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PubMed2004

Synthesis of novel 2-[2-(substituted amino)phenethyl]-1 H-benzimidazoles; 3,4-dihydro and 1,2,3,4,-tetrahydropyrimido[1,6-a]-benzimidazoles as potential antiulcer agents.

In an effort to establish new antiulcer agents a series of 2-(2-substituted amino)-1 H-benzimidazoles 8, 9, 14; 1,3-disubstituted-3,4-dihydropyrimido[1,6-a]benzimidazoles 4, 7, 11, 12; 3-substituted-3,4-dihydropyrimido[1,6-a]benzimidazol-1 (2H)-thiones (or (2H)-ones) 10, 17 and 3-substituted-1,2,3,4-tetrahydropyrimido[1,6-a]benzimidazoles 15 were synthesized. Representative members were selected to evaluate their gastric antisecretory activity using an in vivo pylorus ligated rat method. Omeprazole was used as reference. The results indicated that the test compounds exhibit gastric antisecretory activity. The percent inhibition+/-SEM at the indicated dose level was demonstrated as omeprazole (59%+/-0.16 at 3 mg/kg) > 15a (53%+/-1.39 at 3 mg/kg) > 7a (51%+/-1.04 at 1 mg/kg) > 10a (50%+/-1.36 at 3 mg/kg).

Animals↗

PubMed1996

The effectiveness of benzimidazole-levamisole combination drenches in the presence of resistance to both benzimidazole and levamisole anthelmintics in New Zealand sheep.

Examination of 25 cases of multiple benzimidazole and levamisole resistance, identified in sheep by faecal egg count reduction testing at the Batchelar, Lincoln and Invermay Animal Health Laboratories, showed that benzimidazole-levamisole combinations provided effective control in eight (47%) of 17 cases in which they were tested. Overall, the use of combination drenches resulted in average improvements in faecal egg count reductions of 25.6% (p<0.01) and 23.2% (p<0.05), respectively, over those achieved by the use of benzimidazole or levamisole drenches alone. The results suggest that instances of multiple resistance in which combination drenches might be effective are unlikely to be predictable either by identification of the parasites involved, or from the levels of benzimidazole or levamisole resistance present.

Journal Article↗

PubMed2005

Synthesis, dopamine D2 receptor binding studies and docking analysis of 5-[3-(4-arylpiperazin-1-yl)propyl]-1H-benzimidazole, 5-[2-(4-arylpiperazin-1-yl)ethoxy]-1H-benzimidazole and their analogs.

5-[3-(4-Arylpiperazin-1-yl)propyl]-1H-benzimidazoles and 5-[2-(4-arylpiperazin-1-yl)ethoxy]-1H-benzimidazoles were synthesized and their affinity for the D1, D2 and 5-HT1A receptors examined. They expressed a rather high affinity for the D2 dopamine receptor. The main features of ligand-D2 receptor interactions revealed by docking analyses were: salt bridge between piperazine ring protonated N1 and Asp 86, hydrogen bonds of ligand bezimidazole part with Ser 141, Ser 122 and His 189, edge-to-face interactions of arylpiperazine aromatic ring with Phe 178, Tyr 216 and Trp 182 and hydrogen bond between ethereal oxygen in ethylenoxy ligands and hydrogen of Phe 185 or Trp 115. The most active 5-[2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethoxy]-1,3-dihydro-2H-benzimidazole-2-thione (27) has a maximal number of attractive interactions. A satisfactory correlation between docking of the compounds into the D2 receptor and competition binding results was observed.

Animals↗

PubMed2002

Synthesis and anti-hIV activity of 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole structurally-related 1,2-substituted benzimidazoles.

The synthesis of 1,2-substituted benzimidazoles is reported. These novel derivatives share chemical similarities with 1-aryl-1H,3H-thiazolo[3,4-a]benzimidazoles, a class of HIV-1 NNRTIs studied widely. All compounds prepared were tested in MT-4 cells to explore their potential anti-HIV activity and were found to be less potent than 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole (TBZ).

Anti-HIV Agents↗

PubMed1999

Benzimidazole derivatives. 2. Synthesis and structure-activity relationships of new azabicyclic benzimidazole-4-carboxylic acid derivatives with affinity for serotoninergic 5-HT(3) receptors.

A new series of azabicyclic benzimidazole-4-carboxamides 2-21 and -carboxylates 22-30 were synthesized and evaluated for binding affinity at serotoninergic 5-HT(3) and 5-HT(4) receptors in the CNS. Most of the synthesized compounds exhibited high or very high affinity for the 5-HT(3) binding site and low to no significant affinity for the 5-HT(4) receptor. SAR observations indicated that a halogen atom at the 6-position and a nitro group at the 7-position of the benzimidazole ring is the best substitution pattern for 5-HT(3) affinity and 5-HT(3)/5-HT(4) selectivity, as well as no substitution in this ring. (S)-(-)-N-(Quinuclidin-3-yl)benzimidazole-4-carboxamides 2, 8, and 14 bound at central 5-HT(3) sites with high affinity (K(i) = 2.6, 0. 13, and 1.7 nM, respectively) and excellent selectivity over serotonin 5-HT(4) and 5-HT(1A) receptors (K(i) > 1000-10000 nM). Furthermore, these new 5-HT(3) receptor ligands were pharmacologically characterized as potent and selective 5-HT(3) antagonists in the isolated guinea pig ileum (pA(2) = 9.6, 9.9, and 9.1, respectively).

Animals↗

PubMed1979

[Determination of residues of the fungicide benzimidazole carbamic acid methyl ester and its metabolites 2-aminobenzimidazole and benzimidazole].

The authors describe a method for extracting and determining benzimidazole carbamic acid methyl ester (MBC) in the presence of its metabolites 2-aminobenzimidazole and benzimidazole. The determination is performed thin-layer and paper chromatographically using visual spot comparison. A sensitive biological method is employed for the detection of MBC. The metabolites are assayed by chemical procedures. The smallest amounts of residues that the authors could detect were: 0.01 p.p.m. of MBC and approximately 0.2 p.p.m. of the metabolites, the recovery rate ranging from 70--85%.

Benzimidazoles↗

PubMed1990

Effect of benzimidazole drugs on tubulin in benzimidazole resistant and susceptible strains of Caenorhabditis elegans.

An in vitro assay was used to determine efficacy and if side resistance was present to benzimidazole anthelmintics tested against Caenorhabditis elegans after selection with albendazole. Side resistance was present to all the benzimidazoles tested, except for oxibendazole and parbendazole. At a concentration of 1 mM, all of the drugs, except thiabendazole, were effective in killing 100% of the albendazole susceptible worms. Tubulin from albendazole resistant and susceptible C. elegans was isolated and run on polyacrylamide gels. Western blots with anti-tubulin antibody showed that the albendazole resistant strain had an altered tubulin. Electron microscopy of albendazole-treated drug resistant worms showed microtubules throughout the intestinal cells. Microtubules were not observed in albendazole-treated drug susceptible worms.

Animals↗

PubMed2005

Benzimidazoles as non-peptide luteinizing hormone-releasing hormone (LHRH) antagonists. Part 3: Discovery of 1-(1H-benzimidazol-5-yl)-3-tert-butylurea derivatives.

1-(1H-Benzimidazol-5-yl)-3-tert-butylurea derivatives have been identified as a novel class of non-peptide luteinizing hormone-releasing hormone (LHRH) antagonists. Herein, we disclose the synthesis and structure-activity relationships (SAR) of this class resulting in the identification of compound 12c, with dual functional activity on human and rat receptors (rat LHRH: IC50=120 nM; human LHRH: IC50=18 nM). These SAR studies suggest that 1-(1H-benzimidazol-5-yl)-3-tert-butylurea is a new pharmacophore for small molecule LHRH antagonists.

Animals↗

PubMed2006

Benzimidazole inhibitors of hepatitis C virus NS5B polymerase: identification of 2-[(4-diarylmethoxy)phenyl]-benzimidazole.

A series of 1-cycloalkyl-2-phenyl-1H-benzimidazole-5-carboxylic acid derivatives was synthesized and evaluated for inhibitory activity against HCV NS5B RNA-dependent RNA polymerase (RdRp). A SAR study was performed and led to identify the 2-[(4-diarylmethoxy)phenyl]-benzimidazoles as potent inhibitors. They inhibit subgenomic HCV RNA replication in the replicon cells at low micromolar concentrations (EC(50) as low as 1.1microM). They are selective against DNA polymerases (IC(50)>10microM) and exhibit low cytotoxicity.

Benzimidazoles↗

PubMedDate not supplied

Benzimidazole condensed ring systems. XI. Synthesis of some substituted cycloalkyl pyrido[1,2-a]benzimidazoles with anticipated antineoplastic activity.

As part of a research project on the synthesis of a number of pyrido[1,2-a]benzimidazole derivatives with possible antineoplastic activity, and as a result of the interesting antineoplastic activity recorded for one such compound (NSC 649900), some new cycloalkylpyrido[1,2-a]benzimidazoles were prepared and evaluated for such activity. Compound (7c, NSC 682011) exhibited a good in vitro antineoplastic activity especially against most of the leukaemia cell lines. This compound has been selected by the NCI for further testing in a new in vivo anticancer hollow fibre assay.

Antineoplastic Agents↗

PubMed1999

Benzimidazole derivatives. Part 1: Synthesis and structure-activity relationships of new benzimidazole-4-carboxamides and carboxylates as potent and selective 5-HT4 receptor antagonists.

New benzimidazole-4-carboxamides 1-16 and -carboxylates 17-26 were synthesized and evaluated for binding affinity at serotonergic 5-HT4 and 5-HT3 receptors in the CNS. Most of the synthesized compounds exhibited moderate-to-very high affinity (in many cases subnanomolar) for the 5-HT4 binding site and no significant affinity for the 5-HT3 receptor. SAR observations and structural analyses (molecular modeling, INSIGHT II) indicated that the presence of a voluminous substituent in the basic nitrogen atom of the amino moiety and a distance of ca. 8.0 A from this nitrogen to the aromatic ring are of great importance for high affinity and selectivity for 5-HT4 receptors. These results confirm our recently proposed model for recognition by the 5-HT4 binding site. Amides 12-15 and esters 24 and 25 bound at central 5-HT4 sites with very high affinity (Ki = 0.11-2.9 nM) and excellent selectivity over serotonin 5-HT3, 5-HT2A, and 5-HT1A receptors (Ki > 1000-10,000 nM). Analogues 12 (Ki(5-HT4) = 0.32 nM), 13 (Ki(5-HT4) = 0.11 nM), 14 (Ki(5-HT4) = 0.29 nM) and 15 (Ki(5-HT4) = 0.54 nM) were pharmacologically characterized as selective 5-HT4 antagonists in the isolated guinea pig ileum (pA2 = 7.6, 7.9, 8.2 and 7.9, respectively), with a potency comparable to the 5-HT4 receptor antagonist RS 39604 (pA2 = 8.2). The benzimidazole-4-carboxylic acid derivatives described in this paper represent a novel class of potent and selective 5-HT4 receptor antagonists. In particular, compounds 12-15 could be interesting pharmacological tools for the understanding of the role of 5-HT4 receptors.

Amides↗

PubMed1987

The pathogenesis of benzimidazole-resistant and benzimidazole-susceptible strains of Trichostrongylus colubriformis in the Mongolian gerbil (Meriones unguiculatus).

Mongolian gerbils were infected with either a benzimidazole-susceptible or a benzimidazole-resistant strain of Trichostrongylus colubriformis larvae. The comparative pathogenesis of both strains of T. colubriformis was investigated for 50 days post-infection. The gerbils infected with the drug-susceptible strain of the parasite showed lower survival rates, reduced body weights, higher parasite egg output and higher worm burdens than animals infected with the drug-resistant strain of parasite. There was also evidence of an enhanced hypoalbuminaemia and a more marked gastrointestinal plasma leak in the gerbils infected with the drug-susceptible strain of parasite. Scanning electron microscope examination of the small intestine showed signs of villus atrophy in both groups of infected gerbils.

Animals↗

PubMed2003

Screening for tolerance to bavistin, a benzimidazole fungicide containing methyl benzimidazol-2-yl carbamate (MBC), in Beauveria bassiana: sequence analysis of the beta-tubulin gene to identify mutations conferring tolerance.

The entomopathogenic Beauveria bassiana is a potential biopesticide. Fungicide-tolerant isolates of this fungus would have an added advantage of being compatible with the conventional chemical methods of pest control. Therefore, 30 isolates of the fungus were screened for tolerance to bavistin a commonly used benzimidazole fungicide containing methyl benzimidazol-2-yl carbamate (MBC). Germination and growth bioassays in the presence of 0.05% bavistin were conducted for screening. Three tolerant isolates were identified, showing tolerance up to 2% bavistin. Mutation in the beta-tubulin gene is known to confer tolerance to MBC; the nine known mutation sites in the gene involved were sequenced in the tolerant strains. The beta-tubulin gene from codons 1-405 was amplified using two pairs of degenerate primers, designed for the conserved region of the beta-tubulin gene and sequenced. From the sequence suitable primers were designed for the regions flanking the nine known sites involved in mutations conferring MBC tolerance. The amplified products with these primers from the MBC-tolerant isolates were sequenced and in two (ARSEF 1315 and ARSEF 1316) a mutation was detected in the 198 codon resulting in replacement of glutamic acid with lysine. In the third tolerant isolate (ITCC 913) no mutation could be detected in any of the nine known sites conferring tolerance to MBC. To complete the sequencing of the beta-tubulin gene, the remaining part (from codon 405 onwards) of the gene was isolated by a three-prime gene walk. The gene sequence showed a close homology to fungal beta-tubulin genes with four introns.

Amino Acid Sequence↗

PubMed1997

Synthesis and evaluation of (S)-4-(3-(2'-[11C]isopropylamino)-2-hydroxypropoxy) -2H-benzimidazol -2-one ((S)-[11C]CGP 12388) and (S)-4-(3-((1'-[18F]-fluoroisopropyl)amino)-2-hydroxypropoxy) -2H- benzimidazol-2-one ((S)-[18F]fluoro-CGP 12388) for visualization of beta-adrenoceptors with positron emission tomography.

The beta-adrenoceptor antagonist (S)-[11C]CGP 12177 (4-(3-(tert-butylamino)-2-hydroxypropoxy)-2H-benzimidazol -2[11C]- one) is a generally accepted radioligand for cardiac and pulmonary PET studies. The synthesis of [11C]CGP 12177 is a laborious and often troublesome procedure. Therefore, (S)-CGP 12388 (4-(3-(isopropylamino)-2-hydroxypropoxy) -2H-benzimidazol-2-one), 5, the isopropyl analogue of CGP 12177, has been labeled with carbon-11 in the isopropyl group via a reductive alkylation by [11C]acetone (3) of the corresponding (S)-desisopropyl compound 2. The fluoro-substituted analogue of (S)-CGP 12388 was prepared by reacting 2 with [18F]fluoroacetone (4). (S)-[11C]CGP 12388 (5) was easily prepared via a one-pot procedure. The radiochemical yield of (S)-[11C]CGP 12388 (600-800 Ci/mmol, EOS) was 18% (EOB) with a total synthesis time of 35 min, whereas (S)-[18F]fluoro-CGP 12388 (6) (> 2000 Ci/mmol, EOS) was synthesized in 105 min with a radiochemical yield of 12% (EOB). Biodistribution studies in rats demonstrated specific binding to beta-adrenoceptors of (S)-[18F]fluoro-CGP 12388 and (S)-[11C]CGP 12388 in lung and heart. The lungs were clearly visualized with PET studies of rats. Total/nonspecific binding at 60 min postinjection was 5.6 for (S)-[11C]CGP 12388 and 2.0 for the (S)-18F compound. Due to its facile synthetic procedure and in vivo data, (S)-[11C]CGP 12388 is a promising beta-adrenoceptor ligand for clinical PET.

Adrenergic beta-Antagonists↗

PubMed2002

2-(4-Bromophenyl)-1,2-dihydropyrimido[1,2-a]benzimidazol-4(3H)-one and 4-(4-methylphenyl)-3,4-dihydropyrimido[1,2-a]benzimidazol-2(1H)-one form hydrogen-bonded base-paired dimers.

The title compounds, 2-(4-bromophenyl)-1,2-dihydropyrimido[1,2-a]benzimidazol-4-(3H)-one, C(16)H(12)BrN(3)O, (IVa), and 4-(4-methylphenyl)-3,4-dihydropyrimido[1,2-a]benzimidazol-2-(1H)-one, C(17)H(15)N(3)O, (Vb), both form R(2)(2)(8) centrosymmetric dimers via N-H...N hydrogen bonds. The N...N distance is 2.943(3)A for (IVa) and 2.8481(16)A for (Vb), with the corresponding N-H...N angles being 129 and 167 degree, respectively. However, in other respects, the supramolecular structures of the two compounds differ. Both compounds contain different C-H...pi interactions, in which the C-H...pi(centroid) distances are 2.59 and 2.47A for (IVa) and (Vb), respectively (the latter being a short distance), with C-H...pi(centroid) angles of 158 and 159 degree, respectively. The supramolecular structures also differ, with a short Br...O distance of 3.117(2)A in bromo derivative (IVa), and a C-H...O interaction with a C...O distance of 3.2561(19)A and a C-H...O angle of 127 degree in tolyl system (Vb). The dihydropyrimido part of (Vb) is disordered, with a ratio of the major and minor components of 0.9:0.1. The disorder consists of two non-interchangeable envelope conformers, each with an equatorial tolyl group and an axial methine H atom.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMedDate not supplied

Stereospecific synthesis by the sodium salt glycosylation method of halogeno benzimidazole 2'-deoxyribose analogues of the inhibitor of hnRNA synthesis, 5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole (DRB).

The recently developed stereospecific sodium salt glycosylation procedure has been successfully applied to the synthesis of the beta-D-2'-deoxyribofuranosides of benzimidazole, 5,6-dihalogeno benzimidazoles, and some 2-substituted analogues in high yield. The 5,6-dibromo analogue was obtained by bromination of the parent nucleoside. These have all been characterized by spectroscopic methods, including 1H NMR, which permitted analyses of their solution conformations and comparison with those of the corresponding ribofuranosides. Some biological aspects, including preliminary results on cytotoxicity and antiviral activity, are briefly considered.

Animals↗

PubMed1992

Benzimidazole condensed ring systems. 8 (1). Synthesis of some substituted 1-oxo-1H,5H-pyrido[1,2-a] benzimidazole-4-carbonitriles with anticipated antimicrobial activity.

As a part of research project on the syntheses of a number of pyrido[1,2-a]benzimidazole derivatives with possible antimicrobial activity, some 3-(chloro or morpholino)-acetyloxy (2,3), 3-(N,N-dimethylcarbamoyloxy) (4,5) and 3-tosyloxy-1-oxo-1H,5H-pyrido[1,2a]benzimidazole-4-carbonitrile s (6) were prepared and evaluated for such activity. Many compounds exhibited in vitro antimicrobial activity and structure-activity relationship is discussed.

Anti-Bacterial Agents↗

PubMed1989

Piperazine derivatives of benzimidazole as potential anthelmintics. Part 1: Synthesis and activity of methyl-5-(4-substituted piperazin-1-yl)benzimidazole-2-carbamates.

A series of 5-(4-substituted piperazin-1-yl)-2-nitroanilines (4) and 5-(4-substituted piperazin-1-yl)benzimidazole-2-carbamates (6) has been synthesized starting from 5-chloro-2-nitroaniline (3) and N-monosubstituted piperazines. Catalytic reduction of 4 with Pd/C followed by treatment with 1,3-dicarbomethoxy-S-methylisothiourea yielded the corresponding methyl-5-(4-substituted piperazin-1-yl)benzimidazole-2-carbamates (6) which were for anthelmintic activity against experimental infections of Trichinella spiralis.

Animals↗