Design, synthesis and biological evaluation of berberine-benzimidazole hybrids as new type of potentially DNA-targeting antimicrobial agents

• Berberine-benzimidazole hybrids as a new type of potential antimicrobial agents.
• Pivotal antimicrobial potency and broad spectrum for some berberine–benzimidazoles.
• Interaction of 5d with pET-28a plasmid revealed DNA-cleaving activity.
• Compound 5d could effectively intercalate in to DNA.
• Compound 5d could be effectively stored and carried by HSA.

A series of novel berberine-benzimidazole derivatives were conveniently and efficiently synthesized and characterized by NMR, IR, MS and HRMS spectra. Most of the prepared compounds showed effective antimicrobial activities in contrast with clinical norfloxacin, chloromycin and fluconazole. Especially, compound 5d exhibited good anti-MRSA, anti-Escherichia coli, and anti-Salmonella typhi activity with low MIC values of 2–8 μg/mL, which were comparable or even superior to reference drugs. The preliminarily interactive investigation revealed that the most active compound 5d could effectively intercalate into DNA to form 5d-DNA complex and cleavage DNA by agarose gel electrophoresis experiments. It was also found that compound 5d was able to efficiently permeabilize the membranes of both Gram-positive (MRSA) and Gram-negative (E. coli DH52) bacteria. Experiments and molecular docking both showed that human serum albumin (HSA) could effectively transport compound 5d and hydrophobic interactions and hydrogen bonds play important roles in the association of compound 5d with HSA.

A series of berberine–benzimidazole hybrids were synthesized and screened for their antimicrobial activities, further studies with pET-28a (Escherichia coli DNA), calf thymus DNA, human serum albumin and molecular docking simulation were investigated.Figure optionsDownload as PowerPoint slide