Respiratory syncytial virus inhibitors. Part 2: Benzimidazol-2-one derivatives

Structure-activity relationships for a series of benzimidazol-2-one-based inhibitors of respiratory syncytial virus are described. These studies focused on structural variation of the benzimidazol-2-one substituent, a vector inaccessible in a series of benzotriazole derivatives on which 2 is based, and revealed a broad tolerance for substituent size and functionality.     

Synthesis and evaluation of N-3 substituted phenoxypropyl piperidine benzimidazol-2-one analogues as NOP receptor agonists with analgesic and sedative properties

A series of 3-phenoxypropyl piperidine benzimidazol-2-one analogues have been discovered as novel NOP receptor agonists. Structure-activity relationships have been explored via N-3 substitution of the benzimidazol-2-one with a range of functionality. The N-methyl acetamide derivative (+)-7f was found to be a high-affinity, potent NOP agonist with greater than 100-fold selectivity over the MOP receptor. Furthermore (+)-7f was shown to be both antinociceptive and sedative when administered iv to rodents.     

New generation dopaminergic agents. Part 8: heterocyclic bioisosteres that exploit the 7-OH-2-(aminomethyl)chroman D(2) template

Based on the 7-OH-2-(aminomethyl)chroman dopamine D(2) template (2) is described the preparation and resolution of two bioisosteric analogues. The benzimidazol-2-one derivative (6) had similar affinity to the known indolone derivative (4).     

Respiratory syncytial virus fusion inhibitors. Part 6: an examination of the effect of structural variation of the benzimidazol-2-one heterocycle moiety

The effect of structural variation of the benzimidazol-2-one ring of RSV fusion inhibitors related to BMS-433771 (1) was examined in conjunction with side chain modifications and the introduction of an aminomethyl substituent at the 5-position of the core benzimidazole moiety. Replacement of the benzimidazol-2-one moiety with benzoxazole, oxindole, quinoline-2-one, quinazolin-2,4-dione and benzothiazine derivatives provided a series of potent RSV fusion inhibitors 4. However, the intrinsic potency of 6,6-fused ring systems was generally less than that of comparably substituted 5,6-fused heterocycles of the type found in BMS-433771 (1). The introduction of an aminomethyl substituent to the benzimidazole ring enhanced antiviral activity in the 6,6-fused ring systems.     

New generation dopaminergic agents. 7. Heterocyclic bioisosteres that exploit the 3-OH-phenoxyethylamine D2 template.

The synthesis of several bioisosteric analogs based on the 3-OH-phenoxyethylamine dopamine D2 agonist template (i.e., 3) is described. The benzimidazol-2-ones and benzthioimidazol-2-ones (7-10) and 2-trifluoromethyl-benzimidazole (13) were observed to have excellent affinity for the D2 receptor.     

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 (K_i <1 nM) of p70S6K, with >100-fold selectivity against PKA, ROCK and GSK3.     

Synthesis of new 2-substituted 6-bromo-3-methylthiazolo[3,2-alpha]-benzimidazole derivatives and their biological activities

1-(6-Bromo-3-methyl-1,3-thiazolo[3,2-alpha]benzimidazol-2-yl)ethanone (2) was prepared by bromination at ambient temperature of 1-(3-methylthiazolo[3,2-alpha]benzimidazol-2-yl)ethanone (1). The structure of 2 was determined by single-crystal X-ray diffraction. The precursor 5 was synthesized by heating a mixture of acetyl 2 and bromine. Various 2-substituted 6-bromo-3-methylthiazolo[3,2-alpha]benzimidazoles containing 1,3-thiazole, 1,4-benzothiazine, quinoxaline or imidazo[1,2-alpha]pyridine moieties were prepared starting from bromoacetyl 5. Taken together from the biological investigations, 2, 5, and 7a were potent immunosuppressors against both macrophages and T-lymphocytes, and 7b, 11b, and 14 were potent immunostimulators towards both types of immune cells. The results also revealed that, among others, 2 and 14 were the most significant inhibitors of LPS-stimulated NO generation, and that 5, 7a, and 7b had a weak radical scavenging activity against DPPH radicals. Moreover, 2, 5, and 7a had a concomitant strong cytotoxicity against colon carcinoma, hepatocellular carcinoma, and lymphoblastic leukemia cells. Collectively, compounds 2, 5, and 7a are multipotent compounds with promising biological activities.     

Novel 1H-(benzimidazol-2-yl)-1H-pyridin-2-one inhibitors of insulin-like growth factor I (IGF-1R) kinase

A novel class of 1H-(benzimidazol-2-yl)-1H-pyridin-2-one inhibitors of insulin-like growth factor I (IGF-1R) kinase is described. This report discusses the SAR of 4-(2-hydroxy-2-phenylethylamino)-substituted pyridones with improved IGF-1R potency.     

Rapid access towards follow-up NOP receptor agonists using a knowledge based approach

A knowledge based approach has been adopted to identify novel NOP receptor agonists with simplified hydrophobes. Substitution of the benzimidazol-2-one piperidine motif with a range of hydrophobic groups and pharmacophore guided bio-isosteric replacement of the benzimidazol-2-one moiety was explored. Compound 51 was found to be a high affinity, potent NOP receptor agonist with reduced affinity for the hERG channel.     

Glasshouse evaluation of some systemic fungicides for control of clubroot of brassicae

Of nine systemic fungicides screened as soil mixes against clubroot, only the precursors of methyl benzimidazol-2-ylcarbamate (MBC) or ethyl benzimidazol-2-ylcarbamate (EBC) gave promising results. Benomyl was the most effective, usually giving control at 250 mg/kg dry soil. Most fungicides were less effective against an isolate of Plasmodiophora brassicae from Brussels sprouts than against one from rape. Disease control was slightly better on cabbage than on a highly susceptible rape variety.     

Synthesis and antitrichinellosis activity of some bis(benzimidazol-2-yl)amines

Novel bis(benzimidazol-2-yl)amines were synthesized using two methods and studied for antitrichinellosis activity. DFT calculations were performed in order to determine the geometry of molecules. All derivatives of 2-aminobenzimidazole exhibited higher activity in vitro against Trichinella spiralis larvae in regard to the activity of albendazole, moreover compounds 4f-i manifested antitrichinellosis effect, which surpassed five times the activity of albendazole. The in vivo screening of intestinal phase of the T. spiralis revealed 100% effectiveness of compounds 4g-i at oral dosages of 50 and 100mg/kgmw, while albendazole possesses 100% efficacy only at a dose of 100mg/kgmw.     

Structure-activity relationships and CoMFA of N-3 substituted phenoxypropyl piperidine benzimidazol-2-one analogues as NOP receptor agonists with analgesic properties

The N-3 position of a series of 3-phenoxypropyl piperidine benzimidazol-2-one analogues was optimised using the predictive power of a CoMFA model. The model was used to prioritise compounds for synthesis culminating in the triazole (+)-24. (+)-24 was found to be a high affinity, potent NOP agonist and demonstrated both antinociceptive and antiallodynic effects when administered iv to rodents.     

Geometrical isomers of bis(benzimidazol-2-ylethyl)sulfide)cobalt(II) diperchlorates: synthesis, structure, spectra and redox behavior of pink-[Co(bbes)2](ClO4)2 and blue-[Co(bbes)2](ClO4)2

1:1 and 1:2 cobalt complexes of bis(benzimidazol-2-ylmethyl)amine (bbma) bis(benzimidazol-2-ylmethyl)sulfide (bbms), bis(benzimidazol-2-ylethyl)sulfide (bbes) and diethylenetriamine (dien) were prepared and their spectral and redox behavior studied. Two geometrical isomers pink-[Co(bbes)₂]²⁺ and blue-[Co(bbes)₂]²⁺ were obtained when the complexes were prepared by using with bbes and they were separated manually and recrystallized. The octahedral structure of pink-[Co(bbes)₂]²⁺ was resolved by X-ray analysis. The electronic spectra show the presence of two geometrical isomers for Co(bbes)₂²⁺ in the solid state; for example, the spectral bands of pink-[Co(bbes)₂]²⁺ differs markedly with those of blue-[Co(bbes)₂]²⁺. This is consistent with the results obtained from magnetic measurements (5.10 BM for pink-Co(bbes)₂²⁺ and 4.72 BM for blue-[Co(bbes)₂]²⁺). Further, the behavior of the ligands (bbma, bbms, bbes) at different pH conditions was determined on the basis of ¹³C NMR studies. The redox potentials [Co(II)/Co(I)] of the complexes follow the trend [Co(bbma)₂]²⁺ < [Co(bbms)₂]²⁺ ≈ [Co(bbes)₂]²⁺ which demonstrates the stabilization of the Co(II) ion is more by both weak σ-donor and weak π-acceptor ligands rather than by σ-donor ligand.     

DFT,QTAIM, and NBO investigations of the ability of the Fe or Ni doped CNT to absorb and sense CO and NO

Journal of Molecular Modeling - The ruthenium complex with (N,N,N-tris(benzimidazol-2yl-methyl)amine, L1) was prepared, and characterized. Fukui data were used to localize the reactive sites on the...     

Reactivities of neutral and cationic forms of 2,2''-dipyridyl disulphide towards thiolate anions. Detection of differences between the active centres of actinidin, papain and ficin by a three-protonic-state reactivity probe.

The second-order rate constants (k) for the reactions of 2,2'-dipyridyl disulphide (pKa2,45) with 2-mercaptoethanol (pKa9.6) and with benzimidazol-2-ylmethanethiol (pKa values 5.6 and 8.3) were determined at 25 degrees C at I 0.1 by stopped-flow spectral analysis over a wide range of pH. These were used to calculate the pH-independent second-order rate constants (k) for the reactions of neutral 2,2'-dipyridyl disulphide and of its monocation with the 2-mercaptoethanol thiolate anion (associated pKa9.6) and with the benzimidazol-2-ylmethanethiol zwitterion (associated pKa5.6). For both thiolate ions, the rate-enhancement factor (kmonocation/kneutral disulphide) is about 1.5x10(3). The dependence on pH in acidic media of k for the reaction of 2,2'-dipyridyl disulphide with actinidin, the thiol proteinase from Actinidia chinensis, was shown to differ from the forms of pH-dependence observed for the analogous reactions with papain (EC 3.4.22.2) and ficin (3.4.22.3). The reactivity of the 2,2'-dipyridyl disulphide dication and its apparent sensitivity to the presence and location of a positive charge in the attacking thiol are discussed.     

Antiproliferative effects of 6-anilino-5-chloro-1H-benzo[d]imidazole-4,7-dione in vascular smooth muscle cells

It has been known that benzimidazol-4,7-diones have antiproliferative activity against various cancer cell lines. Recently, we have also reported that these compounds strongly inhibited the proliferation of vascular smooth muscle cell (SMC) and human umbilical vein endothelial cells (HUVECs). Although benzimidazol-4,7-diones have important biological activities, the molecular mechanism of the compounds in these cells remains to be elucidated. In order to investigate the anti-proliferation mechanism of the compounds in smooth muscle cell, we selected 6-anilino-6-chloro-5-chloro-1H-benzo{d}midazole-4,7-dione (BUD-0203) among 12 benzimidazol-4,7-dione derivatives and examined its antiproliferative effects. Phosphorylation of the extracellular-signal regulated kinase (ERK) reached a maximal level at 1h after treatment with BUD-0203 and was sustained during the examined period. We also observed that phosphorylation of p38 reached a maximal level at 4h and decreased to control levels after 8h. These results showed that BUD-0203 sustainedly activated MAP kinase pathways in SMC. However, this compound did not induce cell cycle arrest in G1 or G2 phase in these cells. We also demonstrated that BUD-0203 not only induced apoptosis of SMC, but it also strongly inhibited SMC migration induced by platelet-derived growth factor (PDGF) or serum. Taken together, our experiments indicate that benzimidazol-4,7-diones induce apoptosis of smooth muscle cell via simultaneously prolonged activation of MAP kinase pathways including ERK, p38, and JNK/SAPK, similar with the apoptosis mechanism reported previously.     

Traceless synthesis of benzimidazoles on solid support

Traceless solid-phase syntheses of benzimidazoles and 5-(benzimidazol-2-yl)benzimidazoles on 2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene are described. No auxiliary functional groups are left in the products after ultimate cleavage and cyclization.     

Ketonization of methylene of bis(benzimidazol-2-yl)methane by molecular oxygen under the catalysis of cobalt(II) ion

A cobalt(II) complex [Co((bnzim)₂CO)Cl₂] (1) (where (bnzim)₂CO; bis(benzimidazol-2-yl)methanone), was obtained by reacting cobalt(II) chloride with bis(benzimidazol-2-yl)methane ((bnzim)₂CH₂) in CH₃OH/CH₃CN and characterized using EA, IR, XRD and X-ray single crystal diffraction. The process of ketonization of methylene of (bnzim)₂CH₂ was investigated using spectroscopy and electrochemistry method. The experimental results reveal that there were new species forming in the reaction system and the formation of new species was related to the dissolving oxygen in the mixture. Oxygenation mechanism was thus proposed, in which oxygen atom transfer from a superoxo intermediate species {((bnzim)₂CH₂)Co(III)-O-O} to the methylenic carbon of (bnzim)₂CH₂, and then goes O-O hemolytic cleavage and hydrogen migration to give intermediate species [Co((bnzim)₂CHOH)]²⁺. The ketonization was achieved after [Co((bnzim)₂CHOH)]²⁺repeating the process.     

Synthesis, characterization and DNA binding studies of a zinc complex with 2,6-bis(benzimidazol-2-yl) pyridine

A zinc(II) complex having planar tridentate ligand, bzimpy, where bzimpy is 2,6-bis(benzimidazol-2-yl) pyridine was synthesized and characterized by UV, NMR, infrared spectroscopy and fluorescence spectra. The zinc complex acts as dibasic acids, in which N-H protons on benzimidazole moieties are responsible for a deprotonation site. Both the absorption spectra and reduction potentials are strongly dependent on the solution pH, which leads to the basis of a proton-induced molecular switch. The binding of this complex with calf thymus DNA has been investigated by absorption, luminescence titrations and viscosity measurements. The results suggest that the zinc(II) complex intercalates into DNA base pairs via the ligand bzimp.