2. Academic Validation
  3. Discovery and evolution of berberine analogues as anti-Helicobacter pylori agents with multi-target mechanisms

Discovery and evolution of berberine analogues as anti-Helicobacter pylori agents with multi-target mechanisms

  • Bioorg Chem. 2024 Jul 10:151:107628. doi: 10.1016/j.bioorg.2024.107628.
Xin Zhang 1,  Genzhu Wang 2,  Wenhua Kuang 3,  Liting Xu 3,  Yuting He 3,  Lirun Zhou 3,  Ying Zhang 3,  Ruixing Chen 3,  Huiying Li 4,  Tianyun Fan 5,  Yali Song 6,  Jigang Wang 7
Affiliations

Affiliations

  • 1 Department of Clinical Pharmacy, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, 272000, China.
  • 2 Department of Clinical Pharmacy, Electric Power Teaching Hospital, Capital Medical University, Beijing, 100073, China.
  • 3 State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
  • 4 Dongguan Maternal and Child Health Care Hospital, Postdoctoral Innovation Practice Base of Southern Medical University, Dongguan, Guangdong, 523000, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
  • 5 Dongguan Maternal and Child Health Care Hospital, Postdoctoral Innovation Practice Base of Southern Medical University, Dongguan, Guangdong, 523000, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China. Electronic address: fty1668@163.com.
  • 6 Dongguan Maternal and Child Health Care Hospital, Postdoctoral Innovation Practice Base of Southern Medical University, Dongguan, Guangdong, 523000, China. Electronic address: syl@smu.edu.cn.
  • 7 Dongguan Maternal and Child Health Care Hospital, Postdoctoral Innovation Practice Base of Southern Medical University, Dongguan, Guangdong, 523000, China; Department of Critical Medicine, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong 518020, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China. Electronic address: jgwang@icmm.ac.cn.
PMID: 39018799 DOI: 10.1016/j.bioorg.2024.107628
Abstract

Thirty protoberberine derivatives, of which twenty five were new, were synthesized and evaluated for their anti-Helicobacter pylori (HP) activities, taking 2,3,10-trimethoxy-9-p-methylbenzylaminoprotopalmatine chloride 1 as the lead. Among them, berberine (BBR) derivative 7c displayed the highest potency against six tested metronidazole (MTZ)-resistant strains and two tested MTZ-susceptible strains with the MIC values of 0.4-1.6 μg/mL with favorable druglike profiles including low toxicity and high stabilities in plasma and artificial gastric fluid. Mechanistic study revealed that 7c might target HP urease with IC50 value of 0.27 μg/mL against Jack bean urease. Furthermore, 7c might change the permeability of the Bacterial membrane and direct interact with HP DNA, which also contribute to its bactericidal activity. Therefore, BBR derivatives constituted a new family of anti-HP candidates, with the advantage of good safety profile and multi-target mechanisms, and are worthy for further investigation.

Keywords

Berberine analogues; DNA; Helicobacter pylori; Structure–activity relationship; Urease.

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