Novel benzimidazolyl tetrahydroprotoberberines: Design, synthesis, antimicrobial evaluation and multi-targeting exploration

[Display omitted] A series of novel benzimidazolyl tetrahydroprotoberberines were conveniently designed and efficiently synthesized from berberine via direct cyclization of tetrahydroprotoberberine aldehyde and o-phenylene diamines under metal-free aerobic oxidation. All the new compounds were chara...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2017-04, Vol.27 (8), p.1737-1743
Main Authors: Jeyakkumar, Ponmani, Liu, Han-Bo, Gopala, Lavanya, Cheng, Yu, Peng, Xin-Mei, Geng, Rong-Xia, Zhou, Cheng-He
Format: Article
Language:English
Subjects:
Animals
Anti-Infective Agents - chemistry
Anti-Infective Agents - pharmacology
Antibacterial
Antifungal
Bacteria - drug effects
Bacterial Infections - drug therapy
Benzimidazole
Benzimidazoles - chemistry
Benzimidazoles - pharmacology
Berberine Alkaloids - chemistry
Berberine Alkaloids - pharmacology
Cattle
DNA
DNA - metabolism
Fungi - drug effects
Humans
Microbial Sensitivity Tests
Molecular Docking Simulation
Mycoses - drug therapy
Tetrahydroprotoberberine
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Summary:[Display omitted] A series of novel benzimidazolyl tetrahydroprotoberberines were conveniently designed and efficiently synthesized from berberine via direct cyclization of tetrahydroprotoberberine aldehyde and o-phenylene diamines under metal-free aerobic oxidation. All the new compounds were characterized by IR, 1H NMR, 13C NMR and HRMS spectra. The antimicrobial evaluation revealed that the 5-fluorobenzimidazolyl derivative 5b was the most active antibacterial and antifungal molecule with broad spectrum in comparison to Berberine, Chloromycin, Norfloxacin and Fluconazole. It triggered almost no resistance development against MRSA even after 15 passages. Further studies demonstrated that compound 5b could not only effectively interact with Topo IA by hydrogen bonds, but also intercalate into calf thymus DNA and cleave pBR322 DNA, which might be responsible for its powerful bioactivities.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2017.02.071