- Design, Synthesis and Antimicrobial Evaluation of Novel Benzimidazole-incorporated Naphthalimide Derivatives as Salmonella typhimurium DNA Intercalators, and Combination Researches
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Objective: A series of novel benzimidazole-incorporated naphthalimide derivatives were designed and prepared in an effort to overcome the increasing antibiotic resistance. Methods: The target novel benzimidazole-incorporated naphthalimide derivatives were synthesized from commercial 4-bromo-1,8-naphthalic anhydride and o-phenylene diamine by aminolysis, N-alkylation and so on. The antimicrobial activity of the synthesized compounds was evaluated in vitro by a two-fold serial dilution technique. The interaction of compound 10g with Salmonella typhimuri-um DNA was studied using UV-vis spectroscopic methods. Results: Compound 10g bearing a 2,4-dichlorobenzyl moiety exhibited the best antimicrobial activities in this series relatively; especially, it exhibited comparable activity against Salmonella typhi-murium in comparison with the reference drug Norfloxacin (MIC = 4 μg/mL). Further research showed that compound 10g could effectively intercalate into the Salmonella typhimurium DNA to form the 10g–DNA complex, which might correlate with the inhibitory activity. Molecular docking results demonstrated that naphthalimide compound 10g could interact with base-pairs of DNA hex-amer duplex by π–π stacking. Additionally, the combination of the strong active compound with clinical drugs exhibited better antimicrobial efficiency with less dosage and broader antimicrobial spectrum than the separate use of them alone. Notably, these combined systems were more sensitive to Fluconazole-insensitive M. ruber. Conclusion: This work provides a promising starting point to optimize the structures of benzimidaz-ole-incorporated naphthalimide derivatives as potent antimicrobial agents.
- Ning, Zhi-Wei,Zhang, Hui-Zhen,Zhou, cheng-He
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p. 544 - 557
(2022/03/09)
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- Evaluation of Cytotoxic Activity of New Benzimidazole-Piperazine Hybrids Against Human MCF-7 and A549 Cancer Cells
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A series of benzimidazole-piperazine hybrids (14 – 37) were designed, synthesized and evaluated for their cytotoxic activity against human lung (A549) and breast (MCF-7) cancer cell lines. Preliminary evaluation revealed that most of these hybrid molecules (i.e., 16 – 25) exhibited noteworthy and preferential antiproliferative effect against human lung cancer (A549) with IC50 values of 2.8 – 7.8 μM. Among the synthesized molecules, compound 17 showed the most balanced cytotoxic effect against lung (A549) and breast (MCF-7) cancer cells with IC50 values of 5.4 and 4.2 μM, respectively. To explore the mechanistic aspects fundamental to the observed activity, further biological studies of compounds 16, 17 and 22 were carried out. In addition, these compounds induced PARP-1 cleavage and caspase 7 activation, caused morphological changes such as bleb formation in the treated cells, and significantly increased the nuclear fragmentation. Taken all together, our findings indicate that cytotoxic activities of newly synthesized benzimidazole-piperazine hybrids are mediated through the apoptotic cell death induction. These benzimidazole derivatives have the potential for further development as anticancer agents.
- ?zdemir, Aysun,Turanli, Sümeyye,?ali?kan, Burcu,Arka, Mustafa,Banoglu, Erden
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p. 1036 - 1046
(2020/03/11)
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- Novel purine benzimidazoles as antimicrobial agents by regulating ROS generation and targeting clinically resistant Staphylococcus aureus DNA groove
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A novel series of purine benzimidazole hybrids were designed and synthesized for the first time with the aim to circumvent the increasing antibiotic resistance. Hexyl appended hybrid 3c gave potent activities against most of the tested bacteria and fungi especially against multidrug-resistant strains Staphylococcus aureus (MIC = 4 μg/mL). Structure-activity relationships revealed that the benzimidazole fragment at the 9-position of purine played an important role in exerting potentially antibacterial activity. Both cell toxicity and ROS generation assays indicated that the purine derivative 3c showed low cytotoxicity and could be used as a safe agent. Molecular modeling suggested that hybrid 3c could bind with the residues of Topo IA through hydrogen bonds and electrostatic interactions. Quantum chemical studies were also performed on the target compound 3c to understand the structural features essential for activity. The active molecule 3c could effectively interact with S. aureus DNA to form 3c–DNA complex through groove binding mode, which might block DNA replication to display their powerful antimicrobial activity.
- Wang, Ya-Nan,Bheemanaboina, Rammohan R. Yadav,Cai, Gui-Xin,Zhou, Cheng-He
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p. 1621 - 1628
(2018/03/29)
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- Discovery of Benzimidazole–Quinolone Hybrids as New Cleaving Agents toward Drug-Resistant Pseudomonas aeruginosa DNA
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A series of benzimidazole–quinolone hybrids as new potential antimicrobial agents were designed and synthesized. Bioactive assays indicated that some of the prepared compounds exhibited potent antibacterial and antifungal activities. Notably, 2-fluorobenzyl derivative 5 b (ethyl 7-chloro-6-fluoro-1-[[1-[(2-fluorophenyl)methyl]benzimidazol-2-yl]methyl]-4-oxo-quinoline-3-carboxylate) showed remarkable antimicrobial activity against resistant Pseudomonas aeruginosa and Candida tropicalis isolated from infected patients. Active molecule 5 b could not only rapidly kill the tested strains, but also exhibit low toxicity toward Hep-2 cells. It was more difficult to trigger the development of bacterial resistance of P. aeruginosa against 5 b than that against norfloxacin. Molecular docking demonstrated that 5 b could effectively bind with topoisomerase IV–DNA complexes, and quantum chemical studies theoretically elucidated the good antimicrobial activity of compound 5 b. Preliminary experimental reaction mechanism exploration suggested that derivative 5 b could not intercalate into DNA isolated from drug-resistant P. aeruginosa, but was able to cleave DNA effectively, which might further block DNA replication to exert powerful bioactivities. In addition, compound 5 b is a promising antibacterial agent with membrane disruption abilities.
- Wang, Ya-Nan,Bheemanaboina, Rammohan R. Yadav,Gao, Wei-Wei,Kang, Jie,Cai, Gui-Xin,Zhou, Cheng-He
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p. 1004 - 1017
(2018/04/30)
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- DEUTERIUM MODIFIED BENZIMIDAZOLES
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This invention relates to derivatives of 1-(p-chIorobenzyI)-2-(1-pyrrolidinylmethyl)benzimidazole according to Formula I wherein at least one Y is deuterium described herein and pharmaceutically acceptable salts thereof. This invention also provides compo
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Page/Page column 30-31
(2010/12/17)
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- BENZIMIDAZOLE MODULATORS OF H1 RECEPTOR AND/OR NS4B PROTEIN ACTIVITY
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The present invention relates to new benzimidazole modulators of H1 receptor activity and/or inhibitors of NS4B protein activity, pharmaceutical compositions thereof, and methods of use thereof formula (I).
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Page/Page column 30
(2010/11/03)
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