Synthesis and Structure-Activity Relationship of Palmatine Derivatives as a Novel Class of Antibacterial Agents against Helicobacter pylori.

Tianyun Fan,Wei Wei,Yanxiang Wang,Xixi Guo,Qingxuan Zeng,Xuefu You,Danqing Song,Jing Pang

doi:10.3390/molecules25061352

Abstract

Taking palmatine (PMT) as the lead, 20 new PMT derivatives were synthesized and examined for their antibacterial activities against six tested metronidazole (MTZ)-resistant Helicobacter pylori (H. pylori) 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 1c 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 (LD50) of over 1000 mg/kg. Meanwhile, 1c might exert its antimicrobial activity through targeting H. pylori urease. These results suggested that PMT derivatives might be a new family of anti-H. pylori components.

Highlights

Helicobacter pylori (H. pylori), spiral shaped gram-negative bacteria, has infected more than 50% of humans globally
The synthetic route used for the preparations of all amine and amide derivatives of PMT is presented in Scheme wasthe firstpreparations heated withofamines, which used as the nucleophilic
The mixture was cooled and filtered, and the resulting residue was washed with CH2 Cl2 and 80% EtOH to acquired desired compounds 4a–i (Figure S1–S20)

Summary

Introduction

Helicobacter pylori (H. pylori), spiral shaped gram-negative bacteria, has infected more than 50% of humans globally. It is believed that gastrointestinal diseases, such as gastritis and peptic ulcer, were highly related to H. pylori infections [1]. The damage to gastric structure and function might lead to the development of gastric cancer, which becomes a major cause of morbidity and mortality worldwide [2,3]. H. pylori has been classified as a class I carcinogen by the World Health. Triple therapy regimens comprising amoxicillin and metronidazole (MTZ) or clarithromycin, as well as proton pump inhibitor, are recommended as first-line treatment for H. pylori infections [5,6]. The prevalence of antibiotic resistance, including MTZ and clarithromycin [3], decreased the efficacy and has become a great challenge to the clinical treatment

Methods

Results

Conclusion