Unique Thiazolidinedione Conjugation of Metronidazole to Largely Enhance the Antibacterial Performance of Natural Berberine against Bacterial Pathogens

作者：Yu Zhou, Shi-Yu Huang, Zhenzhen Li, Li Li, Shaolin Zhang, Hang Sun, Cheng-He Zhou · 发表于：Journal of Medicinal Chemistry · 年份：2026 · DOI：10.1021/acs.jmedchem.6c00924 · 被引用次数：2 · 研究领域：Berberine and alkaloids research、Quinazolinone synthesis and applications、Traditional and Medicinal Uses of Annonaceae

Abstract This work performed a unique conjugation of metronidazole with berberine via thiazolidinedione to afford a novel structural skeleton of metronidazolyl vinylthiazolidionyl tetrahydroberberines (MVTs) with multitargeting antibacterial potential to conquer bacterial resistance. Most of the prepared MVTs exhibited an effective activity against most of the tested bacteria. Notably, butyl MVT 7b (MIC = 0.005 mM) demonstrated the strongest antibacterial activity against S. aureus 25923, being 3- and 69-fold more active than norfloxacin and berberine, respectively. Low hemolysis, cytotoxicity, and drug resistance, effective biofilm eradication, and efficient transport by human serum albumin suggested the favorable druggability of MVT 7b. Highly active MVT 7b could cause bacterial death through multitargeting effects, including disrupting the bacterial membrane, triggering oxidative stress, and intercalating into DNA without cleaving DNA. Moreover, MVT 7b was more potent than norfloxacin in vivo against S. aureus 25923. These medicinal chemobiological investigations demonstrated MVTs as potential multitargeting antibacterial candidates for alleviating bacterial resistance.