Design, Synthesis, Antibacterial Evaluation, and Induced Apoptotic Behaviors of Epimeric and Chiral 18β-Glycyrrhetinic Acid Ester Derivatives With an Isopropanolamine Bridge Against Phytopathogens

J Agric Food Chem. 2019 Dec 4;67(48):13212-13220. doi: 10.1021/acs.jafc.9b06147. Epub 2019 Nov 15.

Abstract

Because only a handful of agrochemicals can manage bacterial infections, the discovery and development of innovative, inexpensive, and high-efficiency antibacterial agents targeting these infections are challenging. Herein, a series of novel epimeric and chiral 18β-glycyrrhetinic acid (GA) ester derivatives with various tertiary amine pendants were designed, synthesized, and screened for pharmacological activity. Results showed that some of the title compounds were conferred with significantly enhanced antibacterial activity toward phytopathogens Xanthomonas oryzae pv oryzae (A2, B1-B3, and C1, EC50 values within 3.81-4.82 μg/mL) and Xanthomonas axonopodis pv citri (B1, EC50 = 3.18 μg/mL; B2, EC50 = 2.76 μg/mL). These activities are superior to those of GA (EC50 > 400 μg/mL), thiodiazole copper, and bismerthiazol. Pharmacophore studies revealed that the synergistic combination of GA skeleton and tertiary amine scaffolds contributed to the biological actions. In vivo experiments displayed their promising applications in controlling bacterial infections. Antibacterial mechanism studies revealed that the title compounds could trigger apoptosis in the tested pathogens, evident by bacteria morphological changes observed in scanning electron microscopy images. This outcome should motivate the development of various apoptosis inducers against plant bacterial diseases by a novel mode of action compared to that of existing agricultural chemicals.

Keywords: 18β-glycyrrhetinic acid hybrids; antibacterial; apoptosis; in vitro and in vivo bioassays.

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology*
  • Apoptosis / drug effects*
  • Drug Design
  • Esters / chemistry
  • Glycyrrhetinic Acid / analogs & derivatives*
  • Glycyrrhetinic Acid / chemical synthesis
  • Glycyrrhetinic Acid / chemistry
  • Glycyrrhetinic Acid / pharmacology
  • Microbial Sensitivity Tests
  • Plant Diseases / microbiology
  • Propanolamines / chemistry
  • Stereoisomerism
  • Structure-Activity Relationship
  • Xanthomonas / cytology
  • Xanthomonas / drug effects

Substances

  • Anti-Bacterial Agents
  • Esters
  • Propanolamines
  • 18alpha-glycyrrhetinic acid
  • Glycyrrhetinic Acid
  • monoisopropanolamine