| Summary: | Taking palmatine (PMT) as the lead, 20 new PMT derivatives were synthesized and examined for their antibacterial activities against six tested metronidazole (MTZ)-resistant <i>Helicobacter pylori</i> (<i>H. pylori</i>) strains. The structure−activity relationship (SAR) indicated that the introduction of a suitable secondary amine substituent at the 9-position might be beneficial for potency. Among them, compound <b>1c</b> exhibited the most potent activities against MTZ-resistant strains, with minimum inhibitory concentration (MIC) values of 4−16 μg/mL, better than that of the lead. It also exhibited a good safety profile with a half-lethal dose (LD<sub>50</sub>) of over 1000 mg/kg. Meanwhile, <b>1c</b> might exert its antimicrobial activity through targeting <i>H. pylori</i> urease. These results suggested that PMT derivatives might be a new family of anti-<i>H. pylori</i> components.
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