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Scientific Reports Mar 2017Activation of efflux systems and the formation of biofilm are majorly adapted by microbes to resist antimicrobial agents. PPEF (bisbenzimidazole) targeting topoisomerase...
Activation of efflux systems and the formation of biofilm are majorly adapted by microbes to resist antimicrobial agents. PPEF (bisbenzimidazole) targeting topoisomerase IA is observed to be an effective bactericidal agent against both Gram-positive and Gram-negative bacterial strains and thus can be developed as potent broad-spectrum antibiotic against MDR strains. PPEF treatment did not cause target specific mutation instead it leads to up-regulation of efflux gene in E. coli K12 as a mechanism of resistance. Microscopy, fluorescence spectroscopy and flow cytometry result demonstrate higher accumulation of PPEF in efflux gene deleted E. coli K12 mutants, and also suggest that Carbonyl Cyanide 3-Chlorophenylhydrazone (CCCP), resist the efflux of PPEF, and thus increases efficacy of PPEF. Herein, we report, PPEF and CCCP synergistically killed the persistent bacterial cells, which are not killed by PPEF alone. The above two compounds together inhibited biofilm formation, eradicate preformed biofilms and kills the biofilm cells of P. aeruginosa. PPEF and CCCP together reduced bacterial load of E. coli ATCC25922 by 6 log in neutropenic thigh infection model of balb/c mice. Present study suggests that combination therapy could be a promising antimicrobial strategy to handle MDR pathogenic strains.
Topics: Animals; Anti-Bacterial Agents; Biofilms; Bisbenzimidazole; DNA Topoisomerases, Type I; Disease Models, Animal; Drug Combinations; Drug Resistance, Multiple, Bacterial; Drug Synergism; Escherichia coli Infections; Escherichia coli K12; Female; Gene Expression; Genes, MDR; Hydrazones; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Neutropenia; Pseudomonas aeruginosa; Thigh
PubMed: 28303897
DOI: 10.1038/srep44419 -
ACS Infectious Diseases Feb 2018Alkylated aminoglycosides and bisbenzimidazoles have previously been shown to individually display antifungal activity. Herein, we explore for the first time the...
Alkylated aminoglycosides and bisbenzimidazoles have previously been shown to individually display antifungal activity. Herein, we explore for the first time the antifungal activity (in liquid cultures and in biofilms) of ten alkylated aminoglycosides covalently linked to either mono- or bisbenzimidazoles. We also investigate their toxicity against mammalian cells, their hemolytic activity, and their potential mechanism(s) of action (inhibition of fungal ergosterol biosynthetic pathway and/or reactive oxygen species (ROS) production). Overall, many of our hybrids exhibited broad-spectrum antifungal activity. We also found them to be less cytotoxic to mammalian cells and less hemolytic than the FDA-approved antifungal agents amphotericin B and voriconazole, respectively. Finally, we show with our best derivative (8) that the mechanism of action of our compounds is not the inhibition of ergosterol biosynthesis, but that it involves ROS production in yeast cells.
Topics: Antifungal Agents; Biofilms; Bisbenzimidazole; Candida albicans; Dose-Response Relationship, Drug; Framycetin; Hemolysis; Microbial Sensitivity Tests; Molecular Structure; Reactive Oxygen Species; Sterols; Time Factors
PubMed: 29227087
DOI: 10.1021/acsinfecdis.7b00254 -
Magnetic hysteresis and large coercivity in bisbenzimidazole radical-bridged dilanthanide complexes.Chemical Science May 2023A judicious combination of radical ligands innate to diffuse spin orbitals with paramagnetic metal ions elicits strong magnetic exchange coupling which leads to...
A judicious combination of radical ligands innate to diffuse spin orbitals with paramagnetic metal ions elicits strong magnetic exchange coupling which leads to properties important for future technologies. This metal-radical approach aids in effective magnetic communication of especially lanthanide ions as their 4f orbitals are contracted and not readily accessible. Notably, a high spin density on the donor atoms of the radical is required for strong coupling. Such molecules are extremely rare owing to high reactivity rendering their isolation challenging. Herein, we present two unprecedented series of bisbenzimidazole-based dilanthanide complexes [(Cp*Ln)(-Bbim)] (1-Ln = Gd, Tb, Dy, Bbim = 2,2'-bisbenzimidazole) and [K(crypt-222)][(Cp*Ln)(μ-Bbim˙)] -(2-Ln = Gd, Tb, Dy), where the latter contains the first Bbim˙ radical matched with any paramagnetic metal ion. The magnetic exchange constant for 2-Gd of = -1.96(2) cm suggests strong antiferromagnetic Gd-radical coupling, whereas the lanthanides in 1-Gd are essentially uncoupled. calculations on 2-Tb and 2-Dy uncovered coupling strengths of -4.8 and -1.8 cm. 1-Dy features open hysteresis loops with a coercive field of of 0.11 T where the single-molecule magnetism can be attributed to the single-ion effect due to lack of coupling. Excitingly, pairing the effective magnetic coupling with the strong magnetic anisotropy of Dy results in magnetic hysteresis with a blocking temperature of 5.5 K and coercive field of 0.54 T, ranking 2-Dy as the second best dinuclear single-molecule magnet containing an organic radical bridge. A Bbim species is formed electrochemically hinting at the accessibility of Bbim-based redox-active materials.
PubMed: 37265712
DOI: 10.1039/d3sc01562a -
ACS Omega Mar 2017Human telomeric G-quadruplex DNA stabilization has emerged as an exciting novel approach for anticancer drug development. In the present study, we have designed and...
Human telomeric G-quadruplex DNA stabilization has emerged as an exciting novel approach for anticancer drug development. In the present study, we have designed and synthesized three C-symmetric bisubstituted bisbenzimidazole naphthalenediimide (NDI) ligands, , , and , which stabilize human telomeric G-quadruplex DNA with high affinity. Herein, we have studied the binding affinities and thermodynamic contributions of each of these molecules with G-quadruplex DNA and compared the same to those of the parent NDI analogue, . Results of fluorescence resonance energy transfer and surface plasmon resonance demonstrate that these ligands have a higher affinity for G-DNA over duplex DNA and induce the formation of a G-quadruplex. The binding equilibrium constants obtained from the microcalorimetry studies of , , and were 8.47, 6.35, and 3.41 μM, respectively, with 22-mer quadruplex. These showed 10 and 100 times lower binding affinity with 12-mer and duplex DNA quadruplexes, respectively. Analysis of the thermodynamic parameters obtained from the microcalorimetry study suggests that interactions were most favorable for among all of the synthesized compounds. The Δ obtained from molecular mechanics Poisson-Boltzmann surface area calculations of molecular dynamics (MD) simulation studies suggest that interacted strongly with G-DNA. MD simulation results showed the highest hydrogen bond occupancy and van der Waals interactions were between the side chains of and the DNA grooves. A significant inhibition of telomerase activity (IC = 4.56 μM) and induced apoptosis in cancer cell lines by suggest that this molecule has the potential to be developed as an anticancer agent.
PubMed: 30023623
DOI: 10.1021/acsomega.6b00523 -
Isolation of the elusive bisbenzimidazole Bbim˙ radical anion and its employment in a metal complex.Chemical Science May 2022The discovery of singular organic radical ligands is a formidable challenge due to high reactivity arising from the unpaired electron. Matching radical ligands with...
The discovery of singular organic radical ligands is a formidable challenge due to high reactivity arising from the unpaired electron. Matching radical ligands with metal ions to engender magnetic coupling is crucial for eliciting preeminent physical properties such as conductivity and magnetism that are crucial for future technologies. The metal-radical approach is especially important for the lanthanide ions exhibiting deeply buried 4f-orbitals. The radicals must possess a high spin density on the donor atoms to promote strong coupling. Combining diamagnetic Y ( = 1/2) with organic radicals allows for invaluable insight into the electronic structure and spin-density distribution. This approach is hitherto underutilized, possibly owing to the challenging synthesis and purification of such molecules. Herein, evidence of an unprecedented bisbenzimidazole radical anion (Bbim˙) along with its metalation in the form of an yttrium complex, [K(crypt-222)][(Cp*Y)(μ-Bbim˙)] is provided. Access of Bbim˙ was feasible through double-coordination to the Lewis acidic metal ion and subsequent one-electron reduction, which is remarkable as Bbim was explicitly stated to be redox-inactive in closed-shell complexes. Two molecules containing Bbim (1) and Bbim˙ (2), respectively, were thoroughly investigated by X-ray crystallography, NMR and UV/Vis spectroscopy. Electrochemical studies unfolded a quasi-reversible feature and emphasize the role of the metal centre for the Bbim redox-activity as neither the free ligand nor the Bbim complex led to analogous CV results. Excitingly, a strong delocalization of the electron density through the Bbim˙ ligand was revealed temperature-dependent EPR spectroscopy and confirmed through DFT calculations and magnetometry, rendering Bbim˙ an ideal candidate for single-molecule magnet design.
PubMed: 35685798
DOI: 10.1039/d1sc07245e -
Molecules (Basel, Switzerland) Sep 2017The vacuolar (H⁺)-ATPases (V-ATPases) are a family of ATP-driven proton pumps and they have been associated with cancer invasion, metastasis, and drug resistance....
The vacuolar (H⁺)-ATPases (V-ATPases) are a family of ATP-driven proton pumps and they have been associated with cancer invasion, metastasis, and drug resistance. Despite the clear involvement of V-ATPases in cancer, the therapeutic use of V-ATPase-targeting small molecules has not reached human clinical trials to date. Thus, V-ATPases are emerging as important targets for the identification of potential novel therapeutic agents. We identified a bisbenzimidazole derivative () as an initial hit from a similarity search using four known V-ATPase inhibitors (-). Based on the initial hit (), we designed and synthesized a focused set of novel bisbenzimidazole analogs (-). All newly prepared compounds have been screened for selected human breast cancer (MDA-MB-468, MDA-MB-231, and MCF7) and ovarian cancer (A2780, Cis-A2780, and PA-1) cell lines, along with the normal breast epithelial cell line, MCF10A. The bisbenzimidazole derivative () is active against all cell lines tested. Remarkably, it demonstrated high cytotoxicity against the triple-negative breast cancer (TNBC) cell line, MDA-MB-468 (IC = 0.04 ± 0.02 μM). Additionally, it has been shown to inhibit the V-ATPase pump that is mainly responsible for acidification. To the best of our knowledge the bisbenzimidazole pharmacophore has been identified as the first V-ATPase inhibitor in its class. These results strongly suggest that the compound could be further developed as a potential anticancer V-ATPase inhibitor for breast cancer treatment.
Topics: Antineoplastic Agents; Bisbenzimidazole; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Screening Assays, Antitumor; Female; Humans; Ovarian Neoplasms; Triple Negative Breast Neoplasms; Vacuolar Proton-Translocating ATPases
PubMed: 28926955
DOI: 10.3390/molecules22091559 -
ACS Omega Dec 2022A facile synthesis of benzimidazoles was described by a one-pot process containing acylation-cyclization of -arylamidoxime. This method provided an alternative synthesis...
A facile synthesis of benzimidazoles was described by a one-pot process containing acylation-cyclization of -arylamidoxime. This method provided an alternative synthesis of benzimidazoles with a certain diversity of substituted groups in acceptable yields (up to 96%). More importantly, the construction of bis-benzimidazole (), the key intermediate for making telmisartan, was achieved by adopting this method that enabled avoiding the undesired nitration with nitric/sulfuric acid and the cyclization in polyphosphoric acid in the existing operations.
PubMed: 36530318
DOI: 10.1021/acsomega.2c06554 -
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 -
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 -
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