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Potential of bisbenzimidazole-analogs toward metronidazole-resistant Trichomonas vaginalis isolates.Chemical Biology & Drug Design Oct 2017A bisoxyphenylene-bisbenzimidazole series with increasing aliphatic chain length (CH to C H ) containing a meta- (m) or para (p)-benzimidazole linkage to the phenylene...
A bisoxyphenylene-bisbenzimidazole series with increasing aliphatic chain length (CH to C H ) containing a meta- (m) or para (p)-benzimidazole linkage to the phenylene ring was tested for ability to inhibit the growth of metronidazole-susceptible (C1) and metronidazole-refractory (085) Trichomonas vaginalis isolates under aerobic and anaerobic conditions. Compound 3m, 2,2'-[α,ω-propanediylbis(oxy-1,3-phenylene)]bis-1H-benzimidazole, displayed a 5.5-fold lower minimum inhibitory concentration (MIC) toward T. vaginalis isolate 085 than metronidazole under aerobic growth conditions, (26 μm compared to 145 μm). A dose of 25 mg/kg per day for four days of compound 3m cured a subcutaneous mouse model infection using T. vaginalis isolates 286 (metronidazole susceptible) and 085 (metronidazole refractory). Compound 3m was weakly reduced by pyruvate:ferredoxin oxidoreductase, but unlike metronidazole was not dependent upon added ferredoxin. It is concluded from structure-activity relationships that there was no obvious trend based on the length of the central aliphatic chain, or the steric position of the bisbenzimidazole enabling prediction of biological activity. The compounds generally fulfill Lipinski's rile of five, indicating their potential as drug leads.
Topics: Animals; Antiprotozoal Agents; Bisbenzimidazole; Cell Line, Tumor; Drug Resistance; Female; Humans; Metronidazole; Mice; Microbial Sensitivity Tests; Trichomonas Vaginitis; Trichomonas vaginalis
PubMed: 28296056
DOI: 10.1111/cbdd.12972 -
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 -
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 -
Bioorganic & Medicinal Chemistry Letters Jun 2015Cancer is a leading cause of death in developed countries and second cause in developing countries. Herein we are reporting the synthesis of novel bisbenzimidazole...
Cancer is a leading cause of death in developed countries and second cause in developing countries. Herein we are reporting the synthesis of novel bisbenzimidazole derivatives and their anticancer properties. Among the newly synthesized bisbenzimidazoles, 3-(4-flurophenylsulfonyl)-1,7-dimethyl-2-propyl-1H,3H-2,5-bibenzo[d]imidazole (FDPB) presented as a potent antiproliferative agent against HeLa, HCT116 and A549 cells with selectivity over normal Vero cells (IC50 >50 μM). Additionally, we evaluated the efficacy of lead compound against Ehrlich ascites tumor (EAT) bearing mice for its antitumor and antiangiogenic properties. Our lead compound significantly reduced the cell viability, body weight, ascites volume and downregulated the formation of neovasculature and production of Vascular Endothelial Growth Factor (VEGF).
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Ascites; Bisbenzimidazole; Body Weight; Carcinoma, Ehrlich Tumor; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chlorocebus aethiops; Down-Regulation; HCT116 Cells; HeLa Cells; Humans; Mice; Vascular Endothelial Growth Factor A; Vero Cells
PubMed: 25920563
DOI: 10.1016/j.bmcl.2015.04.010 -
Biochimie Jan 2015In this study, a monomeric (MB) and a dimeric (DB) bisbenzimidazoles were identified as novel proteasome inhibitors of the trypsin-like activity located on β2c sites of...
In this study, a monomeric (MB) and a dimeric (DB) bisbenzimidazoles were identified as novel proteasome inhibitors of the trypsin-like activity located on β2c sites of the constitutive 20S proteasome (IC50 values at 2-4 μM range). Remarkably, they were further shown to be 100- and 200-fold more potent inhibitors of the immunoproteasome trypsin-like activity (β2i sites, IC50=24 nM) than of the homologous constitutive activity. Molecular models of inhibitor/enzyme complexes in the two types of trypsin-like sites and corresponding computed binding energy values corroborated kinetic data. Different binding modes were suggested for MB and DB to the β2c and β2i trypsic sites. Each pointed to better contacts of the ligand inside the β2i active site than for β2c site. MB and DB represent the first selective inhibitors of the immunoproteasome trypsin-like activity described to date and can be considered as prototypes for inhibiting this activity.
Topics: Animals; Bisbenzimidazole; Calpain; Catalytic Domain; Cathepsin B; HeLa Cells; Humans; Isoenzymes; Mice; Molecular Docking Simulation; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Trypsin
PubMed: 25446655
DOI: 10.1016/j.biochi.2014.11.002 -
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 -
Medicinal Chemistry (Shariqah (United... 2020Nitrogen-containing heterocycles are one of the most common structural motifs in approximately 80% of the marketed drugs. Of these, benzimidazoles analogues are known to... (Review)
Review
Nitrogen-containing heterocycles are one of the most common structural motifs in approximately 80% of the marketed drugs. Of these, benzimidazoles analogues are known to elicit a wide spectrum of pharmaceutical activities such as anticancer, antibacterial, antiparasitic, antiviral, antifungal as well as chemosensor effect. Based on the benzimidazole core fused heterocyclic compounds, crescent-shaped bisbenzimidazoles were developed which provided an early breakthrough in the sequence-specific DNA recognition. Over the years, a number of functional variations in the bisbenzimidazole core have led to the emergence of their unique properties and established them as versatile ligands against several classes of pathogens. The present review provides an overview of diverse pharmacological activities of the bisbenzimidazole analogues in the past decade with a brief account of its development through the years.
Topics: Bisbenzimidazole; Drug Discovery; Humans
PubMed: 31038072
DOI: 10.2174/1573406415666190416120801 -
Bioorganic & Medicinal Chemistry Nov 2016A series of bisbenzimidazole derivatives starting from o-phenylenediamine and 4-nitro-o-phenylenediamine were prepared with oxalic acid. Most of the reactions were...
A series of bisbenzimidazole derivatives starting from o-phenylenediamine and 4-nitro-o-phenylenediamine were prepared with oxalic acid. Most of the reactions were conducted using both the microwave and conventional methods to compare yields and reaction times. The operational simplicity, environmental friendly conditions and high yield in a significantly short reaction time were the major benefits. All substances' inhibitory activities against α-glucosidase were evaluated. The results may suggest a significant role for the nature of bisbenzimidazole compounds in their inhibitory action against α-glucosidase. They showed different range of α-glucosidase inhibitory potential with IC value ranging between 0.44±0.04 and 6.69±0.01μM when compared to the standard acarbose (IC, 13.34±1.26μM). This has described a new class of α-glucosidase inhibitors. Molecular docking studies were done for all compounds to identify important binding modes responsible for inhibition activity of α-glucosidase.
Topics: Bisbenzimidazole; Dose-Response Relationship, Drug; Glycoside Hydrolase Inhibitors; Humans; Intestines; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship; alpha-Glucosidases
PubMed: 27576293
DOI: 10.1016/j.bmc.2016.08.024 -
Molecular Pharmacology Oct 2015Radiotherapy, a therapeutic modality of cancer treatment, nonselectively damages normal tissues as well as tumor tissues. The search is ongoing for therapeutic agents...
Radiotherapy, a therapeutic modality of cancer treatment, nonselectively damages normal tissues as well as tumor tissues. The search is ongoing for therapeutic agents that selectively reduce radiation-induced normal tissue injury without reducing tumoricidal effect, thereby increasing the therapeutic ratio of radiation therapy. Our laboratory established 5-(4-methylpiperazin-1-yl)-2-[2'-(3,4-dimethoxyphenyl)-5'benzimidazolyl] benzimidazole (DMA) as noncytotoxic radioprotector in mammalian cells. DMA showed an excellent radioprotection in mice at single nontoxic oral dose by a dose-reduction factor of 1.28. An oxygen radical absorbing capacity assay confirmed its free-radical quenching ability. Single bolus dose and 28-days of repeated administration of DMA in mice for toxicity studies determined an LD50 of >2000 mg/kg body weight (bw) and 225 mg/kg bw, respectively, suggesting DMA is safe. Histopathology, biochemical parameters, and relative organ weight analysis revealed insignificant changes in the DMA-treated animals. The pharmacokinetic study of DMA at oral and intravenous doses showed its C(max) = 1 hour, bioavailability of 8.84%, elimination half-life of 4 hours, and an enterohepatic recirculation. Biodistribution study in mice with Ehrlich ascites tumors showed that (99m)Tc-DMA achieved its highest concentration in 1 hour and was retained up to 4 hours in the lungs, liver, kidneys, and spleen, and in a low concentration in the tumor, a solicited property of any radioprotector to protect normal cells over cancerous cells. We observed that the single-dose treatment of tumor-bearing mice with DMA 2 hours before 8 Gy total body irradiation showed an impressive rescue of radiation-induced morbidity in terms of weight loss and mortality without a change in tumor response.
Topics: Animals; Benzimidazoles; Bisbenzimidazole; Carcinoma, Ehrlich Tumor; Dose-Response Relationship, Radiation; Drug Evaluation, Preclinical; Female; HEK293 Cells; Humans; Male; Mice; Mice, Inbred BALB C; Piperazines; Radiation-Protective Agents; Survival Rate; Tissue Distribution
PubMed: 26240287
DOI: 10.1124/mol.115.098376 -
Current Medicinal Chemistry Apr 2001Recent work on a number of different classes of anticancer agents that alkylate DNA in the minor groove is reviewed. There has been much work with nitrogen mustards,... (Review)
Review
Recent work on a number of different classes of anticancer agents that alkylate DNA in the minor groove is reviewed. There has been much work with nitrogen mustards, where attachment of the mustard unit to carrier molecules can change the normal patterns of both regio- and sequence-selectivity, from reaction primarily at most guanine N7 sites in the major groove to a few adenine N3 sites at the 3'-end of poly(A/T) sequences in the minor groove. Carrier molecules discussed for mustards are intercalators, polypyrroles, polyimidazoles, bis(benzimidazoles), polybenzamides and anilinoquinolinium salts. In contrast, similar targeting of pyrrolizidine alkylators by a variety of carriers has little effect of their patterns of alkylation (at the 2-amino group of guanine). Recent work on the pyrrolobenzodiazepine and cyclopropaindolone classes of natural product minor groove binders is also reviewed.
Topics: Alkylating Agents; Animals; Anthramycin; Antibiotics, Antineoplastic; Benzofurans; Bisbenzimidazole; Chlorambucil; Cyclohexanecarboxylic Acids; Cyclohexenes; DNA; Distamycins; Duocarmycins; Humans; Indoles; Netropsin; Nitrogen Mustard Compounds; Pyrroles; Structure-Activity Relationship
PubMed: 11281840
DOI: 10.2174/0929867003373283