the Higher Fungi. Part 19. Serpenone, 3-Methoxy-4-methyl-5-prop-1-enylfuran-2(5H)-one, a new γ-Butyrolactone from the Fungus Hypoxylon serpens (Barrons strain) (Persoon ex Fries)Kickx
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Culture solutions of the fungus Hypoxylon serpens (Barrons strain) contain a new butyrolactone as the major metabolite, which has been identified as 3-methoxy-4-methyl-5-prop-1-enylfuran-2(5H)-one (2),and small quantities of the reduced analogue, 3-methoxy-4-methyl-5-propylfuran-2(5H)-one (3); the structures have been established by synthesis of compound (3).A new rapid synthesis of the isomeric 4-methoxy-3,5-disubstituted analogues is described and the two groups of compounds are compared spectroscopically.
- Anderson, John R.,Edwards, Raymond L.,Whalley, Anthony J. S.
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p. 215 - 222
(2007/10/02)
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- Nucleophilic Addition to Double Bond Systems, II. Kinetics of the Reaction of Sulfit with Aromatic Aldehydes
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The rate constants of the addition of sulfit to aromatic aldehydes have been measured directly at pH=7 using stopped flow and temperature jump methods. - Keywords: Aromatic aldehydes; Nucleophile addition; Stopped flow; Temperature jump.
- Basu, Sukumar,Schuster, Peter,Wolschann, Peter
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p. 421 - 428
(2007/10/02)
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- A NOVEL AND VERSATILE SEPARATION METHOD FOR ALDEHYDES
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An aqueous solution of sodium ε-amino-n-caproate can be used for efficient and simple separation of aldehydes, overcoming the difficulties associated with the NaHSO3 method.Keywords - separation of aldehydes; Schiff base of amino acid; ω-amino acid; sodium ε-amino-n-caproate; sodium bisulfite adduct of aldehydes
- Ohta, Shunsaku,Okamoto, Masao
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p. 1917 - 1919
(2007/10/02)
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