- Half-sandwich Iridium(III) Benzimidazole-Appended Imidazolium-Based N-heterocyclic Carbene Complexes and Antitumor Application
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A series of half-sandwich iridium(III) benzimidazole-appended imidazolium-based N-heterocyclic carbene (NHC) antitumor complexes [(η5-Cpx)Ir(C^N)Cl]Cl, where Cpx is pentamethylcyclopentadienyl (Cp*) or its biphenyl derivative (Cpxbiph) and C^N is a NHC chelating ligand, were successfully synthesized and characterized. The IrIII complexes showed potential antitumor activity against A549 cells, at most three times more potent than cis-platin under the same conditions. Complexes could bind to BSA by a static quenching mode, catalyzing the change of NADH to NAD+ and inducing the production of reactive oxygen species (maximum turnover number, 9.8), which play an important role in regulating cell apoptosis. Confocal microscopy showed that the complexes could specifically target lysosomes in cells with a Pearson's co-localization coefficient 0.76 and 0.72 after 1 h and 6 h, respectively, followed an energy-dependent cellular uptake mechanism and damaged the integrity of lysosomes. At the same time, complexes caused a marked loss of mitochondrial membrane potential.
- Han, Yali,Liu, Xicheng,Tian, Zhenzhen,Ge, Xingxing,Li, Juanjuan,Gao, Min,Li, Yanru,Liu, Yi,Liu, Zhe
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- Synthesis of 1-alkyl-2-chloromethylbenzimidazole under green conditions
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A green approach for the synthesis of 1-alkyl-2-chloromethylbenzimidazoles (3) (R1 = CH3, C2H5, CH2Ph) under, different conditions has been developed from 2-chloromethylbenzimidazole (2) by reaction with an alkylating agent (i.e. DMS, DES, PhCH2Cl) by physical grinding or by using green solvent like PEG-600 or by using micro-wave irradiation technique.
- Rao, S. Srinivas,Reddy, Ch. Venkata Ramana,Dubey
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- Dicopper(II) complexes of chiral C2-symmetric diamino-bis(2-methylpyridyl) and diamino-bis(2-methylbenzimidazolyl) ligands
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Reaction of the chiral ligands (1S,4S)-2,5-bis(6-methylpyridyl)- diazabicyclo[2.2.1]heptane (L1), and (1S,4S)-2,5-bis(2- methylbenzimidazolyl)-diazabicyclo[2.2.1]heptane (L2) with copper(II) acetate results in the hydroxo-bridged dic
- Pérez, Viridiana,Monsalvo, Iván,Demare, Patricia,Gómez-Vidales, Virginia,Regla, Ignacio,Castillo, Ivan
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- Structure, magnetism and reactivity of a {MnIII(μ-O)2MnIV}3+ core towards oxidation of phenols
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Two complexes [(L)2MnII(OClO3)(CH3CN)](ClO4)·CH3CN (1) and [(L)4MnIII/IV 2(μ-O)2](ClO4)3·2CH3CN·Et2O (2), where L is 2-((1H-pyrazol-1-yl)methyl)-1-methyl-1H-benzimidazole, have been synthesized, structurally characterized, UV–Vis and EPR spectral properties, variable-temperature (2–300 K) magnetic susceptibility and redox behavior investigated. Structural analysis reveals that the {MnIII(μ-O)2MnIV}3+ core in 2 is an example of delocalized class III system. Complex 1 has S = 5/2 ground-state. The MnIII and MnIV centres in 2 are antiferromagnetically coupled (J = ?192 cm?1) and has S = 1/2 ground-state. Complex 2 exhibits characteristic 16-line EPR spectrum (120 K) centered at g ≈ 2. Reactivity of 2 towards p-X-2-tert-butylphenols (X = H, Me, OMe, tBu) has been investigated. The oxidation of phenols generate phenoxyl radical (2,4,6-tri-tert-butylphenol exhibits EPR signal due to radical)/radical-coupled bis-phenol product (in the case of 2,4-di-tert-butylphenol, DTBP). Kinetic experiments have allowed us to evaluate second-order rate constant values for the faster initial step (k2 × 10?2 M?1 s?1) for p-X-2-tert-butylphenols: 0.6 (X = H), 1.95 (Me), 3.0 (OMe), 1.85 (tBu) and for the slower second step (k2 × 10?3 M?1 s?1) for p-X-2-tert-butylphenols: 0.9 (X = H), 2.5 (Me), 4.0 (OMe). Reaction between {MnIII(μ-O)2MnIV}3+ of 2 and phenols proceeds via hydrogen atom transfer mechanism to produce oxidation products. Initial reaction supposedly generates {MnIII(O)(OH)MnIII}3+ species, which finally ends up as (L)-coordinated MnII species (ESI-MS spectrum for the reaction between 2 and DTBP).
- Kumar, Akhilesh,Sengupta, Arunava,Demeshko, Serhiy,Mukherjee, Rabindranath
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- Synthesis of Carbophosphinocarbene and Their Donating Ability: Expansion of the Carbone Class
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In recent years, carbones (CL2) have established themselves to be reliable ligands in organometallic and catalytic reactions. With its superb donating ability as well as a second lone pair for extra coordination, it distinguishes itself from the widely used carbenes and phosphines. However, a lack of modular structural diversity in carbones has limited its use. A carbophosphinocarbene (CPC), a subclass of carbones containing a carbene and phosphine as flanking groups, offers an easy structural modification. In this work, we report a new modular synthetic procedure for CPCs by using readily available starting materials. In addition, the phosphine moiety can be easily exchanged and directly used out of the bottle. The resulting CPCs offer a strong donating ability. Their electronic properties have been determined using Ga and Au complexes.
- Liu, Shu-Kai,Chen, Wen-Ching,Yap, Glenn P. A.,Ong, Tiow-Gan
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supporting information
p. 4395 - 4401
(2020/12/23)
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- Design, synthesis, and antitumor activity of novel benzoheterocycle derivatives as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase
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The vascular endothelial growth factor receptor-2 signaling pathway promotes the formation of new blood vessels, and vascular endothelial growth factor receptor-2 tyrosine kinase exists in both active and inactive conformations. Novel indole–benzimidazole and indole–benzothiazole derivatives joined by different linkers are designed and synthesized as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. All the synthesized compounds were evaluated for their cytotoxicity against four human cancer cell lines (HeLa, HT29, A549, and MDA-MB-435) and human umbilical vein endothelial cell. Meanwhile, the inhibitory activities against vascular endothelial growth factor receptor-2 are estimated in vitro and the binding interactions with dual conformations of vascular endothelial growth factor receptor-2 tyrosine kinase are evaluated by molecular docking. Compounds 5a–c and 14 show inhibitory activity against vascular endothelial growth factor receptor-2 tyrosine kinase and promising cytotoxicity, specifically with IC50 values ranging between 0.1 and 1 μM, which imply broad-spectrum antitumor activity. These results provide a deep insight into potential structural modifications for developing potent vascular endothelial growth factor receptor-2 tyrosine kinase inhibitors.
- Ding, Yangyang,Liu, Kai,Zhao, Xinyu,Lv, Yingtao,Yu, Rilei,Kang, Congmin
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p. 286 - 294
(2020/01/28)
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- Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility
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Following the approval of delamanid and pretomanid as new drugs to treat drug-resistant tuberculosis, there is now a renewed interest in bicyclic nitroimidazole scaffolds as a source of therapeutics against infectious diseases. We recently described a nitroimidazopyrazinone bicyclic subclass with promising antitubercular and antiparasitic activity, prompting additional efforts to generate analogs with improved solubility and enhanced potency. The key pendant aryl substituent was modified by (i) introducing polar functionality to the methylene linker, (ii) replacing the terminal phenyl group with less lipophilic heterocycles, or (iii) generating extended biaryl side chains. Improved antitubercular and antitrypanosomal activity was observed with the biaryl side chains, with most analogs achieved 2- to 175-fold higher activity than the monoaryl parent compounds, with encouraging improvements in solubility when pyridyl groups were incorporated. This study has contributed to understanding the existing structure-activity relationship (SAR) of the nitroimidazopyrazinone scaffold against a panel of disease-causing organisms to support future lead optimization.
- Ang, Chee Wei,Tan, Lendl,Sykes, Melissa L.,Abugharbiyeh, Neda,Debnath, Anjan,Reid, Janet C.,West, Nicholas P.,Avery, Vicky M.,Cooper, Matthew A.,Blaskovich, Mark A. T.
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p. 15726 - 15751
(2020/12/02)
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- Synthesis, molecular docking, α-glucosidase inhibition, and antioxidant activity studies of novel benzimidazole derivatives
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A novel series of N-methyl/benzyl-substituted benzimidazolyl-linked para-substituted benzyl-based compounds containing 2,4-thiazolidinediones, dimethyl malonate (DMM), and diethyl malonate (DEM) 17–27 were designed, docked, synthesized, and evaluated for their antidiabetic activity studies. Structures of all the synthesized compounds were confirmed through 1H NMR, 13C NMR, FTIR, and mass spectrometry. Four targeted compounds (17–18 and 22–23) showed good inhibitory potential in the range of 4.10 ± 0.01 to 9.12 ± 0.06 μM. Furthermore, synthesized compounds 17–27 were evaluated for their antioxidant potential and compared with standard ascorbic acid and results showed that compound 18 (EC50 = 0.176 ± 0.002 mM) being the most active. Compounds 17–18 and 22–23 exhibited prominent antidiabetic as well as antioxidant activity. Compound 18 was considered a promising candidate for this series. The designed molecules were docked into α-glucosidase protein (PDB Code. 3TOP) to develop a correlation with the α-glucosidase inhibition studies and were also additionally docked into PPARγ proteins (PDB ID: 2PRG) with rosiglitazone (standard drug) to study their PPARγ binding affinity in comparison with rosiglitazone and to classify these compounds for their PPARγ agonistic behavior.
- Singh, Gagandeep,Singh, Amanjot,Singh, Varinder,Verma, Raman K.,Tomar, Jyoti,Mall, Rajiv
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p. 1846 - 1866
(2020/08/03)
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- Anti-oligomerization sheet molecules: Design, synthesis and evaluation of inhibitory activities against α-synuclein aggregation
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Aggregation of α-synuclein (α-Syn) play a key role in the development of Parkinson Disease (PD). One of the effective approaches is to stabilize the native, monomeric protein with suitable molecule ligands. We have designed and synthesized a series of sheet-like conjugated compounds which possess different skeletons and various heteroatoms in the two blocks located at both ends of linker, which have good π-electron delocalization and high ability of hydrogen-bond formation. They have shown anti-aggregation activities in vitro towards α-Syn with IC50 down to 1.09 μM. The molecule is found binding in parallel to the NACore within NAC domain of α-Syn, interfering aggregation of NAC region within different α-Syn monomer, and further inhibiting or slowing down the formation of α-Syn oligomer nuclei at lag phase. The potential inhibitor obtained by our strategy is considered to be highly efficient to inhibit α-Syn aggregation.
- Liu, Hao,Chen, Li,Zhou, Fei,Zhang, Yun-Xiao,Xu, Ji,Xu, Meng,Bai, Su-Ping
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supporting information
p. 3089 - 3096
(2019/06/14)
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- High performance benzoimidazolyl-based aminophenolate zinc complexes for isoselective polymerization of: Rac -lactide
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Zinc complexes supported by achiral benzoimidazolyl-based aminophenolate ligands exhibit high catalytic activities and excellent isoselectivities toward the ring-opening polymerization of rac-lactide under mild conditions.
- Gong, Yanmei,Ma, Haiyan
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p. 10112 - 10115
(2019/08/30)
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- Enantioselective Epoxidation of Electron-Deficient Alkenes Catalyzed by Manganese Complexes with Chiral N4 Ligands Derived from Rigid Chiral Diamines
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A series of tetradentate sp2N/sp3N hybrid chiral N4 ligands derived from rigid chiral diamines were synthesized, which enabled the first manganese-catalyzed enantioselective epoxidation of electron-deficient alkenes with hydrogen peroxide (H2O2) as an oxidant. The reaction furnishes enantiomerically pure epoxy amides, epoxy ketones as well as epoxy esters in good yields and excellent enantioselectivities (up to 99.9% ee) with lower catalyst loading. Preliminary studies on structure–activity relationship demonstrated that maintaining comparatively lower electron-donating ability of the sp3N and relatively higher electron-donating ability of sp2N of the N4 ligands is beneficial to getting higher activity and selectivity, thus providing us a new view to understand epoxidation with H2O2. (Figure presented.).
- Chen, Xiangning,Gao, Bao,Su, Yijin,Huang, Hanmin
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supporting information
p. 2535 - 2541
(2017/08/16)
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- Efficient Synthesis and Biological Activity of Novel Indole Derivatives as VEGFR-2 Tyrosine Kinase Inhibitors
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A series of novel indole derivatives were synthesized as potent inhibitors for the vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase. Among those, compound 10b demonstrated the highest growth inhibition rate of 66.7% against the VEGFR-2 tyrosine kinase at 10 μM which indicates that indole-benzothiazole might be the favorable structure. The binding mode of compound 10b with VEGFR-2 tyrosine kinase was evaluated by molecular docking.
- Zhang,Xu,Wang,Kang
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p. 3006 - 3016
(2018/02/21)
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- Synthesis and antinociceptive activity of meperidine-like benzimidazole derivatives
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(Graph presented) A series of novel benzimidazole derivatives have been prepared and characterized by IR, 1H-NMR spectroscopic data and elemental analysis. All the final compounds were screened for their antinociceptive activities with tail flick test. Among the synthesized compounds 3a, 4a, 4c, 8a, 9a exhibited significant antinociceptive activity. Compound 9a was found to have the highest antinociceptive activity at both 60 minutes and 120 minutes. Additionally, compounds 3a, 4a, 8a and 9a showed naloxone-reversible antinociceptive activity.
- Ercanli, Taner,Bal, Nur Banu,?zdemir, Elif Derya,Dündar, Yasemin,Uluda?, M. Orhan,?akir, Bilge,?zden, Tuncel,?nkol, Tijen
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- Synthesis and in vitro antifungal evaluation of benzoimidazolyl-piperazinyl-phenylmethanone derivatives
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Benzimidazole and piperazines are the important pharmacophores in the structures of many antifungal compounds. Further, the phenylmethanone are also a unique class of compounds whose antifungal profile is not much exploited. So to exploit their antifungal potential we have selected these three combinations and framed the novel parent structure for our research work. In this study a novel series of benzimidazoles derivatives was synthesized by microwave irradiation and characterized by 1H NMR, 13C NMR, Infra Red (IR), and Mass Spectroscopy (MS), and by elemental analysis. The screening of compound for in vitro (turbidimetric method) antifungal activity against C.albicans revealed activity in many of the compounds as comparable to that of ketoconazole.
- Kankate, Rani S.,Gide, Parag S.,Belsare, Deepak P.
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p. 1855 - 1863
(2015/04/22)
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- Synthesis and antifungal activity of 2-chloromethyl-1 H -benzimidazole derivatives against phytopathogenic fungi in vitro
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A series of 35 benzimidazole derivatives were synthesized from 2-chloromethyl-1H-benzimidazole in good yields. Their structures were characterized by 1H and 13C NMR and HRESIMS. Antifungal activities of all of the synthesized compounds were evaluated against five phytopathogens fungi (Cytospora sp., Colletotrichum gloeosporioides, Botrytis cinerea, Alternaria solani, and Fusarium solani) using the mycelium growth rate method. Compound 4m displayed strong growth inhibition of C. gloeosporioides, A. solani, and F. solani with IC50 of 20.76, 27.58, and 18.60 μg/mL, respectively. Selective inhibition of B. cinerea instead of the other fungal pathogenes was observed with 7f (IC50 of 13.36 μg/mL), comparable to that of positive control, a commercial agricultural fungicide hymexazol (IC50 of 8.92 μg/mL). Compound 5b exhibited remarkable antifungal properties against Cytospora sp., C. gloeosporioides, B. cinerea, and F. solani with IC50 values of 30.97, 11.38, 57.71, and 40.15 μg/mL, respectively; among the target fungi, 5b was the most active compound and superior to the reference against C. gloeosporioides alone. Structure-activity relationship (SAR) data of these compounds are as follows: (1) introduction of the chlorine atom on para-position in the benzene ring help to increase activity (4f vs 4c; 7f vs 7n), (2) the sulfonyl group is critical for the inhibition of C. gloeosporioides (5b and 5c vs 5a), and (3) the unsubstituted benzene ring improve activity (4m vs 4n, 4e and 4a). Thus, compounds 5b, 4m, and 7f emerged as a new leading structure for the development of new fungicides.
- Bai, Yu-Bin,Zhang, An-Ling,Tang, Jiang-Jiang,Gao, Jin-Ming
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p. 2789 - 2795
(2013/06/04)
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- Design and synthesis of benzimidazole-linked meta-substituted benzylidenes/benzyls as biologically significant new chemical entities
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meta-Linked thiazolidinedione (TZD)-and diethyl malonate (DEM)-based benzylidenes and methyl acetoacetate (MAA)-based benzyl moieties linked to the 2-position of N-methyl benzimidazole were synthesized. TZD-and DEM-based compounds were synthesized by condensation of 2,4-thiazolidinedone and DEM respectively with the corresponding 3-substituted benzaldehyde, whereas MAA-based compounds were obtained by halogen displacement with the corresponding 3-substituted phenol. These new chemical entities were designed to provide a balanced agonism at the peroxisome proliferator activated receptor alpha/gamma (PPARα/γ) in the management of type 2 diabetes: a move from glitazones to selective PPARγ modulators (SPPARγMs). Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.
- Verma, Raman K.,Mall, Rajiv,Ghosh, Prithwish,Kumar, Vijay
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supporting information
p. 1882 - 1895
(2013/06/04)
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- DNA switches on the two-photon efficiency of an ultrabright triphenylamine fluorescent probe specific of at regions
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We report on the design and synthesis of two-photon fluorescent triphenylamines bearing two or three vinyl branches terminated by a N-methyl benzimidazolium moiety. The new compounds (TP-2Bzim, TP-3Bzim) are light-up fluorescent DNA probes with a long wavelength emission (>580 nm). Compared to their pyridinium models, the TP-Bzim dyes exhibit a remarkable improvement of both their DNA affinity and fluorescence quantum yield, especially for the two-branch derivative (TP-2Bzim: ΦF = 0.54, Ka = 107 M-1), resulting in a large fluorescence emission turn-on ratio of up to 140. Concomitantly, the two-photon absorption cross-section of TP-2Bzim is dramatically enhanced upon DNA binding (δ = 1080 vs 110 GM for the free form). This effect of the DNA matrix on the nonlinear absorption is uncovered for the first time. This is attributed to a tight fit of the molecule inside the minor groove of AT-rich DNA which induces geometrical rearrangements in the dye ground state as supported by circular dichroism and molecular modeling data. Consequently, TP-2bzim displays an exceptional two-photon molecular brightness (δ×ΦF = 583 GM), a value unrivalled for a small biofluorophore. These properties enable to image nuclear DNA in fixed cells at submicromolar concentration ([TP-2Bzim] = 100 nM) and to visualize ultrabright foci of centromeric AT-rich chromatin. Finally TP-2Bzim exhibits a high photostability, is live-cell permeant, and does not require RNase treatment. This outstanding combination of optical and biological properties makes TP-2Bzim a bioprobe surpassing the best DNA stainers and paves the way for studying further nonlinear optical processes in DNA.
- Dumat, Blaise,Bordeau, Guillaume,Faurel-Paul, Elodie,Mahuteau-Betzer, Florence,Saettel, Nicolas,Metge, Germain,Fiorini-Debuisschert, Celine,Charra, Fabrice,Teulade-Fichou, Marie-Paule
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p. 12697 - 12706
(2013/09/23)
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- Heterocyclyl linked anilines and benzaldehydes as precursors for biologically significant new chemical entities
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Benzylidene and benzyl thiazolidinediones, oxazolidinediones, isoxazolidinediones and their acyclic analogs like alpha alkylthio/alkoxy phenylpropanoic acids, beta-keto esters and tyrosine-based compounds possess broad therapeutic potential in general and as Peroxisome Proliferator Activated Receptors (PPARs) agonists in particular in the management of hyperglycemia and hyperlipidaemia for the treatment of Type 2 Diabetes (T2D). We have synthesised and characterized some novel and suitably substituted heterocyclyl linked benzaldehydes and anilines, which can be easily and very readily derivatized to all the above mentioned classes to generate new chemical entities of broader biological significance. Synthesis of their benzylidene thiazolidinedione and diethyl malonate and also benzyl diethyl malonate and alpha-bromoesters derivatives is reported in some of the cases in the present work. Indian Academy of Sciences.
- Verma, Raman K.,Kumar, Vijay,Ghosh, Prithwish,Wadhwa, Lalit K.
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p. 1063 - 1069
(2013/03/13)
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- HETEROCYCLIC MGLU5 ANTAGONISTS
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Compounds (I) (R1 is an optionally substituted C1-C13 heteromonocyclic, heterobicyclic or heterotri cyclic group containing from 1 to 5 heteroatoms selected from N, O and S; R2 is H, an optionally substituted mo
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Page/Page column 72
(2011/04/18)
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- A facile solvent-free synthesis of 1-alkyl/aralkyl-2-(1-arylsulfonyl alkyl) benzimidazoles using "tBAB" as surface catalyst
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Reaction 2-(α-chloroalkyl)benzimidazoles 1 with aryl sulphinate sodium salt 2 under solvent-free conditions in the presence of tetrabutylammonium bromide as surface catalyst, by simple physical grinding using mortar and pestle, gives 1H-2-(α-arylsulfonylalkyl)benzimidazoles 3. The latter on treatment with alkylating agents under solvent-free conditions results in 1-alkyl/aralkyl-2-(α-arylsulfonylalkyl)benzimidazoles 4. Alternatively, 4 can also be prepared directly from 1-alkyl/aralkyl-2-(α- chloroalkyl)benzimidazoles 5 by reaction with 2, which in turn could be prepared by reaction of 1 with alkylating agents under solvent-free conditions and all these reactions are free from organic solvents including experimental procedures.
- Dubey,Prasada Reddy,Srinivas
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experimental part
p. 1317 - 1322
(2010/12/29)
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- Bicyclic Benzimidazole Compounds and Their Use as Metabotropic Glutamate Receptor Potentiators
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Compounds of Formula I: wherein A, B, D, L, R1, R2, R3, R4, m, and n are as defined for Formula I in the description. The invention also relates to processes for the preparation of the compounds and to new intermediates employed in the preparation, pharmaceutical compositions containing the compounds, and to the use of the compounds in therapy.
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Page/Page column 60
(2009/08/14)
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- Synthesis, cytotoxicity, and DNA interactions of new cisplatin analogues containing substituted benzimidazole ligands
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Six new platinum(II) complexes with 1-H or methyl-2-chloromethyl or acetoxymethyl or 2′-hydroxyethyl- benzimidazole carrier ligands were synthesized and evaluated for their reactivity against model nucleophile I -, cellular uptake, and in vitro antiproliferative activities against the human MCF-7 breast and HeLa cervix cancer cell lines. The effect of the compounds on pBR322 plasmid DNA was studied by gel electrophoretic mobility measurements. Flow cytometric analysis was also carried out to study the effect of representative compounds 1 and 2, bearing 2-chloromethyl or -acetoxymethylbenzimidazole carrier ligands, on the cell cycle distribution of MCF-7 and HeLa cells, respectively. In general, it was found that Pt(II) complexes were less cytotoxic than cisplatin and were comparable to carboplatin. The results of the plasmid DNA interaction and the restriction studies suggest that changing the chemical structure of the benzimidazole ligands may modulate DNA binding mode and the sequence selectivity. Compounds 1 and 2 had no significant effect on the cell cycle profile of the cells used. However, compound 2 induced a significant increase in the SubG1 cell population at a concentration of 20 μM.
- Gümü?, Fatma,Eren, G?k?en,A?ik, Leyla,?elebi, Ayten,?ztürk, Fatma,Yilmaz, ?ükran,Sa?kan, Rah?an Ilik?i,Gür, Sibel,?zkul, Aykut,Elmali, Ayhan,Elerman, Yal?in
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scheme or table
p. 1345 - 1357
(2009/12/26)
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- COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS THEREFOR
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Compounds active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.
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Page/Page column 105-106
(2008/12/07)
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- PIPERIDINONES USEFUL IN THE TREATMENT OF INFLAMMATION
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There is provided compounds of formula (I): wherein R1, R2, R3, R4, R5, R6, R7, m and n have meanings given in the description, and pharmaceutically acceptable derivatives thereof, which compounds are useful in the treatment of diseases and conditions associated with inflammation.
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Page/Page column 109
(2008/12/07)
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- Synthesis of 1-alkyl/aralkyl-2-(1-arylsulfonylalkyl)benzimidazoles under PTC conditions
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2-(α-chloroalkyl)benzimidazoles 1 on reaction with arylsulphinate sodium salt 2, in CH3CN under PTC conditions, gives 3 which on alkylation yields 1-alky/aralkyl-2-(α-aryl sulfonylalkyl)benzimidazoles 4. Alternatively, 4 can also be prepared by the reaction of 2 with 1-alkyl/aralkyl-2-(α-chloroalkyl)benzimidazole 5 in CH3CN using triethylbenzylammonium chloride (TEBAC) as PTC. 5 are obtained from 1 in turn, by alkylation in CH3CN under PTC conditions.
- Dubey,Prasada Reddy,Srinivas
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p. 488 - 491
(2008/09/18)
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- Discovery of imidazolidine-2,4-dione-linked HIV protease inhibitors with activity against lopinavir-resistant mutant HIV
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A new series of HIV protease inhibitors has been designed and synthesized based on the combination of the (R)-(hydroxyethylamino)sulfonamide isostere and the cyclic urea component of lopinavir. The series was optimized by replacing the 6-membered cyclic urea linker with an imidazolidine-2,4-dione which readily underwent N-alkylation to incorporate various methylene-linked heterocycle groups that bind favorably in site 3 of HIV protease. Significant improvements compared to lopinavir were seen in cell culture activity versus wild-type virus (pNL4-3) and the lopinavir-resistant mutant virus A17 (generated by in vitro serial passage of HIV-1 (pNL4-3) in MT-4 cells). Select imidazolidine-2,4-dione containing PIs were also more effective at inhibiting highly resistant patient isolates Pt1 and Pt2 than lopinavir. Pharmacokinetic data collected for compounds in this series varied considerably when coadministered orally in the rat with an equal amount of ritonavir (5 mg/kg each). The AUC values ranged from 0.144 to 12.33 μg h/mL.
- Flosi, William J.,DeGoey, David A.,Grampovnik, David J.,Chen, Hui-ju,Klein, Larry L.,Dekhtyar, Tatyana,Masse, Sherie,Marsh, Kennan C.,Mo, Hong Mei,Kempf, Dale
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p. 6695 - 6712
(2007/10/03)
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- Chemical compounds
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The invention relates to quinazoline derivatives of the formula: [wherein: Y1represents —O—, —S—, —CH2—, —SO—, —SO2—, —NR5CO—, —CONR6—, —SO2NR7—, —NR8SO2— or —NR9— (wherein R5, R6, R8and R9each independently represents hydrogen, alkyl or alkoxyalkyl); R1represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, alkyl, alkoxy, alkylthio, amino or alkylamino. R2represents hydrogen, hydroxy, halogeno, alkyl, alkoxy, trifluoromethyl, cyano, amino or nitro; m is an integer from 1 to 5; R3represents hydroxy, halogeno, alkyl, alkoxy, alkanoyloxy, trifluoromethyl, cyano, amino or nitro; R4represents a group which is or which contains an optionally substituted pyridone, phenyl or aromatic heterocyclic group] and salts thereof; processes for their preparation and pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof as active ingredient. The compounds of formula I and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.
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- Microwave assisted synthesis of new benzimidazoles
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New potentially bioactive and highly functionalized benzimidazoles were synthesized by using microwave irradiation methodology in multi-steps: construction of benzimidazole ring, N-methylation and electron transfer C-alkylation (followed by base-promoted nitrous acid elimination) or S-alkylation.
- Njoya, Yves,Boufatah, Narimene,Gellis, Armand,Rathelot, Pascal,Crozet, Michel P.,Vanelle, Patrice
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p. 1423 - 1432
(2007/10/03)
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- Substituted arylsulfonamides and benzamides
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This invention relates to substituted arylsulfonamides and benzamides possessing aniarrhythmic activity, to pharmaceutical compositions and to methods for production thereof.
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- Synthesis and Selective Class III Antiarrhythmic Activity of Novel N-Heteroaralkyl-Substituted 1-(Aryloxy)-2-propanolamine and Related Propylamine Derivatives
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The synthesis and biological evaluation of a series of novel 1-(aryloxy)-2-propanolamines and several related deshydroxy analogues are described.Compounds 4-29 were prepared and investigated for their class III electrophysiological activity in isolated canine Purkinje fibers and in anesthetized open-chest dogs.None of these compounds showed any class I activity.On the basis of the in vitro data, structure-activity relationships for the series are discussed.Two compounds, N-propoxy>phenyl>methanesulfonamide (12, WAY-123,223) and N-phenoxy>propyl>amino>methyl>-6-quinolinyl>methanesulfonamide (24, WAY-125,971) were identified and characterized as potent and specific class III antiarrhythmic agents in vitro and in vivo.Compound 12 was found to be orally bioavailable, to produce large increases of ventricular fibrillation threshold (VFT), and, in some instances, to restore sinus rhythm from ventricular fibrillation in anesthetized open-chest dogs at a dose of 5 mg/kg (iv).The enantiomers of 12 (i.e., 13 and 14) were synthesized and were found to exhibit similar electrophysiological effects in the Purkinje fiber screen.Compound 24, a propylamine analogue with potency and efficacy comparable to those of UK-68798 (2) and E-4031 (3), was studied in voltage-clamp experiments (isolated cat myocytes) and was found to be a potent and specific blocker of the delayed rectifier potassium current (IK).
- Butera, John A.,Spinelli, Walter,Anantharaman, Viji,Marcopulos, Nicholas,Parsons, Roderick W.,et al.
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p. 3212 - 3228
(2007/10/02)
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- Leukotriene D4 antagonists and 5-lipoxygenase inhibitors. Synthesis of benzoheterocyclic [(methoxyphenyl)amino]oxoalkanoic acid esters.
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A series of novel benzoheterocyclic [(methoxyphenyl)amino]oxoalkanoic acid esters has been prepared. These compounds were tested as inhibitors of rat polymorphonuclear leukocyte 5-lipoxgenase (LO) in vitro and as inhibitors of leukotriene D4 (LTD4) and ovalbumin (OA) induced bronchospasm in the guinea pig (GP) in vivo. In general, inhibitory activity against 5-LO, LTD4, and OA was broadest for benzthiazole-containing analogues (benzthiazole greater than benzimidazole much greater than benzoxazole, benzofuran). The most potent 5-LO inhibitor, 4-[[3-(2-benzthiazolylmethoxy)-phenyl]hydroxyamino]-4-oxobutanoic acid methyl ester (7), had an IC50 of 0.36 microM. Compound 7, however, was inactive vs. OA. The most potent compound in vivo, 4-[[3-[(1-methyl-2-benzimidazolyl)methoxy]phenyl]-amino] -4-oxobutanoic acid methyl ester 4, inhibited both LTD4- and OA-induced bronchospasm by 83% and 60%, respectively, at 50 mg/kg intraduodenally. Compound 4 was studied in the Ames assay employing five strains of bacteria (TA1535, TA1537, TA1538, TA98, and TA100) with and without S-9 rat liver enzyme metabolic activation, and there was no significant number of reversions noted.
- Musser,Kubrak,Chang,DiZio,Hite,Hand,Lewis
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p. 400 - 405
(2007/10/02)
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