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Polymers Mar 2023A series of aliphatic polybenzimidazoles (PBIs) with methylene groups of varying length were synthesized by the high-temperature polycondensation of...
A series of aliphatic polybenzimidazoles (PBIs) with methylene groups of varying length were synthesized by the high-temperature polycondensation of 3,3'-diaminobenzidine (DAB) and the corresponding aliphatic dicarboxylic acid in Eaton's reagent. The influence of the length of the methylene chain on PBIs' properties was investigated by solution viscometry, thermogravimetric analysis, mechanical testing and dynamic mechanical analysis. All PBIs exhibited high mechanical strength (up to 129.3 ± 7.1 MPa), glass transition temperature (≥200 °C) and thermal decomposition temperature (≥460 °C). Moreover, all of the synthesized aliphatic PBIs possess a shape-memory effect, which is a result of the presence of soft aliphatic segments and rigid -benzimidazole groups in the macromolecules, as well as strong intermolecular hydrogen bonds that serve as non-covalent crosslinks. Among the studied polymers, the PBI based on DAB and dodecanedioic acid has high adequate mechanical and thermal properties and demonstrates the highest shape-fixity ratio and shape-recovery ratio of 99.6% and 95.6%, respectively. Because of these properties, aliphatic PBIs have great potential to be used as high-temperature materials for application in different high-tech fields, including the aerospace industry and structural component industries.
PubMed: 36987180
DOI: 10.3390/polym15061399 -
Acta Crystallographica. Section E,... Jun 2010In the title compound, [CuBr(2)(C(27)H(36)N(4))], the Cu(II) ion exhibits a distorted tetra-hedral coordination geometry provided by two bromide ions and by chelation of...
In the title compound, [CuBr(2)(C(27)H(36)N(4))], the Cu(II) ion exhibits a distorted tetra-hedral coordination geometry provided by two bromide ions and by chelation of two imine N-atom donors from a bis-(benzimidazole) ligand. Chelation results in a six-membered boat-shaped ring which links the benzimidazole groups. Each bis-(benzimidazole) fragment contains three n-butyl substituents, two of which have the expected trans conformation; the third exhibits the higher-energy cis conformation, an orientation consistent with several short intra-molecular C-H⋯Br inter-actions. Essentially planar (r.m.s. deviations of 0.0101 and 0.0183 Å) benzimidazole groups are oriented so as to give the bis-(benzimidazole) fragment a V-shaped appearance in profile with the cis and trans n-butyl groups directed to opposite sides of the planes. In the crystal, columns of mol-ecules along the b-axis direction form layers parallel to the (202) planes. Within a given column, the mol-ecules are linked by C-H⋯Br hydrogen bonds. The mol-ecules in adjacent columns are also linked by inter-molecular C-H⋯π interactions, forming a three-dimensional network.
PubMed: 21587699
DOI: 10.1107/S160053681002088X -
Journal of Virology Sep 2017Virus infection of humans and livestock can be devastating for individuals and populations, sometimes resulting in large economic and societal impact. Prevention of...
Virus infection of humans and livestock can be devastating for individuals and populations, sometimes resulting in large economic and societal impact. Prevention of virus disease by vaccination or antiviral agents is difficult to achieve. A notable exception was the eradication of human smallpox by vaccination over 30 years ago. Today, humans and animals remain susceptible to poxvirus infections, including zoonotic poxvirus transmission. Here we identified a small molecule, bisbenzimide (bisbenzimidazole), and its derivatives as potent agents against prototypic poxvirus infection in cell culture. We show that bisbenzimide derivatives, which preferentially bind the minor groove of double-stranded DNA, inhibit vaccinia virus infection by blocking viral DNA replication and abrogating postreplicative intermediate and late gene transcription. The bisbenzimide derivatives are potent against vaccinia virus and other poxviruses but ineffective against a range of other DNA and RNA viruses. The bisbenzimide derivatives are the first inhibitors of their class, which appear to directly target the viral genome without affecting cell viability. Smallpox was one of the most devastating diseases in human history until it was eradicated by a worldwide vaccination campaign. Due to discontinuation of routine vaccination more than 30 years ago, the majority of today's human population remains susceptible to infection with poxviruses. Here we present a family of bisbenzimide (bisbenzimidazole) derivatives, known as Hoechst nuclear stains, with high potency against poxvirus infection. Results from a variety of assays used to dissect the poxvirus life cycle demonstrate that bisbenzimides inhibit viral gene expression and genome replication. These findings can lead to the development of novel antiviral drugs that target viral genomes and block viral replication.
Topics: Animals; Antiviral Agents; Bisbenzimidazole; Cell Line; DNA Replication; Fluorescent Dyes; Humans; Transcription, Genetic; Vaccinia virus; Virus Replication
PubMed: 28659488
DOI: 10.1128/JVI.00838-17 -
ACS Omega Dec 2017A blue fluorescent -dimesitylboryl-phenyl-functionalized 1,3-bisbenzimidazolyl benzene molecule () has been synthesized in high yield by Stille coupling of...
A blue fluorescent -dimesitylboryl-phenyl-functionalized 1,3-bisbenzimidazolyl benzene molecule () has been synthesized in high yield by Stille coupling of bisbenzimidazolyl bromobenzene with -BMes-SnBu-benzene. Methylation of led to the formation of the bisbenzimidazolium salt (). The utility of both and in sensing CN and halide (F, Cl, Br, and I) was examined, and it was found that only the small fluoride and cyanide anions were able to bind to the boron atom with binding constants in the range of 2.9 × 10 to 5 × 10 M. Computational studies provided insight into the photophysical properties of the molecules and verified that a charge-transfer process is quenched in these "turn-off" molecular sensors.
PubMed: 31457395
DOI: 10.1021/acsomega.7b01631 -
Scientific Reports Jun 2021At present, nuclear condensation and fragmentation have been estimated also using Hoechst probes in fluorescence microscopy and flow cytometry. However, none of the...
At present, nuclear condensation and fragmentation have been estimated also using Hoechst probes in fluorescence microscopy and flow cytometry. However, none of the methods used the Hoechst probes for quantitative spectrofluorometric assessment. Therefore, the aim of the present study was to develop a spectrofluorometric assay for detection of nuclear condensation and fragmentation in the intact cells. We used human hepatoma HepG2 and renal HK-2 cells cultured in 96-well plates treated with potent apoptotic inducers (i.e. cisplatin, staurosporine, camptothecin) for 6-48 h. Afterwards, the cells were incubated with Hoechst 33258 (2 µg/mL) and the increase of fluorescence after binding of the dye to DNA was measured. The developed spectrofluorometric assay was capable to detect nuclear changes caused by all tested apoptotic inducers. Then, we compared the outcomes of the spectrofluorometric assay with other methods detecting cell impairment and apoptosis (i.e. WST-1 and glutathione tests, TUNEL, DNA ladder, caspase activity, PARP-1 and JNKs expressions). We found that our developed spectrofluorometric assay provided results of the same sensitivity as the TUNEL assay but with the advantages of being fast processing, low-cost and a high throughput. Because nuclear condensation and fragmentation can be typical markers of cell death, especially in apoptosis, we suppose that the spectrofluorometric assay could become a routinely used method for characterizing cell death processes.
Topics: Antineoplastic Agents; Apoptosis; Bisbenzimidazole; Camptothecin; Cell Death; Cell Line; Cell Nucleus; Cisplatin; DNA Fragmentation; Flow Cytometry; Hep G2 Cells; Humans; Microscopy, Fluorescence; Reproducibility of Results; Spectrometry, Fluorescence; Staurosporine
PubMed: 34099803
DOI: 10.1038/s41598-021-91380-3 -
Bioorganic & Medicinal Chemistry Letters Dec 2016Neomycin and Hoechst 33258 are two well-known nucleic acid binders that interact with RNA and DNA duplexes with high affinities respectively. In this manuscript, we...
Neomycin and Hoechst 33258 are two well-known nucleic acid binders that interact with RNA and DNA duplexes with high affinities respectively. In this manuscript, we report that covalent attachment of bisbenzimidazole unit derived from Hoechst 33258 to neomycin leads to intercalative binding of the bisbenzimidazole unit (oriented at 64-74° with respected to the RNA helical axis) in a linker length dependent manner. The dual binding and intercalation of conjugates were supported by thermal denaturation, CD, LD and UV-Vis absorption experiments. These studies highlight the importance of linker length in dual recognition by conjugates, for effective RNA recognition, which can lead to novel ways of recognizing RNA structures. Additionally, the ligand library screens also identify DNA and RNA selective compounds, with compound 9, containing a long linker, showing a 20.3°C change in RNA duplex T with only a 13.0°C change in T for the corresponding DNA duplex. Significantly, the shorter linker in compound 3 shows almost the reverse trend, a 23.8°C change in DNA T, with only a 9.1°C change in T for the corresponding RNA duplex.
Topics: Amino Sugars; Binding Sites; Bisbenzimidazole; DNA; Dose-Response Relationship, Drug; Ligands; Molecular Structure; RNA; Structure-Activity Relationship; Temperature
PubMed: 27884695
DOI: 10.1016/j.bmcl.2016.10.076 -
Scientific Reports Oct 2019Bisbenzimidazoles with terminal alkynyl linkers, selective inhibitors of bacterial topoisomerase I, have been evaluated using bacterial cytological profiling (BCP) to...
Bisbenzimidazoles with terminal alkynyl linkers, selective inhibitors of bacterial topoisomerase I, have been evaluated using bacterial cytological profiling (BCP) to ascertain their mechanism of action and screened for synergism to improve Gram-negative bacterial coverage. Principal component analysis of high throughput fluorescence images suggests a dual-mechanism of action affecting DNA synthesis and cell membrane integrity. Fluorescence microscopy of bacteria challenged with two of the alkynyl-benzimidazoles revealed changes in the cellular ultrastructure that differed from topoisomerase II inhibitors including induction of spheroplasts and membrane lysis. The cytoskeleton recruitment enzyme inhibitor A22 in combination with one of the alkynyl-benzimidazoles was synergistic against Acinetobacter baumannii and Escherichia coli. Gram-positive coverage remained unchanged in the A22-alkynyl bisbenzimidazole combination. Efflux inhibitors were not synergistic, suggesting that the Gram-negative outer membrane was a significant barrier for alkynyl-bisbenzimidazole uptake. Time-kill assays demonstrated the A22-bisbenzimidazole combination had a similar growth inhibition curve to that of norfloxacin in E.coli. Bisbenzimidazoles with terminal alkynyl linkers likely impede bacterial growth by compromising cell membrane integrity and by interfering with DNA synthesis against Gram-positive pathogens and in the synergistic combination against Gram-negative pathogens including E. coli and multidrug-resistant A. baumanii.
Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Bisbenzimidazole; Cell Membrane; Drug Synergism; Escherichia coli; Topoisomerase I Inhibitors
PubMed: 31578425
DOI: 10.1038/s41598-019-48898-4 -
The Journal of General Virology Dec 2021The shortcomings of current anti-human cytomegalovirus (HCMV) drugs has stimulated a search for anti-HCMV compounds with novel targets. We screened collections of...
The shortcomings of current anti-human cytomegalovirus (HCMV) drugs has stimulated a search for anti-HCMV compounds with novel targets. We screened collections of bioactive compounds and identified a range of compounds with the potential to inhibit HCMV replication. Of these compounds, we selected bisbenzimide compound RO-90-7501 for further study. We generated analogues of RO-90-7501 and found that one compound, MRT00210423, had increased anti-HCMV activity compared to RO-90-7501. Using a combination of compound analogues, microscopy and biochemical assays we found RO-90-7501 and MRT00210423 interacted with DNA. In single molecule microscopy experiments we found RO-90-7501, but not MRT00210423, was able to compact DNA, suggesting that compaction of DNA was non-obligatory for anti-HCMV effects. Using bioinformatics analysis, we found that there were many putative bisbenzimide binding sites in the HCMV DNA genome. However, using western blotting, quantitative PCR and electron microscopy, we found that at a concentration able to inhibit HCMV replication our compounds had little or no effect on production of certain HCMV proteins or DNA synthesis, but did have a notable inhibitory effect on HCMV capsid production. We reasoned that these effects may have involved binding of our compounds to the HCMV genome and/or host cell chromatin. Therefore, our data expand our understanding of compounds with anti-HCMV activity and suggest targeting of DNA with bisbenzimide compounds may be a useful anti-HCMV strategy.
Topics: Antiviral Agents; Binding Sites; Bisbenzimidazole; Capsid; Cell Line; Cytomegalovirus; DNA; DNA Replication; Humans; Molecular Structure; Viral Load; Virus Replication
PubMed: 34882533
DOI: 10.1099/jgv.0.001702 -
PloS One 2012Ionizing radiation (IR) exposure often occurs for human beings through occupational, medical, environmental, accidental and/or other sources. Thus, the role of...
BACKGROUND
Ionizing radiation (IR) exposure often occurs for human beings through occupational, medical, environmental, accidental and/or other sources. Thus, the role of radioprotector is essential to overcome the complex series of overlapping responses to radiation induced DNA damage.
METHODS AND RESULTS
Treatment of human glioma U87 cells with DMA (5- {4-methylpiperazin-1-yl}-2-[2'-(3, 4-dimethoxyphenyl)-5'-benzimidazolyl] in the presence or absence of radiation uncovered differential regulation of an array of genes and proteins using microarray and 2D PAGE techniques. Pathway construction followed by relative quantitation of gene expression of the identified proteins and their interacting partners led to the identification of MAP3K14 (NFκB inducing kinase, NIK) as the candidate gene affected in response to DMA. Subsequently, over expression and knock down of NIK suggested that DMA affects NFκB inducing kinase mediated phosphorylation of IKKα and IKKβ both alone and in the presence of ionizing radiation (IR). The TNF-α induced NFκB dependent luciferase reporter assay demonstrated 1.65, 2.26 and 3.62 fold increase in NFκB activation at 10, 25 and 50 µM DMA concentrations respectively, compared to control cells. This activation was further increased by 5.8 fold in drug + radiation (50 µM +8.5 Gy) treated cells in comparison to control. We observed 51% radioprotection in control siRNA transfected cells that attenuated to 15% in siRNA NIK treated U87 cells, irradiated in presence of DMA at 24 h.
CONCLUSIONS
Our studies show that NIK/IKK mediated NFκB activation is more intensified in cells over expressing NIK and treated with DMA, alone or in combination with ionizing radiation, indicating that DMA promotes NIK mediated NFκB signaling. This subsequently leads to the radioprotective effect exhibited by DMA.
Topics: Bisbenzimidazole; Cell Line, Tumor; Cell Survival; Glioma; Humans; I-kappa B Kinase; NF-kappa B; Protein Serine-Threonine Kinases; Radiation, Ionizing; NF-kappaB-Inducing Kinase
PubMed: 22745752
DOI: 10.1371/journal.pone.0039426 -
Bulletin of the World Health... 1975Two groups of compounds, identifiable by structural similarity, have been found to interfere with the in vitro replication of arenaviruses. All 4 members of the...
Two groups of compounds, identifiable by structural similarity, have been found to interfere with the in vitro replication of arenaviruses. All 4 members of the benzimidazole group contain dipolar fused benzene and 5-membered nitrogen-containing rings and share potential chelating ability through the different bidentate structures formed with their side-chains. The biological activity of one of these compounds, metisazone, has been shown to depend on the presence of divalent metals of the first transition series, Cu(++) being the most effective. Furthermore, whereas metisazone inactivates cell-free virus, two other members of the group, HBB and 1,2-bis(5-methoxy-1H-benzimidazol-2-yl)-1,2-ethanediol, act intracellularly. The site of action of the fourth member, SKF 30097, is not known. Using murine lymphocytic choriomeningitis infections as an in vivo model, the bisbenzimidazole derivative has been found to increase life-span without interfering with virus replication. Medication with SKF 30097 or metisazone and copper (2(+)) sulfate did not significantly or reproducibly change the expected day of death of the animals. The amantadine compounds of the second group have unusual symmetric structures with a 10-carbon cage. The parent compound acts intracellularly, while the site of action of an octachloro derivative is not known. Medication with the parent compound, but not the derivative, shortened the interval between LCM infection and death of the mouse. Tissue culture and animal screening of the many available derivatives in these two groups may uncover compounds more efficacious than those already examined.
Topics: Amantadine; Animals; Benzimidazoles; Hemorrhagic Fevers, Viral; Lassa virus; Lymphocytic Choriomeningitis; Mice; Virus Diseases
PubMed: 1085227
DOI: No ID Found