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Deciphering the Influence of Meridional versus Facial Isomers in Spin Crossover Complexes
Chelate coordination of non-symmetrical didentate pyrazine-benzimidazole (L1) or pyridine-benzimidazole (L2) N-donor ligands around divalent iron in acetonitrile produces stable homoleptic triple-helical spin crossover [Fe(Lk)3]2+ complexes existing as mixtures of meridional (C1-symmetry) and facial (C3-symmetry) isomers in slow exchange on the NMR timescale. The speciation deviates from the expected statistical ratio mer/fac=3:1, a trend assigned to the thermodynamic trans-influence, combined with solvation effects. Consequently, the observed spin state FeIIlow-spin?FeIIhigh-spin equilibria occurring in [Fe(Lk)3]2+ refer to mixtures of complexes in solution, an issue usually not considered in this field, but which limits rational structure-properties correlations. Taking advantage of the selective and quantitative formation of isostructural facial isomers in non-constrained related spin crossover d-f helicates (HHH)-[LnFe(Lk)3]5+ (Ln is a trivalent lanthanide, Lk=L5, L6), we propose a novel strategy for assigning pertinent thermodynamic driving forces to each spin crossover triple-helical isomer. The different enthalpic contributions to the spin state equilibrium found in mer-[Fe(Lk)3]2+ and fac-[Fe(Lk)3]2+ reflect the Fe?N bond strengths dictated by the trans-influence, whereas a concomitant solvent-based entropic contribution reinforces the latter effect and results in systematic shifts of the spin crossover transitions toward higher temperature in the facial isomers.
Lathion, Timothée,Guénée, Laure,Besnard, Céline,Bousseksou, Azzedine,Piguet, Claude
p. 16873 - 16888
(2018)
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Tuning spin-crossover transition temperatures in non-symmetrical homoleptic meridional/facial [Fe(didentate)3]2+complexes: what for and who cares about it?
The [FeN6] chromophores found in [Fe(didentate)3]2+complexes, where didentate is a non-symmetrical 2-(6-membered-heterocyclic ring)-benzimidazole ligand (Lk), exist as mixtures of two geometricalmer(C1-symmetry) andfac(C3-symmetry) isomers. Specific alkyl-substituted six-membered heterocyclic rings connected to the benzimidazole unit (pyridines in ligandsL1-L3, pyrazines inL4-L5and pyrimidines inL6-L7) control the ligand field strength and the electron delocalization so that [FeII(Lk)3]2+display tunable thermally-induced spin transitions in solution. Thermodynamic, spectroscopic (UV-Vis, NMR) and magnetic studies in solution demonstrate that [Fe(L6)3]2+(L6= 1-methyl-2-(pyrimidin-2-yl)-1H-benzo[d]imidazole) exhibits a close to room temperature spin transition (T1/2= 273(3) K) combined with a high stability formation constant n acetonitrile), which makes this complex suitable for the potential modulation of lanthanide-based luminescence in polymetallic helicates. A novel method is proposed for assigning specific thermodynamic spin crossover parameters tofac-[Fe(L6)3]2+andmer-[Fe(L6)3]2+isomers in solution. The observed difference relies mainly on the entropic content ΔSmerSCO? ΔSfacSCO= 11(1) J mol?1K?1, which favors the spin transition for the meridional isomer. Intermolecular interactions occurring in the crystalline state largely overcome minor thermodynamic trends operating in diluted solutions and a single configurational isomer is usually observed in the solid state. Among the thirteen solved crystal structures1-13containing the [M(Lk)3]2+cations (M = Fe, Ni, Zn,Lk=L6-L7), pure meridional isomers are observed six times, pure facial isomers also six times and a mixture (44%merand 56%fac) is detected only once. Solid-state magnetic data recorded for the FeIIcomplexes show the operation of slightly cooperative spin transitions in7(fac-[Fe(L6)3]2+) and12(mer-[Fe(L7)3]2+). For the meridional isomer in6, a two-step spin state transition curve, associated with two phase transitions, is detected.
Deorukhkar, Neel,Besnard, Céline,Guénée, Laure,Piguet, Claude
p. 1206 - 1223
(2021/02/09)

N-substituted benzimidazole acrylonitriles as in vitro tubulin polymerization inhibitors: Synthesis, biological activity and computational analysis
We present the design, synthesis and biological activity of novel N-substituted benzimidazole based acrylonitriles as potential tubulin polymerization inhibitors. Their synthesis was achieved using classical linear organic and microwave assisted techniques, starting from aromatic aldehydes and N-substituted-2-cyanomethylbenzimidazoles. All newly prepared compounds were tested for their antiproliferative activity in vitro on eight human cancer cell lines and one reference non-cancerous assay. N,N-dimethylamino substituted acrylonitriles 30 and 41, bearing N-isobutyl and cyano substituents placed on the benzimidazole nuclei, showed strong and selective antiproliferative activity in the submicromolar range of inhibitory concentrations (IC50 0.2–0.6 μM), while being significantly less toxic than reference systems docetaxel and staurosporine, thus promoting them as lead compounds. Mechanism of action studies demonstrated that two most active compounds inhibited tubulin polymerization. Computational analysis confirmed the suitability of the employed benzimidazole-acrylonitrile skeleton for the binding within the colchicine binding site in tubulin, thus rationalizing the observed antitumor activities, and demonstrated that E-isomers are active substances. It also provided structural determinants affecting both the binding position and the matching affinities, identifying the attached NMe2 group as the most dominant in promoting the binding, which allows ligands to optimize favourable cation???π and hydrogen bonding interactions with Lys352.
Perin,Hok,Be?,Persoons,Vanstreels,Daelemans,Vianello,Hranjec
(2020/12/02)

Discovery of a Highly Selective Sigma-2 Receptor Ligand, 1-(4-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (CM398), with Drug-Like Properties and Antinociceptive Effects In Vivo
The sigma-2 receptor has been cloned and identified as Tmem97, which is a transmembrane protein involved in intracellular Ca2+ regulation and cholesterol homeostasis. Since its discovery, the sigma-2 receptor has been an extremely controversial target, and many efforts have been made to elucidate the functional role of this receptor during physiological and pathological conditions. Recently, this receptor has been proposed as a potential target to treat neuropathic pain due to the ability of sigma-2 receptor agonists to relieve mechanical hyperalgesia in mice model of chronic pain. In the present work, we developed a highly selective sigma-2 receptor ligand (sigma-1/sigma-2 selectivity ratio > 1000), 1-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H- benzo[d]imidazol-2(3H)-one (CM398), with an encouraging in vitro and in vivo pharmacological profile in rodents. In particular, radioligand binding studies demonstrated that CM398 had preferential affinity for sigma-2 receptor compared with sigma-1 receptor and at least four other neurotransmitter receptors sites, including the norepinephrine transporter. Following oral administration, CM398 showed rapid absorption and peak plasma concentration (Cmax) occurred within 10?min of dosing. Moreover, the compound showed adequate, absolute oral bioavailability of 29.0%. Finally, CM398 showed promising anti-inflammatory analgesic effects in the formalin model of inflammatory pain in mice. The results collected in this study provide more evidence that selective sigma-2 receptor ligands can be useful tools in the development of novel pain therapeutics and altogether, these data suggest that CM398 is a suitable lead candidate for further evaluation.
Avery, Bonnie A.,Chin, Frederick T.,Intagliata, Sebastiano,King, Tamara I.,Matsumoto, Rae R.,McCurdy, Christopher R.,McLaughlin, Jay P.,Mesangeau, Christophe,Seminerio, Michael,Sharma, Abhisheak,Wilson, Lisa L.
(2020/07/25)

HMOX1 inducers
The present invention is related to compounds of structure (I) as heme oxygenase 1 (HMOX 1) inducers. The present invention is also related a method of controlling the activity or the amount, or both the activity and the amount, of heme-oxygenase 1 in a mammalian subject. The definitions of the variables are provided herein.
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Page/Page column 159

(2020/09/18)

Benzimidazole derivatives as potent and isoform selective tumor-associated carbonic anhydrase IX/XII inhibitors
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
supporting information

(2020/01/08)

Synthesis method of N-methyl-1,2-benzenediamine dihydrochloride
The invention discloses a synthesis method of N-methyl-1,2-benzenediamine dihydrochloride. The synthesis method is characterized by comprising the following steps that 1, o-chloronitrobenzene and a monomethylamine aqueous solution are subjected to a sealing reaction, after the reaction is completed, cooling, standing and layering are conducted, and a lower-layer oil phase is collected to obtain N-methyl-2-nitroaniline; 2, a catalyst is added to a mixed solution of ethyl alcohol and the N-methyl-2-nitroaniline obtained in step 1, after mixing and heating, hydrazine hydrate is slowly dropwise added to the mixed solution, and after drop addition is completed, a heat preservation reaction is conducted; after the reaction is completed, suction filtration is conducted, and a suction filtration mother solution is reserved to obtain N-methyl-o-phenylenediamine; 3, liquid caustic soda, water and EDTA are added to the N-methyl-o-phenylenediamine obtained in step 2 for mixing, after cooling is conducted, dichloromethane is added, stirring, extraction, standing and layering are conducted, a lower-layer oil phase is collected, and through separation and purification, the target product N-methyl-1,2-benzenediamine dihydrochloride is obtained. The N-methyl-1,2-benzenediamine dihydrochloride product prepared through the method has high purity and few impurities and can be widely applied to the field of intermediate synthesis of a medicine tishamitan for reducing the blood pressure.
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Paragraph 0031-0033; 0036; 0037; 0040; 0041

(2019/10/05)

Iridium complex and organic light-emitting device (OLED)
The invention discloses an iridium complex and an organic light-emitting device (OLED), and relates to the technical field of organic photoelectric materials. On the one hand, a guanidine group with acarbene-like structure is introduced into a metal complex molecule as an ancillary ligand, and a four-membered ring coordination structure is constructed, so that a series of green phosphorescence complex material systems with brand-new molecular structures and photoelectric properties are obtained. The iridium complex has more stable central positive trivalent ruthenium atoms, thus having betterchemical stability and thermal stability; furthermore, the iridium complex can reduce unnecessary vibration energy loss, so that the non-radiative transition of the molecules is reduced, and the luminous efficiency of the complex is accordingly increased. On the other hand, an alkyl structure is introduced into the structure, so that the solubility of the ruthenium complex is improved. A device is prepared by carrying out diffraction on the iridium complex, especially using the iridium complex as a doping material; the device shows the advantages of being low in driving voltage, high in luminous efficiency and better in color purity, and is superior to the existing common OLED devices.
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Paragraph 0070-0073

(2018/12/02)

A N - methyl O-phenylenediamine hydrochloride synthetic method (by machine translation)
The invention discloses a N - methyl O-phenylenediamine hydrochloride synthetic method, steps (1) O-nitro-chlorobenzene and under the action of a methyl amine, to obtain the product N - methyl O-nitroaniline, step (2) step (1) the obtained product N - methyl O-nitroaniline crude product is dissolved in the methanol in the solvent, to the palladium-carbon as the catalyst, hydrogenation reduction to obtain N - methyl O-phenylenediamine, filtering out catalyst, to boil off the methanol solvent, adding hydrochloric acid generating N - methyl O-phenylenediamine hydrochloride. Synthesis method of the invention for the purpose of the O-nitro-chlorobenzene route to synthesize the product, low cost has extremely strong competitiveness. The reduction in hydrogen as the reducing agent, the reduction efficiency is high, no iron powder, sodium sulfide, substances such as hydrazine hydrate reduction generated when the pollution problem, nor reduction when the hydrazine hydrate, relates to toxicity problems. And the hydrogenation reduction of the product after the treatment is simple, the product quality is high, to post-drug a reliable guarantee for the quality of the product. In addition the use of the solvent is methanol, can be combined and then recovering the recycled. (by machine translation)
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Paragraph 0004; 0015-0020

(2018/12/02)

Tetraphenylethylene-based blue light material containing benzimidazole unit as well as preparation method and application
The invention discloses a tetraphenylethylene-based blue light material containing a benzimidazole unit. The tetraphenylethylene-based blue light material is shown as a structural formula I or II, wherein R1 is H, tert-butyl, n-butyl or hydroxyl, and R2 is alkyl. A 2-nitro-N-tert-butylphenyl amine or 2-nitro-N-n-butylphenyl amine precursor and a 4-formyl tetraphenylethylene precursor is firstly prepared, and then cyclization reaction is carried out to prepare a compound shown as the formula I or II. A preparation method of the compound is easy to operate, the reaction is moderate and the yield is high; the compound has relatively high decomposition temperature and glass-transition temperature, and shows blue fluorescence; the compound has a relatively good single-color property, so that an OLED (Organic Light Emitting Diode) device prepared by taking the compound as a luminescent material emits blue light; the starting voltage is 3.3V and the maximum brightness efficiency is 1.48cd/A. (The formula I and the formula II are shown in the description).
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Paragraph 0027; 0028; 0029; 0081; 0082; 0083

(2017/10/10)

PYRIMIDINE OR PYRIDINE COMPOUNDS, PREPARATION METHOD THEREFOR AND PHARMACEUTICAL USES THEREOF
The present invention disclosed a class of pyrimidine or pyridine compounds, pharmaceutically acceptable salts, stereoisomers, prodrugs and solvates thereof, preparation method therefor and pharmaceutical compositions and pharmaceutical uses thereof. The compounds can inhibit the variants of EGFR (Epidermis Growth Factor Receptor) proteinases, and therefore can inhibit the growth of a variety of tumor cells effectively. The compounds can be used to prepare antitumor drugs, used for the treatment, combined therapy or prevention of various different cancers. The compounds can overcome the drug resistance induced by the existing first-generation EGFR inhibitors such as gefitinib, erlotinib and so on. Particularly, the compounds can be used to prepare drugs for treating or preventing diseases, disturbances, disorders or conditions mediated by epidermis growth factor receptor variants (such as L858R activated mutants, Exon19 deletion activated mutants and T790M resistant mutants).
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Paragraph 0568-0570

(2017/09/19)

N-Methylation of poorly nucleophilic aromatic amines with dimethyl carbonate
Abstract: Dimethyl carbonate (DMC), an environmentally friendly methylation agent, is a substitute for traditional methylation agents such as methyl halides (CH3X, X?=?I, Br, Cl) or dimethyl sulfate. An efficient, convenient, and green method has been developed for N-methylation of poorly nucleophilic aromatic amines with DMC. It was found that the couple PEG400/K2CO3 provides good selectivity for the N-methylation product. Finally, the mechanism for reaction of amines with DMC was investigated, and a plausible multistep mechanism proposed and verified. Graphical Abstract: [Figure not available: see fulltext.]
Yan, Huidong,Zeng, Liufang,Xie, Yaqiang,Cui, Yu,Ye, Liyi,Tu, Song
p. 5951 - 5960
(2016/06/01)

Smaller than a nanoparticle with the design of discrete polynuclear molecular complexes displaying near-infrared to visible upconversion
This work shows that the operation of near-infrared to visible light-upconversion in a discrete molecule is not limited to non-linear optical processes, but may result from superexcitation processes using linear optics. The design of nine-coordinate metallic sites made up of neutral N-heterocyclic donor atoms in kinetically inert dinuclear [GaEr(L1)3]6+ and trinuclear [GaErGa(L2)3]9+ helicates leads to [ErN9] chromophores displaying unprecedented dual visible nanosecond Er(4S3/2→4I15/2) and near-infrared microsecond Er(4I13/2→4I15/2) emissive components. Attempts to induce one ion excited-state absorption (ESA) upconversion upon near-infrared excitation of these complexes failed because of the too-faint Er-centred absorption cross sections. The replacement of the trivalent gallium cation with a photophysically-tailored pseudo-octahedral [CrN6] chromophore working as a sensitizer for trivalent erbium in [CrEr(L1)3]6+ improves the near-infrared excitation efficiency, leading to the observation of a weak energy transfer upconversion (ETU). The connection of a second sensitizer in [CrErCr(L2)3]9+ generates a novel mechanism for upconversion, in which the superexcitation process is based on the CrIII-sensitizers. Two successive Cr→Er energy transfer processes (concerted-ETU) compete with a standard Er-centred ETU, and a gain in upconverted luminescence by a factor larger than statistical values is predicted and observed.
Zare, Davood,Suffren, Yan,Gune, Laure,Eliseeva, Svetlana V.,Nozary, Homayoun,Aboshyan-Sorgho, Lilit,Petoud, Stphane,Hauser, Andreas,Piguet, Claude
supporting information
p. 2529 - 2540
(2015/02/19)

N-Substituted Formamides as C1-Sources for the Synthesis of Benzimidazole and Benzothiazole Derivatives by Using Zinc Catalysts
An efficient and convenient one-pot protocol has been developed for the synthesis of a variety of benzimidazole, benzoxazole, and benzothiazole derivatives. This novel approach uses various o-phenylenediamines and N-substituted formamides (C1 sources) in a zinc-catalyzed cyclization in the presence of poly(methylhydrosiloxane) to afford the corresponding derivatives as sole products in moderate to excellent yields.
Nale, Deepak B.,Bhanage, Bhalchandra M.
p. 2835 - 2842
(2015/12/18)

Steric-Hindrance-Induced Regio- and Chemoselective Oxidation of Aromatic Amines
Unusual regio- and chemoselective oxidation of aromatic amines hindered with ortho substituents (except -NH2, -NHCH3, and -OH) to the corresponding nitro compounds is described by use of nonanebis(peroxoic acid). The mechanistic investigation for selective oxidation of amines ortho-substituted with -NH2 or -OH showed the involvement of H-bonding between the ortho hydrogen of the adjacent -XH group (where X = NH, NR, or O) and an oxygen atom from the diperoxy acid. Various mono- and diamines are oxidized into corresponding mononitro derivatives in high yield and purity without employing any protection strategies. The protocol was also found to successful on the gram scale.
Patil, Vilas Venunath,Shankarling, Ganapati Subray
p. 7876 - 7883
(2015/09/01)

Amino Azaxylylenes Photogenerated from o-Amido Imines: Photoassisted Access to Complex Spiro-Poly-Heterocycles
Upon irradiation, cyclic imines containing o-amido groups are shown to produce reactive intermediates, amino azaxylylenes, which undergo intramolecular cycloadditions to tethered unsaturated pendants to yield complex N,O-heterocycles having an additional spiro-connected nitrogen heterocyclic moiety. Modular assembly of the photoprecursors allows expeditious increase of the complexity of the target poly-heterocyclic scaffolds with a minimal number of experimentally simple reaction steps. The photocyclization and subsequent postphotochemical transformations are accompanied by an increase of Lovering's fsp3 factor, thus producing unprecedented three-dimensional molecular architectures, and offering extended sampling of chemical space. Rings in three dimensions: Cyclic imines containing an o-amido group undergo excited-state intramolecular proton transfer to generate amino azaxylylenes. The amino azaxylylenes undergo intramolecular cycloadditions to tethered unsaturated pendants to yield complex heterocyclic three-dimensional molecular architectures.
Mukhina, Olga A.,Kuznetsov, Dmitry M.,Cowger, Teresa M.,Kutateladze, Andrei G.
supporting information
p. 11516 - 11520
(2015/11/03)

Pd(OAc)2-catalyzed dinitration reaction of aromatic amines
Taking advantage of Pd(OAc)2-catalyzed dinitration reactions with Bi(NO3)3·5H2O in trifluoroethanol (TFE) and trifluoroacetic acid (TFA), we have developed an efficient and practical method for the synthesis of secondary dinitro-aromatic amines. The products could be applied to the preparation of 5-amine-N-methyl-benzimidazolone, the azo-dyes, economic advantages. The method has also been expanded to the dinitration reaction of some tertiary aromatic amines.
Feng, Yi-Si,Mao, Long,Bu, Xiao-Song,Dai, Jian-Jun,Xu, Hua-Jian
p. 3827 - 3832
(2015/06/02)

HETEROARYL COMPOUNDS AND USES THEREOF
The present invention relates to compounds useful as inhibitors of protein kinases, containing a cysteine residue in the ATP binding site. The invention further provides for pharmaceutically acceptable compositions comprising therapeutically effective amounts of one or more of the protein kinase inhibitor compounds and methods of using said compositions in the treatment of cancers and carcinomas.
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Paragraph 00426

(2014/09/29)

Synthesis and in vitro antifungal evaluation of benzoimidazolyl-piperazinyl-phenylmethanone derivatives
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.
p. 1855 - 1863
(2015/04/22)

Discovery of 2-iminobenzimidazoles as potent hepatitis C virus inhibitors with a novel mechanism of action
In this report we describe 2-iminobenzimidazole (IBI) analogs, identified during the course of a phenotypic high-throughput screening campaign, as novel hepatitis C virus (HCV) inhibitors. A series of IBI derivatives was synthesized and evaluated for their inhibitory activity against infectious HCV. Among the IBIs derivatives studied in this work, we identified promising compounds with high antiviral efficacy, high selectivity index and good microsomal stability. Noteworthy, the IBI series exhibited inhibitory activity on early and late steps of the viral cycle, but not in the HCV replicon system demonstrating a mechanism of action distinct from clinical-stage and approved anti-HCV drugs. Overall, our results suggest that IBIs are predestinated for further exploration as lead compounds for novel HCV interventions.
Windisch, Marc Peter,Jo, Suyeon,Kim, Hee-Young,Kim, Soo-Hyun,Kim, Keumhyun,Kong, Sunju,Jeong, Hyangsuk,Ahn, Sujin,No, Zaesung,Hwang, Jong Yeon
p. 35 - 42
(2014/04/17)

Identification of novel HDAC inhibitors through cell based screening and their evaluation as potential anticancer agents
A series of benzimidazole based HDAC inhibitors have been rationally designed, synthesized and screened. The SAR of this new chemotype is described. The lead compound, 11e, showed strong activity in several cellular assays and demonstrated in vivo efficacy in mouse xenograft pancreatic cancer models.
Wang, Tong,Sepulveda, Mario,Gonzales, Paul,Gately, Stephen
p. 4790 - 4793
(2013/09/02)

Systematic evaluation of structure-activity relationships of the riminophenazine class and discovery of a C2 pyridylamino series for the treatment of multidrug-resistant tuberculosis
Clofazimine, a member of the riminophenazine class of drugs, is the cornerstone agent for the treatment of leprosy. This agent is currently being studied in clinical trials for the treatment of multidrug-resistant tuberculosis to address the urgent need for new drugs that can overcome existing and emerging drug resistance. However, the use of clofazimine in tuberculosis treatment is hampered by its high lipophilicity and skin pigmentation side effects. To identify a new generation of riminophenazines that is less lipophilic and skin staining, while maintaining efficacy, we have performed a systematic structure-activity relationship (SAR) investigation by synthesizing a variety of analogs of clofazimine and evaluating their anti-tuberculosis activity. The study reveals that the central tricyclic phenazine system and the pendant aromatic rings are important for anti-tuberculosis activity. However, the phenyl groups attached to the C2 and N5 position of clofazimine can be replaced by a pyridyl group to provide analogs with improved physicochemical properties and pharmacokinetic characteristics. Replacement of the phenyl group attached to the C2 position by a pyridyl group has led to a promising new series of compounds with improved physicochemical properties, improved anti-tuberculosis potency, and reduced pigmentation potential.
Liu, Binna,Liu, Kai,Lu, Yu,Zhang, Dongfeng,Yang, Tianming,Li, Xuan,Ma, Chen,Zheng, Meiqin,Wang, Bin,Zhang, Gang,Wang, Fei,Ma, Zhenkun,Li, Chun,Huang, Haihong,Yin, Dali
experimental part
p. 4545 - 4559
(2012/07/01)

Indole RSK inhibitors. Part 2: Optimization of cell potency and kinase selectivity
A series of inhibitors for the 90 kDa ribosomal S6 kinase (RSK) based on an 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxamide scaffold were optimized for cellular potency and kinase selectivity. This led to the identification of compound 24, BIX 02565, an attractive candidate for use in vitro and in vivo to explore the role of RSK as a target for the treatment heart failure.
Kirrane, Thomas M.,Boyer, Stephen J.,Burke, Jennifer,Guo, Xin,Snow, Roger J.,Soleymanzadeh, Lida,Swinamer, Alan,Zhang, Yunlong,Madwed, Jeffery B.,Kashem, Mohammed,Kugler, Stanley,O'Neill, Margaret M.
scheme or table
p. 738 - 742
(2012/03/11)

A facile and practical copper powder-catalyzed, organic solvent-and ligand-free ullmann amination of aryl halides
A facile and practical method that the copper powder-catalyzed Ullmann amination of aryl halides with aqueous methylamine under organic solvent-and ligand-free condition at 100 °C and in air gave N-arylamines as sole products in good to excellent yields. The presence of a small amount of air is essential. Other aliphatic primary amines show good to very high reactivity. Secondary amines and aniline are not reactive. Sensitive substituents (i.e., CHO, MeCO, CN and Cl) are tolerable in the reaction.
Jiao, Jiao,Zhang, Xi-Ru,Chang, Ning-Hui,Wang, Jie,Wei, Jun-Fa,Shi, Xian-Ying,Chen, Zhan-Guo
supporting information; experimental part
p. 1180 - 1183
(2011/04/24)

Benzimidazole and imidazole inhibitors of histone deacetylases: Synthesis and biological activity
A series of N-hydroxy-3-[3-(1-substituted-1H-benzoimidazol-2-yl)-phenyl]-acrylamides (5a-5ab) and N-hydroxy-3-[3-(1,4,5-trisubstituted-1H-imidazol-2-yl)-phenyl]-acrylamides (12a-s) were designed, synthesized, and found to be nanomolar inhibitors of human histone deacetylases. Multiple compounds bearing an N1-piperidine demonstrate EC50s of 20-100 nM in human A549, HL60, and PC3 cells, in vitro and in vivo hyperacetylation of histones H3 and H4, and induction of p21waf. Compound 5x displays efficacy in human tumor xenograft models.
Bressi, Jerome C.,Jong, Ron de,Wu, Yiqin,Jennings, Andy J.,Brown, Jason W.,O'Connell, Shawn,Tari, Leslie W.,Skene, Robert J.,Vu, Phong,Navre, Marc,Cao, Xiaodong,Gangloff, Anthony R.
scheme or table
p. 3138 - 3141
(2010/09/03)

1- Or 3-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2- ones: Potent, selective, and orally efficacious norepinephrine reuptake inhibitors
Sequential structural modifications of the aryloxypropanamine template (e.g., atomoxetine, 2) led to a novel series of 1-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors (NRIs). In general, this series of compounds potently blocked the human norepinephrine transporter (hNET) while exhibiting selectivity at hNET against both the human serotonin (hSERT) and dopamine transporters (hDAT). Numerous compounds (e.g., 19-22) had low nonamolar hNET potency with IC 50 values of 7-10 nM and excellent selectivity (>500 fold) at hNET over hSERT and hDAT. Several compounds, such as 20 and 22, were tested in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction and were efficacious at oral doses of 3 mg/kg in reducing the tail skin temperature. In addition, compound 20 was also studied in the rat hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain, respectively, and was orally efficacious at doses of 3-10 mg/kg.
Zhang, Puwen,Terefenko, Eugene A.,Bray, Jenifer,Deecher, Darlene,Fensome, Andrew,Harrison, Jim,Kim, Callain,Koury, Elizabeth,Mark, Lilly,McComas, Casey C.,Mugford, Cheryl A.,Trybulski, Eugene J.,Vu, An T.,Whiteside, Garth T.,Mahaney, Paige E.
experimental part
p. 5703 - 5711
(2010/02/28)

4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: Potent and selective p70S6 kinase inhibitors
We report herein the design and synthesis of 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-amine derivatives as inhibitors of p70S6 kinase. Screening hits containing the 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine scaffold were optimized for p70S6K potency and selectivity against related kinases. Structure-based design employing an active site homology model derived from PKA led to the preparation of benzimidazole 5-substituted compounds 26 and 27 as highly potent inhibitors (Ki 100-fold selectivity against PKA, ROCK and GSK3.
Bandarage, Upul,Hare, Brian,Parsons, Jonathan,Pham, Ly,Marhefka, Craig,Bemis, Guy,Tang, Qing,Moody, Cameron Stuver,Rodems, Steve,Shah, Sundeep,Adams, Chris,Bravo, Jose,Charonnet, Emmanuelle,Savic, Vladimir,Come, Jon H.,Green, Jeremy
scheme or table
p. 5191 - 5194
(2010/03/24)

Discovery of small molecule benzimidazole antagonists of the chemokine receptor CXCR3
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.
p. 1573 - 1576
(2008/09/21)

Synthesis and activity of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors
A series of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors was discovered. Several compounds such as 15 and 20 showed good hNET potency. Compounds 15 and 20 also displayed excellent selectivity at hNET that appeared superior to those of reboxetine and atomoxetine (4 and 5).
Zhang, Puwen,Terefenko, Eugene A.,McComas, Casey C.,Mahaney, Paige E.,Vu, An,Trybulski, Eugene,Koury, Elizabeth,Johnston, Grace,Bray, Jenifer,Deecher, Darlene
scheme or table
p. 6067 - 6070
(2009/08/07)

Lead identification of 2-iminobenzimidazole antagonists of the chemokine receptor CXCR3
Modification of a 2-iminobenzimidazole series derived from an HTS hit resulted in compounds with improved in-vitro species selectivity. Incorporation of an 8-quinoline amide and conformational rigidification of an aliphatic tether furnished potent compounds suitable for further lead optimization.
Hayes, Martin E.,Breinlinger, Eric C.,Wallace, Grier A.,Grongsaard, Pintipa,Miao, Wenyan,McPherson, Michael J.,Stoffel, Robert H.,Green, David W.,Roth, Gregory P.
p. 2414 - 2419
(2008/09/20)

An efficient and impurity-free process for telmisartan: An antihypertensive drug
Telmisartan (1), a substituted dibenzimidazole derivative, is an antihypertensive drug, essentially used to control blood pressure. An improved, cost-effective, and impurity-free process for telmisartan (1) suitable for large-scale production is described here by addressing various process development issues. The overall yield obtained from this newly developed process is around 50% (over five steps) compared to the literature reported process (21%, over eight steps).
Reddy, Kikkuru Srirami,Srinivasan, Neti,Reddy, Chinta Raveendra,Kolla, Naveenkumar,Anjaneyulu, Yerremilli,Venkatraman, Sundaram,Bhattacharya, Apurba,Mathad, Vijayavitthal T.
p. 81 - 85
(2012/12/26)

Highly chemoselective nitration of aromatic amines using the Ph3P/Br2/AgNO3 system
The use of PPh3/Br2/AgNO3 provides a new reagent system for the novel and highly chemoselective nitration of aromatic amines under mild reaction conditions.
Iranpoor, Nasser,Firouzabadi, Habib,Nowrouzi, Najmeh,Firouzabadi, Dena
p. 6879 - 6881
(2007/10/03)

Benzimidazolones and indoles as non-thiol farnesyltransferase inhibitors based on tipifarnib scaffold: Synthesis and activity
A series of analogs of tipifarnib (1) has been synthesized as inhibitors of FTase by substituting the benzimidazolones and indoles for the 2-quinolone of tipifarnib. The novel benzimidazolones are potent and selective FTase inhibitors (FTIs) with IC50 values of the best compounds close to that of tipifarnib. The current series demonstrate good cellular activity as measured in their inhibiting the Ras processing in NIH-3T3 cells, with compounds 2c and 2f displaying EC50 values of 18 and 22 nM, respectively.
Li, Qun,Li, Tongmei,Woods, Keith W.,Gu, Wen-Zhen,Cohen, Jerry,Stoll, Vincent S.,Galicia, Tomas,Hutchins, Charles,Frost, David,Rosenberg, Saul H.,Sham, Hing L.
p. 2918 - 2922
(2007/10/03)

Reduction of polyfunctional aromatic nitro compounds using lithium aluminium hydride
Aromatic nitro compounds containing yet another functional group are reduced using lithium aluminium hydride in ether. The reduction of nitrobenzanilides results in preferential reduction of amide functionality while the isomeric N-(nitrophenyl) benzamides results in preferential cleavage of the amide bond. Besides, the reduction of 2,2′-dinitrodiphenyl amine 5a, reduction of (bis-2-nitroanilino) methane 5b, 2,2′ -dinitrodiphenylether 5c, 2-nitrophenyl-2′-nitrophenoxymethane 5d, 1,3-dinitrobenzene 6a, 2-nitrobenzaldoxime 6b, 2-N(2′-nitrophenylmethyl) amino benzoic acid 6c, 2-nitrophenoxymethyl phenyl ketone 6d are carried out. Nitro group is found reluctant towards reduction in some cases whereas in some others it is reduced into different extents. This points to the limitation of the suggested azo test for aromatic nitro compounds.
Joseph,Jacob, Dominic E.
p. 432 - 436
(2007/10/03)

An improved synthesis of N-substituted-2-nitroanilines
The reaction of 2-chloronitrobenzene with substituted amines/ anilines in the presence of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) gives N-substituted-2-nitroanilines in good to excellent yields (>75-90%).
Chauhan,Singh, Ram,Geetanjali
p. 2899 - 2906
(2007/10/03)

Concomitant rearrangement of [15N-No 2]-N-(4-fluorophenyl)-N-methylnitramine and N-methyl-N-phenylnitramine
-
Daszkiewicz,Kyziol
p. 1217 - 1220
(2007/10/03)

Construction of interconnected acidity functions based on ortho substituted anilines and N-methylanilines as indicators
The log I values of 15 mainly ortho substituted derivatives of aniline and N-methylaniline have been measured spectrophotometrically in sulfuric, perchloric, and methanesulfonic acids. A new algorithm has been suggested for construction of acidity functions enabling simultaneous and independent construction of acidity functions in various media under the condition of equal values of pKa of the same indicators in the given media. The so-called interconnected acidity functions have been constructed with using this algorithm and the log I values measured in the above media, and the pKa values have been calculated. The resulting acidity functions and pKa values agree well with the corresponding literature data.
Pytela, Oldrich,Kulhanek, Jiri,Jiraskova, Eva,Nevecna, Tatjana
p. 1638 - 1658
(2007/10/03)

Butyltriphenylphosphonium tetraborate (BTPPTB) as a selective reducing agent for the reduction of imines, enamines and oximes and reductive alkylation of aldehydes or ketones with primary amines in methanol or under solid-phase conditions
Butyltriphenylphosphonium tetraborate (BTPPTB) 1, generated as white solid from butyltriphenylphosphonium bromide and sodium borohydride, is found to be a selective and versatile reducing agent. The reagent in methanol or under solvent-free conditions is very useful for the reduction of imines, enamines and oximes or reductive amination of aldehydes and ketones. Under solvent-free conditions the reactions are faster and the yields of the products are higher.
Hajipour,Mohammadpoor-Baltork,Noroallhi
p. 152 - 156
(2007/10/03)

Selective one-pot N-monomethylation of 2-nitroanilines under PTC conditions
Direct PTC methylation of 2-nitroanilines with dimethyl sulfate gave selectively N-monomethylated products. A variety of N-methyl-2-nitroanilines were prepared in this way.
Voskresensky,Makosza
p. 3523 - 3526
(2007/10/03)

Some properties of 1-(nitrophenyl)-aminobenzimidazoles
The chemical properties of previously synthesized 1-[2(4)-nitrophenyl]aminobenzimidazoles, in particular, alkylation at the NH group, thiolation, and reduction were studied.
Dyablo,Pozharskii,Shkurupii
p. 37 - 39
(2007/10/03)

Synthesis of triazolo[4,5-f]quinolines. An unusual case of displacement of nitro group in the reaction of 8-acetylamino-6-chloro-5-nitroquinoline with hydrazine and methylhydrazine
Nitration of 1H-, 3-methyl- and 2-methyltriazolo[4,5-f]quinolines (6a-c) as a way to obtain the desired 4-aminotriazolo[4,5-f]quinolines (4) for a medicinal chemistry project was successful only in the case of 6c. Attempted building up of the triazole ring starting from 8-acetylamino-6-chloro-5- nitroquinoline (8) with ammonia, hydrazine and methylhydrazine at 150 °C in ethanol failed. However, the results obtained from these reactions allowed us to observe that, during nucleophilic aromatic substitution of chlorine by these bases an unusual displacement of the nitro group by hydrogen occurred. Comparison of these results with those obtained using different substrates allowed us to evaluate the influence of both para-acetylamino group and pyridine ring in this type of nucleophilic aromatic substitution.
Sanna, Paolo,Carta, Antonio,Paglietti, Giuseppe
p. 693 - 702
(2007/10/03)

By-products in the rearrangement of N-methyl-N-phenylnitramine
N-Methyl-N-phenylnitramine was rearranged in the aqueous dioxane- sulphuric acid mixture to 2-nitro- and 4-nitro-N-methylanilines. The isomer ratio was independent of the acidity within the range of -0.3 > H(o) > -2.8. Some by-products were isolated and i
Daszkiewicz, Zdzislaw,Nowakowska, Ewa,Kyziol, Janusz B.
p. 5991 - 6000
(2007/10/03)

Photolysis of some N-nitroso- and N-nitro-anilines in solution
The photolyses of three N-methyl-N-nitrosoanilines and two N-methyl-N-nitroanilines in organic solvents have been studied in the range of 300-340 nm. The influence of solvent character and the presence or absence of oxygen play important roles in the product composition range. The primary photochemical process involves N-N fission, this being homolytic in aprotic solvents and heterolytic in methanol. Three novel mechanistic conclusions are proposed, namely photosolvolysis of a nitrosamine in methanol, photooxidation of nitrosamines in aprotic solvents and the production of biphenyl derivatives on photolysis of nitro-substituted nitrosamines and nitramines in aromatic solvents.
Gowenlock, Brian G.,Pfab, Josef,Young, Victor M.
p. 915 - 919
(2007/10/03)

Observation of a single-pot aromatic reductive denitration
4,N,N-Trimethyl-3-nitrobenzenamine gave reductive denitration products (ca. 28%) upon treatment with n-butyl nitrite in the presence of catalytic amounts of ammonium chloride and water in an unprecedented one-reagent single-pot process. The three isomeric N,N-dimethylnitrobenzenamines showed the same behaviour to a much lesser extent; the ortho isomer was partially (7%) transformed into 1-methylbenzotriazole.
Giumanini, Angelo G.,Verardo, Giancarlo
p. 469 - 473
(2007/10/03)

Thermal decomposition of arylnitramines
The thermal decomposition of various substituted N-methyl-N-nitroanilines dissolved in indifferent solvents and piperidine has been investigated. Activation volumes and product analyses support evidence that the rate-determining step is the reversible homolysis of the nitramine bond. The activation volumes range from +18 to +36 ml mol-1. A non-linear Hammett relationship is attributed to an increase in secondary caged reactions, namely rearrangement and oxidation. Arylnitramines with electron-donating substituents yield greater amounts of the thermal rearrangement products than those with electron-deactivating groups at ambient pressures. Decomposition of arylnitramines with electron-donating substituents under high pressures (ca. 1.2 GPa) favours caged reactions over separative diffusion.
Naud, Darren L.
p. 1321 - 1324
(2007/10/03)

Amination of dinitrobenzenes with liquid methylamine/potassium permanganate
1,3-Dinitrobenzene (1a) and some simple monosubstituted derivatives (1b-g) were aminated with a liquid methylamine solution of potassium permanganate (LMA/PP) to give the corresponding mono- and bis(methylamino)-substituted compounds (3a-e and 4a). 1,2-Dinitrobenzene (1i) was aminated with LMA/PP to give 2-(methylamino)-1-nitrobenzene (3f) in high yield.The intermediacy of 4-(methylamino) ?-adducts of 1,3-dinitrobenzene (2a), 2-chloro- (2b) and 2-amino-1,3-dinitrobenzene (2c) was established by 1H NMR spectroscopy.Quantum-chemical calculations for the dinitrobenzenes suggest that, in general, the experimentally observed regioselectivity of the methylamination is satisfactorily described by frontier molecular orbital (FMO) interaction of the reagents.
Wozniak, Marian,Grzegozek, Maria,Roszkiewicz, Witold,Szpakiewicz, Barbara
p. 13 - 17
(2007/10/02)

Facile synthesis of substituted n-monoalkylaromatic amines under PTC conditions
Substituted aromatic amides were alkylated under PTC conditions. Compounds with ortho electron withdrawing substituents furnished exclusively monoalkyl amines. A plausible mechanism has been suggested.
Kalkote,Choudhary,Natu,Lahoti,Ayyangar
p. 1889 - 1900
(2007/10/02)

Reaction of 6-Ethylamino-3-methyluracil with Nitrobenzenes
Reaction of 6-ethylamino-3-methyluracil (1) with nitrobenzenes in hexamethylphosphoric triamide gave isoalloxazines in 3.8-18 percent yield.In the presence of potassium carbonate, reaction of 1 with o-fluoronitrobenzene afforded 5-substituted uracil 3 in moderate yield.
Harayama, Takashi,Jinno, Hideto,Tezuka, Yasuhiro,Yoneda, Fumio
p. 1507 - 1509
(2007/10/02)

Basic Hydrolysis of Some N-Phenylcarbamates and Basic Methanolysis of Some N-Phenylacetamides Containing an ortho Nitro Substituent.
Kinetic studies of the basic methanolysis of N-(2-nitrophenyl)acetamides indicate that unlike the 4-nitro isomer, no change of mechanism occurs on inclusion of N-methyl group.Reaction occurs with rate-determining C-N bond breaking for both the N-H and N-methyl compounds.Basic hydrolysis of some methyl N-(2-nitrophenyl)carbamates occurred by the BAC2 mechanism and the tetrahedral intermediate formed during the hydrolysis decomposed with preferential C-O bond breaking.This is in contrast to the basic hydrolysis of methyl N-methyl-N-4-nitrophenylcarbamate, which has previously been shown to occur with preferential C-N bond breaking.For the hydrolysis of methyl N-methyl-N-(2-nitrophenyl)carbamate, an induction period in amine production was detected at 0.45 M hydroxide ion.This was interpreted to mean that the tetrahedral intermediate breaks down by loss of methoxide ion.At 0.93 M hydroxide ion, however, no induction period in amine production was observed.The possibility of reaction through a dianionic intermediate was raised to explain this observation.The amide ion (2-NO2C6H4NMe-) is poorer leaving group than its 4-nitro isomer thi is explained by steric crowding in the 2-nitro compound, resulting in twisting of the nitro group out of the plane of the benzene ring and a consequent reduction in the electron-withdrawing resonance effect of the 2-nitro group compared to the 4-nitro gruop.
Broxton, Trevor J.
p. 2005 - 2011
(2007/10/02)

THE NITRAMINE REARRANGEMENT. SUPPORT OF NONCONCERTEDNESS FROM HEAVY-ATOM KINETIC ISOTOPE EFFECTS
Heavy-atom kinetic isotope effects (KIE) were measured for the formation of 2- (2) and 4-nitro-N-methylaniline (3) from the acid-catalyzed rearrangement of N-nitro-N-methylaniline (1).Separate rearrangements of (15NO2)-1, (2-14C)-1,
Shine, Henry J.,Zygmunt, Jan,Brownawell, Marilyn L.,Filippo, Joseph Jr. San
p. 3610 - 3613
(2007/10/02)